JP2010535701A - Anticancer phosphonate analog - Google Patents

Abstract

The present invention relates to phosphorus-substituted anti-cancer compounds, compositions comprising such compounds, therapeutic methods involving the administration of such compounds, and processes and intermediates useful for the preparation of such compounds. The present invention provides novel analogs of anticancer compounds. Such novel anti-cancer compound analogs have the full utility of anti-cancer compounds and optionally provide cellular accumulation. Furthermore, the present invention provides compositions and methods for cancer treatment or therapeutic activity against cancer. The present invention generally relates to the accumulation or retention of therapeutic compounds within cells. The present invention more particularly relates to achieving high concentrations of phosphate-containing molecules in cancer cells. Such effective targeting can be applied to various therapeutic formulations and procedures.

Description

  This non-provisional application is a 35 U.S. patent application. S. C. Under §119 (e), U.S. Provisional Application Nos. 60 / 465,588; 60 / 465,594; 60 / 465,465; 60 / 465,569; 60 / 465,467; 60 / 465,631; 60/465, 589; 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 (all 003 April 25, filed); US Provisional Patent Application Number. 60 / 493,303 and 60 / 493,310 (both filed August 7, 2003); US Provisional Application Nos. 60 / 495,382; 60 / 495,685; 60 / 495,527; 60 / 495,686 60/495, 625; 60/495, 484; 60/495, 644; 60/495, 297; 60/495, 682; 60/495, 784; 60/495, 751; 60/495, 789; 60/495, 769; 60/495, 647; 60/495, 645; 60/495, 362; 60/495, 339; 60/495 534; 60/495, 669; 60/495, 425; 60/495, 524; 60/495, 426; 60/495, 393 And 60/495, 416 (all filed 15 August 2003); US Provisional Application Nos. 60 / 514,462; 60 / 513,971; 60 / 513,969; 60/514 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; 514, 368; 60/514, 207; 60/514, 115; 60/513, 980; 60/514, 131; 60/514 60/514, 280; 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, 084; 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 And 60 / 514,258 (all filed October 24, 2003); US Provisional Application Nos. 60 / 519,476 and 60 / 519,476 (filed November 12, 2003); Patent Provisional Application Nos. 60 / 524,340 (filed November 20, 2003); US Provisional Application Nos. 60 / 532,230; 60 / 531,960; 60 / 532,160; and 60 / 531,940 (all U.S. Provisional Application No. 60 / 532,591 (December 23,2003); and U.S. Provisional Application No. 60 / 536,007; 60 / 536,006; 60/536. , 005; 60 / 536,054 and 60 / 536,054 (all filed January 12, 2004). The components of all the provisional applications listed above are incorporated herein by reference (incorporated by reference).

(Field of Invention)
The present invention relates to a compound having anticancer activity.

(Background of the Invention)
Improvements in drug and other drug delivery to target cells and tissues have been the focus of many years of research. Despite many attempts to develop effective methods of transferring biologically active molecules into cells both in vivo and in vitro, none has been proven to be completely satisfactory. It is often difficult or ineffective to optimize the binding of a drug to its intracellular target while minimizing intercellular redistribution of the drug, for example to surrounding cells.

  Most drugs currently administered parenterally to patients are untargeted, unnecessary, and often delivered systemically to undesired cells and tissues in the body. This can cause side effects of the drug and can limit the dose of drugs (eg, glucocorticoids and other anti-inflammatory drugs) that can be administered. By comparison, although oral administration of drugs is generally recognized as a convenient and economical method of administration, (a) drugs via cells and tissue barriers (blood / brain, epithelium, cell membrane) May cause undesirable systemic distribution, or (b) the drug may be transiently present in the gastrointestinal tract. Thus, the main objective is to develop a method for specifically targeting drugs to cells and tissues. The benefits of such treatment include avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues.

  Intracellular targeting can be performed by methods and compositions that accumulate or retain bioactive agents within cells.

  Many current treatment regimes for cell proliferative disorders such as psoriasis and cancer use compounds that inhibit DNA synthesis. Such compounds are generally toxic to cells, but their toxicity to rapidly dividing cells such as their tumor cells can be beneficial. Another approach to antiproliferative drugs that act by mechanisms other than inhibition of DNA synthesis has the ability to exhibit enhanced action selectivity.

  Recently, it was discovered that cells can become cancerous by transformation of some of their DNA into oncogenes (ie, genes that form malignant tumor cells upon activation) (Bradshaw, Mutageness 1986, 1, 91). . Several such oncogenes produce peptides that are receptors for growth factors. Thereafter, the growth factor receptor complex increases with cell proliferation. For example, several oncogenes encode tyrosine kinase enzymes, and certain growth factors or receptors are known to be 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 in the transmission of biochemical signals that initiate cell replication. They bridge cell membranes and have an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion that functions as a kinase that phosphorylates tyrosine to amino acids in the protein. Various receptor tyrosine kinase classes are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based on growth factor families that bind to different receptor tyrosine kinases. Classification includes class I receptor tyrosine kinases, including the EGF family of receptor tyrosine kinases such as EGF, TGFα, NEU, erbB, Xmrk, HER, and let23 receptors, insulin, IGFI, and insulin-related receptors (IRR). Includes the class II receptor tyrosine kinases, including the insulin family of receptor tyrosine kinases, and the platelet derived growth factor (PDGF) family of receptor tyrosine kinases, such as the PDGFα, PDGFβ, and colony stimulating factor 1 (CSF1) receptors Class III receptor tyrosine kinases are included. Class I kinases, such as the EGF family of receptor tyrosinase kinases, have been identified in breast 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), non-small cell lung cancer (NSCLCs) (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 squamous cell carcinoma of the lung (Hendler et al., C). ancer Cells, 1989, 7, 347)), bladder cancer (Neal et. al., Lancet, 1985, 366), esophageal cancer (Mukaida et al., Cancer, 1991, 68, 142), colon cancer, Gastrointestinal cancer such as rectal cancer 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), ovarian cancer, bronchial cancer, or pancreatic cancer (European Patent Specification No. 0400586) are known to be frequently present in common human cancers. When additional human tumor tissue is tested for the EGF family of receptor tyrosine kinases, it is expected that morbidity will be further established in additional cancers such as thyroid cancer and uterine cancer. It is also known that EGF-type tyrosine kinase activity is rarely detected in normal cells, whereas it can be detected more frequently in malignant cells (Hunter, Cell, 1987, 50, 823). It has recently been observed that EGF receptors with tyrosine kinase activity are overexpressed in many human cancers including brain, embryonic squamous cells, bladder, stomach, breast, head and neck, esophagus, gynecological, and thyroid tumors. (W. J. Gullick, Brit. Med. Bull., 1991, 47, 87).

  Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of mammalian cancer cell growth (Yaish et al. Science, 1988, 242, 933). This view suggests that ervstatin (an EGF receptor tyrosine kinase inhibitor) reduces the growth of athymic mice in transplanted human mammalian cancers that express EGF receptor tyrosine kinase, but does not express EGF receptor tyrosine kinase. Evidence by not affecting growth (Toi et al., Eur. J. Cancer Clin. Oncol., 1990, 26, 722.). Various derivatives of styrene have also been described as having tyrosine kinase inhibitory properties (European Patent Application Nos. 0211363, 0304493 and 0322738) and are useful as antitumor agents. The in vivo inhibitory effect of two such styrene derivatives that are EGF receptor tyrosine kinase inhibitors on the growth of human squamous cell carcinoma inoculated in nude mice has been demonstrated (Yoneda et al., Cancer Research, 1991, 51, 4430). A variety of known tyrosine kinase inhibitors are described in T.W. R. Burke Jr. In a more recent review (Drugs of the Future, 1992, 17, 119).

  Cancer is a worldwide tumoral health problem. Despite the widespread use and efficacy of drugs that target tumor cells and cancer cells, their usefulness is limited by toxicity and side effects.

  Assay methods that can determine the presence or amount of cancer have utility in the study of anti-cancer compounds and in the diagnosis of the presence of cancer.

  Inhibitors of tumor growth are useful in limiting cancer establishment and progression and in cancer diagnostic assays.

  Anti-cancer therapeutics (ie, improved anti-cancer and pharmacokinetic properties (including enhanced oncogenic activity), improved oral bioavailability, increased efficacy, in vivo Drugs with an extended effective half-life). Such anti-cancer compounds are active against a variety of cancers, have different resistance profiles, have fewer side effects, reduce the complexity of the dosage regimen, and are active orally. Necessary for a once-daily complexity-reduction regimen (especially one pill)

(Summary of the Invention)
Intracellular targeting can be performed by methods and compositions that accumulate or retain bioactive agents within cells. The present invention provides novel analogs of anticancer compounds. Such novel anti-cancer compound analogs have the full utility of anti-cancer compounds and optionally provide the following cellular accumulation. Furthermore, the present invention provides compositions and methods for cancer treatment or therapeutic activity against cancer.

  The present invention generally relates to the accumulation or retention of therapeutic compounds within cells. The present invention more particularly relates to achieving high concentrations of phosphate-containing molecules in cancer cells. Such effective targeting can be applied to various therapeutic formulations and procedures.

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

In another embodiment, the invention provides compounds of formula 500-600 substituted with one or more A ⁰ groups:

(Wherein A ⁰ is A ¹ , A ² , or W ³ when the conjugate comprises at least one A ¹ ;
A ¹ is,

Is;
A ² is,

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 ));
Y ² is independently a bond, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) ( R ^x )), —S (O) _{M 2} —, or —S (O) _{M 2} —S (O) _{M 2} —; when Y ² is bonded to two phosphorus atoms, Y ² is C (R ² ) May be (R ² );
R ^x is independently H, R ¹ , R ² , W ³ , a protecting group, or the formula:

Is;
R ^y is independently 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 R ⁴ , and each R ⁴ is independently substituted with 0-3 R ³ groups or is both 2 at a carbon atom. Two R ² groups form a 3-8 carbon ring, which can be substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , and when R ³ is attached 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 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 and 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 _M2 R ⁵ , or —SO _M2 W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring and W 5 is independently substituted with 0-3 R 2 groups;
W ⁶ is independently W ³ 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 provides any one compound of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

In another embodiment, the present invention provides compounds of the formula:
[DRUG]-(A ⁰ ) _nn
Wherein DRUG is any one compound of formula 500-601;
nn is 1, 2, or 3;
When the conjugate comprises at least one A ¹ , A ⁰ is A ¹ , A ² , or W ³ ;
A ¹ is,

Is;
A ² is,

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 ));
Y ² is independently a bond, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) ( R ^x )), —S (O) _{M 2} —, or —S (O) _{M 2} —S (O) _{M 2} —; Y ² is bonded to two phosphorus atoms, and Y ² is C (R ² ) (R ² ) may be;
R ^x is independently H, R ¹ , R ² , W ³ , a protecting group, or the formula:

Is;
R ^y is independently 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 R ⁴ , and each R ⁴ is independently substituted with 0-3 R ³ groups or is both 2 at the carbon atom. Two R ² groups can form 3 to 8 carbocycles, and the ring can be substituted with 0 to 3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , and when R ³ is attached 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 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 and 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 a carbocyclic or heterocyclic ring, W ⁵ is independently substituted with 0-3 R ² groups;
W ⁶ is independently W ³ 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) or a pharmaceutically acceptable salt or solvate thereof. .

  In another embodiment, the present invention provides compounds of formula 1-336:

(Where
A ⁰ is A ¹ ;
A ¹ is,

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 ));
Y ² is independently a bond, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) ( R ^x )), —S (O) _{M 2} —, or —S (O) _{M 2} —S (O) _{M 2} —; Y ² is bonded to two phosphorus atoms, and Y ² is C (R ² ) ( R ² ) may be;
R ^x is independently H, R ² , W ³ , a protecting group, or the formula:

Is;
R ^y is independently 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 R ⁴ , and each R ⁴ is independently substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , and when 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 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 and each R ⁴ is substituted with 0 to 3 R ³ groups;
R ^5a is independently an alkylene of 1-18 carbon atoms, an alkenylene of 2-18 carbon atoms, or an alkynylene of 2-18 carbon atoms, of alkylene, alkenylene, or alkynylene Any one 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 ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, W ⁵ is independently substituted with 0-3 R ² groups;
W ⁶ is independently W ³ 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 H, F, or Cl;
X ⁵¹ is H or Cl).

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

  The present invention relates to a method for increasing the therapeutic and diagnostic value of a drug compound by increasing the cellular accumulation and retention of the compound, comprising the step of coupling the compound to one or more (1, 2, 3, or 4) phosphonate groups I will provide a.

  The present invention also relates to a method for increasing cellular accumulation and retention of chemotherapeutic agents comprising the step of attaching a compound to one or more phosphonate groups.

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

  The present invention also provides a compound of the invention for use in drug therapy, preferably cancer treatment, as well as the use of a compound of the invention for the manufacture of a drug useful for cancer treatment.

  In another aspect, the present invention also provides a method of inhibiting cancer activity comprising the step of contacting a sample in need of treatment using a compound or composition of the present invention.

  The present invention also provides the processes and novel intermediates disclosed herein that are useful in preparing the compounds of the present invention. Some compounds of the present invention are useful in the preparation of other compounds of the present invention. The present invention also provides a novel method for the synthesis of the compounds of the present invention.

(Detailed description of the invention)
Reference will now be made in detail to certain claims of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated claims, it will be understood that they are not intended to limit the invention to these claims. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.

(Definition)
Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings:
As used herein, when using a trade name, Applicant intends to separately include the product of that trade name and the active pharmaceutical ingredient of the product of that trade name.

  “Bioavailability” is the extent to which a pharmaceutically active agent is made available to the target tissue after it is introduced into the body. Increasing the bioavailability of a pharmaceutically active agent makes more of the pharmaceutically active agent available to the target tissue site for a given dose, thus making the patient more efficient and effective Can be treated.

  The terms “phosphonate” and “phosphonate group” are phosphorus (1) single bonded to carbon, 2) double bonded to heteroatom, and 3) single bonded to heteroatom. And 4) a single bond to another heteroatom, wherein each heteroatom includes a functional group or moiety in the molecule that contains the same or different). The terms “phosphonate” and “phosphonate group” can also be separated from a compound such that the compound contains a phosphorus having the above characteristics, as well as a functional group or moiety containing phosphorus in the same oxidation state as the phosphorus. It contains a functional group or moiety that contains a prodrug moiety. For example, the terms “phosphonate” and “phosphonate group” include phosphoric acid, phosphoric monoester, phosphoric diester, phosphonamidate and phosphonthioate functional groups. In one particular embodiment of the invention, the terms “phosphonate” and “phosphonate group” are phosphorus (which is 1) single bonded to carbon and 2) double bonded to oxygen, 3 A compound so that it contains phosphorus having the above properties as well as functional groups or moieties in the molecule that contain a) a single bond to oxygen and 4) a single bond to another oxygen) A functional group or moiety containing a prodrug moiety that can be separated from In another specific embodiment of the invention, the terms “phosphonate” and “phosphonate group” are phosphorus (which is 1) single bonded to carbon and 2) double bonded to oxygen; 3) a single bond to oxygen or nitrogen and 4) a single bond to another oxygen or nitrogen) as well as the functional groups or moieties in the molecule, It contains a functional group or moiety that contains a prodrug moiety that can be separated from the compound to contain.

  As used herein, the term “prodrug” refers to a drug substance (ie, as a result of spontaneous chemical reaction, enzyme-catalyzed chemical reaction, photolysis and / or metabolic chemical reaction when administered to a biological system. Active compound) means any compound that yields. Prodrugs are therefore covalently modified analogs or latent forms of therapeutically active compounds.

  “Prodrug moiety” means a labile functional group that separates from an active inhibitor compound during metabolism, systemically, intracellularly, by hydrolysis, enzymatic cleavage or some other process. (Bundgaard, Hans, “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, 1991, P. Krogsgaard-Larden. Enzymes that enable an enzyme activation mechanism with the phosphonate prodrug compounds of the present invention include, but are not limited to, amidase, esterase, microbial enzyme, phospholipase, cholinesterase and phosphatase. Prodrug moieties can serve to increase solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy. The prodrug moiety may include an active metabolite or drug itself.

Exemplary prodrug moieties include hydrolysis sensitive or labile acyloxymethyl esters —CH ₂ OC (═O) R ⁹ and acyloxymethyl carbonate —CH ₂ OC (═O) OR ⁹ where: 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. This acyloxyalkyl ester was first used as a prodrug scheme for carboxylic acids and was then used by Farquar et al. (1983) J. MoI. Pharm. Sci. 72: 324; also applied to phosphates and phosphonates according to US Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756. Subsequently, this acyloxyalkyl ester was used to deliver phosphonic acid across cell membranes to enhance oral bioavailability. Alkoxycarbonyloxyalkyl ester (carbonate), which is a modification close to this acyloxyalkyl ester, can also enhance oral bioavailability as a prodrug moiety in the compound of the combination of the present invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH ₂ OC (═O) C (CH ₃ ) ₃ . An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethyl carbonate (POC) —CH ₂ OC (═O) OC (CH ₃ ) ₃ .

  The phosphonate group can be a phosphonate prodrug moiety. The prodrug moiety can be susceptible to hydrolysis, such as, but not limited to, pivaloyloxymethyl carbonate (POC) or POM groups. Alternatively, the prodrug moiety may be susceptible to enzyme-enhanced cleavage, such as a lactate ester group or a phosphonamidate ester group.

  Phosphorus aryl esters, particularly phenyl esters, have been reported to increase oral bioavailability (De Lambert et al. (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic acid ester ortho to its phosphate have also been described (Khamnei and Torrance, (1996) J. Med. Chem. 39: 4109-4115). Benzyl esters have been reported to yield their parent phosphonic acid. In some cases, substituents at the ortho or para position may facilitate hydrolysis. A benzylic analog with an acylated phenol or an alkylated phenol can yield this phenolic compound by the action of an enzyme (eg, esterase, oxidase, etc.), which in turn undergoes cleavage at the benzyl C—O bond. To produce phosphoric acid and quinone methide intermediates. Examples of this type of prodrug are described in Mitchell et al. (1992) J. MoI. Chem. Soc. Perkin Trans. II 2345; Glazier WO 91/19721. Still other benzyl prodrugs have been described, which contain a carboxylic ester containing group attached to its benzylmethylene (Glazier WO 91/19721). Thio-containing prodrugs have been reported to be useful for intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group, where the thiol group is esterified with an acyl group or combined with another thiol group to form a disulfide. De-esterification or reduction of this disulfide yields the free thio intermediate, which subsequently decomposes into phosphate and episulfide (Puch et al. (1993) Antiviral Res., 22: 155-174; Benzaria et al. ( 1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Erion et al., US Pat. No. 6,312,661).

  “Protecting group” means a portion of a compound that masks or alters the properties of the functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. For example, “Protective Groups in Organic Chemistry”, Theodora W. See Greene (John Wiley & Sons, Inc., New York, 1991). Protecting groups are often utilized to mask the reactivity of certain functional groups to aid in the effectiveness of the desired chemical reaction, for example to create and break chemical bonds in an ordered manner. Protection of the functional group of the compound alters other physical properties (eg, polarity, lipophilicity (hydrophobicity), and other properties that can be measured by conventional analytical means) other than the reactivity of the protected functional group. Chemically protected intermediates can themselves be biologically active or inactive.

  Protected compounds may also exhibit altered (in some cases optimized) properties in vitro and in vivo (eg, resistance to cell membrane passage and enzymatic degradation or sequestration). In this role, protected compounds with the desired therapeutic effect can be referred to as prodrugs. Another function of the protecting group is to convert the parent drug into a prodrug, which releases the parent drug when the prodrug is converted in vivo. A prodrug can have a higher potency in vivo than its parent drug because the active prodrug can be absorbed more effectively than the parent prodrug. Protecting groups are removed either in vitro for chemical intermediates or in vivo for prodrugs. For chemical intermediates, it is not particularly important that the products (eg, alcohols) obtained after deprotection are physiologically acceptable, but generally they are pharmacologically harmless. desirable.

Reference to any of the compounds of the present invention includes reference to their physiologically acceptable salts. Examples of physiologically acceptable salts of the compounds of the invention include a suitable base (eg, alkali metal (eg, sodium), alkaline earth metal (eg, magnesium), ammonium and NX ₄ ⁺ (where X _include salts derived from C 1 -C ₄ alkyl)). Physiologically acceptable salts of hydrogen atoms or amino groups include organic carboxylic acids (eg acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid and succinic acid. Acid); organic sulfonic acids (eg methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid); and salts of inorganic acids (eg hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid). For physiologically acceptable salts of compounds having a hydroxyl group, suitable cations (eg, Na ⁺ and NX ^4+, where X is independently selected from H or a C ₁ -C ₄ alkyl group) ) And the anion of the compound in combination.

  For therapeutic use, the active ingredient salts of the compounds of the invention are physiologically acceptable, i.e. they are derived from a physiologically acceptable acid or base. However, salts of acids or bases that are not physiologically acceptable may also find use, for example, in the preparation or purification of physiologically acceptable compounds. All salts are within the scope of the present invention, whether derived from physiologically acceptable acids or bases.

“Alkyl” is a C ₁ -C ₁₈ hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples include 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 CH 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” is a C ₂ -C ₁₈ hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation (ie, carbon-carbon, sp ² double bond). is there. Examples include but are not limited to: 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).

“Alkynyl” is a C ₂ -C ₁₈ hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation (ie, carbon-carbon, sp triple bond). Examples include, but are not limited to: acetylenic (—C≡CH) and propargyl (—CH ₂ C≡CH).

An “alkylene” is a saturated branched or straight chain or cyclic hydrocarbon radical of 1 to 18 carbon atoms that removes two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Which has two monovalent radical centers derived from the above. Typical alkylene radicals include, but are not limited to: 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.

  An “alkenylene” is an unsaturated branched or straight chain or cyclic hydrocarbon radical of 2 to 18 carbon atoms that removes two hydrogen atoms from the same or two different carbon atoms of the parent alkene Means having two monovalent radical centers derived from 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 to 18 carbon atoms that removes two hydrogen atoms from the same or two different carbon atoms of the parent alkyne Means having two monovalent radical centers derived from Typical alkynylene radicals include, but are not limited to: acetylene (—C≡C—), propargyl (—CH ₂ C≡C—) and 4-pentynyl (—CH ₂ CH ₂ CH ₂ C≡CH—).

  “Aryl” means a monovalent aromatic hydrocarbon radical of 6 to 20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” means an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal carbon atom or an sp ³ carbon atom) is replaced with an aryl radical. Typical arylalkyl groups include benzyl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, naphthobenzyl, 2-naphthphenylethane-1-yl, and the like, It is not limited to these. An arylalkyl group contains 6 to 20 carbon atoms, for example, its alkyl moiety (including, for example, an alkanyl, alkenyl or alkynyl group of an arylalkyl group) is 1 to 6 carbon atoms. And the aryl moiety is from 5 to 14 carbon atoms.

“Substituted alkyl”, “substituted aryl” and “substituted arylalkyl” mean alkyl, aryl and arylalkyl, respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. 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 can be substituted as well.

  As used herein, “heterocycle” includes, but is not limited to, the heterocycles described in the following references: Paquette, Leo A. et al. “Principles of Modern Heterocyclic Chemistry” (WA Benjamin, New York, 1968), in particular, Chapter 1, Chapter 3, Chapter 4, Chapter 6, Chapter 7 and Chapter 9; “The Chemistry of HeteroCoedA, United States of Monographs "(John Wiley & Sons, New York, 1950 to present), in particular, 13, 14, 16, 19, and 28; Am. Chem. Soc. (1960) 82: 5566. In one particular embodiment of the invention, “heterocycle” includes a carbocycle as defined herein, wherein one or more (eg, 1, 2, 3 or 4). ) Is replaced by a heteroatom (eg, O, N or S).

  Examples of heterocycles include, but are not limited to, the following: pyridyl, dihydroxypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, tetrahydrothiophenyl sulfurate, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl Imidazolyl, tetrazolyl, benzofuranyl, thiaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroxyl Nolinyl, octahydroisoquinolinyl, azosinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1, , 2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolidinyl, phthalazinyl, naphthalidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, flazadinyl, furazinyl , Chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazi Nyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl and bis-tetrahydrofuranyl:

.

  By way of example and not limitation, a carbon-attached heterocycle includes pyridine 2, 3, 4, 5 or 6 position, pyridazine 3, 4, 5 or 6 position, pyrimidine 2, 4, 5 or 6 position, pyrazine 2, 3, 5 or 6 position of 2, furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole 2, 3, 4 or 5 position, 2, 4 or 5 position of oxazole, imidazole or thiazole, isoxazole, pyrazole or 3, 4 or 5 position of isothiazole, 2 or 3 position of aziridine, 2, 3 or 4 position of azetidine, 2, 3, 4, 5, 6, 7 or 8 position of quinoline, or 1, 3, 3 of isoquinoline Bonded at the 4, 5, 6, 7 or 8 position. More typically, carbon-bonded heterocycles 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.

  By way of example and not limitation, nitrogen-attached heterocycles are aziridines, azetidines, pyrroles, pyrrolidines, 2-pyrrolines, 3-pyrrolines, imidazoles, imidazolidines, 2-imidazolines, 3-imidazolines, pyrazoles, pyrazolines, 2-pyrazolins. 3-pyrazoline, piperidine, piperazine, indole, indoline, 1-position of 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, 9-position of carbazole or β-carboline. More typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl.

  “Carbocycle” means a saturated, unsaturated or monocyclic ring having from 3 to 7 carbon atoms as a monocycle, from 7 to 12 carbon atoms as a bicycle and up to about 20 carbon atoms as a polycycle. An aromatic ring is meant. Monocyclic carbocycles have 3 to 6 ring atoms, more typically 5 to 6 ring atoms. Bicyclic carbocycles are composed of 7 to 12 ring atoms (these are arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system. Or 9 or 10 ring atoms, which are arranged as a bicyclo [5,6] or [6,6] system. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, phenyl, spiryl and naphthyl.

By “linker” or “link” is meant a chemical moiety that contains a covalent bond or an atomic chain or group (which covalently attaches a phosphonate group to a drug). The linker includes moieties of substituents A ¹ and A ³ , which include, for example, the following repeating unit moieties: alkyloxy (eg, polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino ( For example, polyethyleneamino, Jeffamine®); and diacid esters and amides (including succinates, succinamides, diglycolates, malonates and caproamides).

  The term “chiral” refers to molecules that have the non-superimposable properties of their mirror image partners, while the term “achiral” refers to molecules that are superimposable with their mirror image partners.

  The term “stereoisomer” means compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space.

  "Diastereomer" means a stereoisomer with two or more chiral centers but whose molecules are not mirror images of one another. Diastereomers have different physical properties (eg, melting points, boiling points, spectral properties, and reactivity). Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography.

  “Enantiomer” means two stereoisomers of a compound that are not superimposable on each other.

  The term “treatment” or “treating” to the extent that it relates to a disease or condition prevents the occurrence of the disease or condition, prevents the disease or condition, and / or eliminates the disease or condition, and / or Including alleviating one or more symptoms of the disease or condition.

  The stereochemical definitions and conventions used herein are generally described in S.H. P. Parker, Ed. McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E .; and Wilen, S .; , Stereochemistry 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 plane polarization. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, or (+) and (−) are used to specify how the plane polarized light is rotated by the compound, (−) or l means that the compound is levorotatory. To do. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are the same except that they are mirror images of one another. Certain stereoisomers are also referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemic compound” mean an equimolar mixture of two enantiomeric species, which lacks optical activity.

(Protecting group)
In the context of the present invention, protecting groups include prodrug moieties and chemical protecting groups.

  Commonly known and used protecting groups are available, which are optionally protected during the synthetic procedure (ie, route or method for preparing the compounds of the invention). Used to prevent side reactions with. In most cases, the determination of when to protect which groups and when to protect, and the nature of the chemical protecting group “PG” (eg, acidic state, basic state, oxidized state, reduced state or other state) Depending on the chemical nature of the reaction to be protected against and the intended direction of its synthesis. These PG groups need not be the same and are generally not the same if the compound is substituted with multiple PGs. In general, PG is used to protect functional groups (eg, carboxyl, hydroxyl, thio or amino groups), thereby preventing side reactions or otherwise promoting synthesis efficiency. Is done. The order of deprotection to yield a free deprotecting group depends on the intended direction of synthesis and the reaction conditions encountered and can occur in any order determined by one skilled in the art.

  Various functional groups of the compounds of the invention can be protected. For example, protecting groups for —OH groups (whether hydroxyl, carboxylic acid, phosphonic acid or other functional groups) include “ether or ester forming groups”. Ether or ester forming groups can function as chemical protecting groups in the synthetic schemes shown herein. However, some hydroxyl and thio protecting groups are not ether- or ester-forming groups, as will be appreciated by those skilled in the art, and are included with amides as described below.

  A very large number of hydroxyl protecting groups and amide-forming groups and the corresponding chemical cleavage reactions are described in “Protective Groups in Organic Synthesis”, Theodora W. et al. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-63021-6) ("Green"). Also, Kocienski, Philip J. et al. See "Protecting Groups" (Georg Thieme Verlag Stuttgart, New York, 1994), the contents of which are hereby incorporated by reference in their entirety. Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxy Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117C 154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acids, phosphonic acids, phosphonates, sulfonic acids, and other acid protecting groups, see Greene below. Such groups include, but are not limited to, esters, amides, hydrazides, and the like.

(Ether forming protecting group and ester forming protecting group)
Ester forming groups include: (1) phosphonate ester groups (eg, phosphonamidate esters, phosphonethioate esters, phosphonate esters and phosphon-bis-amidates); (2) carboxyl ester forming groups, and ( 3) Sulfur ester forming groups (eg sulfonates, sulfates and sulfinates).

  The phosphonate moiety of the compounds of the present invention may or may not be a prodrug moiety, i.e., they may or may not undergo hydrolytic or enzymatic cleavage or modification. Certain phosphonate moieties are stable under almost or almost all metabolic conditions. For example, dialkyl phosphonates (again, the alkyl group is 2 or more carbons) can have considerable stability in vivo due to the slow rate of hydrolysis.

In connection with phosphonate prodrug moieties, a number of structurally diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997)), which are Included within the scope of the invention. An exemplary phosphonate ester forming group is a phenyl carbocycle in substructure A ₃ having the following formula:

Wherein R ₁ can be H or C ₁ -C ₁₂ alkyl; m 1 is 1, 2, 3, 4, 5, 6, 7 or 8 and the phenyl carbocycle has 0 to Substituted with 3 R ₂ groups. Also, in embodiments where Y ₁ is O, when a lactic acid ester is formed and Y ₁ is N (R ₂ ), N (OR ₂ ) or N (N (R ₂ ) ₂ , the phosphonamidate ester is can get.

In its ester-forming role, the protecting group is typically attached to any acidic group (eg, by way of example and not limitation, a —CO ₂ H or —C (S) OH group), whereby — CO ₂ R ^x is obtained, where R ^x is defined in the universe herein. Examples of R ^x include ester groups listed in WO95 / 07920.

Examples of protecting groups include the following:
C ₃ -C ₁₂ heterocycle (described above) or aryl. These aromatic groups are polycyclic or monocyclic as required. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4 -And 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5-pyrimidinyl Listed;
Substituted below the _C 3 _{-C 12} heterocycle or aryl: _{^{halo, R 1, R 1 -O-}} C 1 ~C 12 _alkylene, C 1 _{-C 12} alkoxy, _CN, NO 2, OH, carboxy, carboxy ester , thiol, _thioesters, C 1 _{-C 12} haloalkyl (1 to 6 halogen _atoms), C 2 _{-C 12} alkenyl or _C 2 _{-C 12} alkynyl. 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-ethoxy -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-halophenyl (2-, 3- and 4-fluorophenyl and 2-, 3- and 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-biscarboxyethylphenyl, 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-dihalophenyl (2,4-difluorophenyl and 3,5-difluorophenyl including in), 2-, 3- and 4-haloalkylphenyl (1 to 5 halogen _atoms, including C 1 _{-C 12} alkyl (4-trifluoromethylphenyl)), 2-, 3- and 4 -Cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-, 3- and 4-haloa Kirubenjiru (one to five halogen _atoms, C 1 _{-C 12} alkyl (4-trifluoromethylbenzyl and 2-, 3- and 4-trichloromethylphenyl and 2-, 3- and 4-trichloromethylphenyl including in)), 4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl, benzyl, alkyl salicylic phenyl _(C 1 -C ₄ alkyl, 2-, 3- and 4 -Including ethyl salicylphenyl), 2-, 3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl (—C ₁₀ H ₆ —OH) and aryloxyethyl [C ₆ -C ₉ aryl (phenoxyethyl Inclusive)], 2,2′-dihydroxybiphenyl, 2-, 3- and 4-N, N-dialkylaminophenol, —C _{6 H 4 CH 2 -N (CH} 3) 2, trimethoxybenzyl, triethoxysilane benzyl, 2-alkylpyridinyl _{(C 1 to 4} alkyl);

; 2-carboxy _C 4 -C ₈ ester of phenyl; and _C 1 -C ₄ alkylene _-C 3 -C ₆ aryl (benzyl, -CH ₂ - pyrrolyl, -CH ₂ - thienyl, -CH ₂ - imidazolyl, -CH ₂ - oxazolyl, -CH ₂ - isoxazolyl, -CH ₂ - thiazolyl, -CH ₂ - isothiazolyl, -CH ₂ - pyrazolyl, -CH ₂ - pyridinyl and -CH ₂ - a pyrimidinyl a included), which, In its aryl moiety, it is substituted with 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from the following: halogen, C ₁ -C ₁₂ alkoxy (including methoxy and ethoxy) , cyano, nitro, _OH, C 1 _{-C 12} haloalkyl (1 to 6 halogen atoms); _- CH 2 CCl ₃ Including _{in), C} 1 ~C ₁₂ alkyl (including methyl and _{ethyl), C} 2 ~C ₁₂ alkenyl or _C 2 _{-C 12} alkynyl; alkoxy ethyl _[C 1 -C ₆ alkyl _(-CH 2 -CH ₂ - O—CH ₃ (including methoxyethyl))]; alkyl, which is substituted with any of the groups indicated above for aryl, in particular OH or 1 to 3 halo atoms _{(-CH 3, -CH (CH 3} ) 2, -C (CH 3) 3, -CH 2 CH 3, - (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, a _-CH 2 CF ₃ and _-CH 2 CCl ₃ including);

-N-2-propyl-morpholino, 2,3, dihydro-6-hydroxy-indene, 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 (OC (O) CH ₂ R ¹ ) —CH ₂ (OC (O) CH ₂ R ¹ ), cholesteryl, pyruvate _{(HOOC-C (= CH 2} ) -), glycerol;
5 or 6 carbon monosaccharides, disaccharides or oligosaccharides (3 to 9 monosaccharide residues);
Triglycerides (e.g., alpha-D-beta-diglycerides) (wherein the fatty acids composing glyceride lipids generally occurs naturally saturated or unsaturated _C 6 to _{26, C having 6 to 18} or _{C 6 to 10} fatty acids (e.g. Fatty acids such as linoleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoyl acid, linolenic acid), which are their parent compounds via the glyceryl oxygen of their triglycerides Bound to the acyl of
A phospholipid, which is linked to the carboxyl group via the phosphate of the phospholipid;
Phthalidyl (this is shown in FIG. 1 of Clayton et al., Antimicrob. Agents Chemo. (1974) 5 (6): 670-671);
A cyclic carbonate (eg, (5-R _d -2-oxo-1,3-dioxolen-4-yl) methyl ester (Sakamoto et al., Chem. Pharm. Bull. (1984) 32 (6) 224-1248). Wherein R _d is R ₁ , R ₄ or aryl); and

The hydroxyl group of the compounds of the present invention is optionally substituted with one of the III, IV or V groups disclosed in WO 94/21604 or substituted with isopropyl.

Table A lists examples of protecting group ester moieties that can be attached to, for example, —C (O) O— and —P (O) (O—) ₂ groups via oxygen. Several amidates are also shown, which are directly attached to -C (O)-or -P (O) ₂ . Esters of structures 1-5, 8-10 and 16, 17, 19-22 have a free hydroxyl group in DMF (or other solvents such as acetonitrile or N-methylpyrrolidone) Compounds can be converted to the corresponding halides (such as chloride or acyl chloride) and N, N-dicyclohexyl-N-morpholinecarboxamidine (or other bases such as DBU, triethylamine, CsCO ₃ , N, N-dimethylaniline, etc. )) And synthesized. When the protecting compound is a phosphonate, the esters of structures 5-7, 11, 12, 21 and 23-26 are alcohols or alkoxide salts thereof (or corresponding amines in the case of compounds such as 13, 14 and 15). Is reacted with monochlorophosphonate or dichlorophosphonate (or other activated phosphonate).

The # -chiral center is (R), (S) or a racemate.

  Other esters suitable for use herein are described in EP 63,2048.

Protecting groups also contain “double ester” forming pro-functionalities (eg, the following): —CH ₂ OC (O) OCH ₃ ,

_{-CH 2 SCOCH 3, -CH 2 OCON} (CH 3) 2 or the structure -CH ^{(R 1} or ^{W 5), O ((CO} ) R 37) or -CH ^{(R 1} or ^W 5) ((CO) R ³⁸ ) alkyl- or aryl-acyloxyalkyl groups, which are attached to the oxygen of the acidic group, wherein R ³⁷ and R ³⁸ are alkyl, aryl or alkylaryl groups ( See U.S. Pat. No. 4,968,788). Often R ³⁷ and R ³⁸ are bulky groups (eg, branched alkyl, ortho-substituted aryl, meta-substituted aryl, or combinations thereof (normal, secondary having 1-6 carbon atoms, secondary , Including iso and tertiary alkyl))). An example is a pivaloyloxymethyl group. It is particularly useful for orally administered prodrugs. Examples of such useful protecting groups include alkylacyloxymethyl esters and derivatives thereof, which include —CH (CH ₂ CH ₂ OCH ₃ ) OC (O) C (CH ₃ ) ₃ ,

_{-CH 2 OC (O) C 10} H 15, -CH 2 OC (O) C (CH 3) 3, -CH (CH 2 OCH 3) OC (O) C (CH 3) 3, -CH (CH ( _{CH 3) 2) OC (O} ) C (CH 3) 3, -CH 2 OC (O) CH 2 CH (CH 3) 2, -CH 2 OC (O) C 6 H 11, -CH 2 OC (O _{) C 6 H 5, -CH 2} OC (O) C 10 H 15, -CH 2 OC (O) CH 2 CH 3, -CH 2 OC (O) CH (CH 3) 2, -CH 2 OC (O ) C _{(CH 3) 3} and _{-CH 2 OC (O) CH 2} C 6 H 5 and the like.

  In some claims, the protected acidic group is an ester of the acidic group and is the residue of a hydroxy-containing functional group. In other claims, amino compounds are used to protect this acid functionality. Suitable hydroxyl or amino-containing functional group residues are found in WO 95/07920. The residues of amino acids, amino acid esters, polypeptides or aryl alcohols are particularly important. Exemplary amino acid, polypeptide and carboxyl-esterified amino acid residues are described as L1 or L2 groups on pages 11-18 of WO 95/07920 and associated text. WO 95/07920 explicitly teaches amidates of phosphonic acids, but it has been found that such amidates are formed with any of the acid groups indicated herein, the amino acid residues of which are It is shown in WO95 / 07920.

Typical esters for protecting acid functional groups are also described in WO 95/07920, and again, like the phosphonates of the '920 publication, using the acid groups herein, the same ester is It can be seen that it can be formed. Typical ester groups are defined at least in WO 95/07920, pages 89-93 (R ³¹ or R ³⁵ ), page 105, and pages 21-23 (as R). Unsubstituted aryl, such as phenyl or arylalkyl (eg benzyl), or hydroxy-, halo-, alkoxy-, carboxy- and / or alkyl ester carboxy-substituted aryl or alkylaryl (especially phenyl, ortho-ethoxyphenyl or C ₁ -C ₄ alkyl ester carboxyphenyl (salicylic acid C ₁ -C ₁₂ alkyl ester)) is particularly important.

  This protected acidic group is useful as a prodrug for oral administration, particularly when using the esters or amides of WO95 / 07920. However, it is not essential to protect this acid group in order to effectively administer the compounds of the invention by the oral route. Compounds of the invention having protecting groups (particularly amino acid amidates or substituted and unsubstituted aryl esters) can be hydrolytically cleaved in vivo when administered systemically or orally to give the free acid.

  One or more of the acidic hydroxyls are protected. If more than one acidic group is protected, the same or different protecting groups can be used, for example, their esters can be the same or different, or mixed amidates and esters can be used.

Typical hydroxy protecting groups described in Greene (pages 14-118) include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters (including sulfonate 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, guaiacol methyl, t-butoxymethyl 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromo Tetrahydropyranyl, tetrahydropthiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydropthiopyranyl S, S-dio 1-[(2-chloro-4-methyl) phenyl] -4-methoxypiperidin-4-yl, 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrofuranyl, 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-benzyloxy-2-fluoro Ethyl, 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-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p, p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl , Di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4′-bromophenacyloxy) phenyldiphenylmethyl, 4,4 ′, 4 ″ -tris (4,5-dichloro Phthalimidophenyl) methyl, 4,4 ', 4 "-tris (levulinoyloxy) Phenyl) methyl, 4,4 ′, 4 ″ -tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylethyl) 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-dioxide);
Silyl ether (trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, Diphenylmethylsilyl, t-butylmethoxyphenylsilyl);
Esters (formate ester, benzoyl formate, acetate ester, chloroacetate ester, dichloroacetate ester, trichloroacetate ester, trifluoroacetate ester, methoxyacetate ester, triphenylmethoxyacetate ester, phenoxyacetate ester, p-chlorophenoxyacetate ester, p Poly-phenylacetic acid ester, 3-phenylpropionic acid ester, 4-oxopentanoic acid ester (levulinic acid ester), 4,4- (ethylenedithio) pentanoic acid ester, pivalic acid ester, adamantate, crotonic acid ester, 4 -Methoxycrotonate, benzoate, p-phenyl benzoate, 2,4,6-trimethyl (mesitoate) benzoate);
Carbonate (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-benzylthiocarbonate, 4-ethoxy-1-naphthyl, methyldidithiocarbonate );
Groups that aid cleavage (2-iodobenzoate, 4-azide butyrate, 4-nitro-4-methyl pentanoate, o- (dibutyromethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethyl carbonate, 4- (Methylthiomethoxy) butyrate, 2 (methylthiomethoxymethyl) benzoate); miscellaneous esters (2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethyl) (Butyl) phenoxyacetate, 2,4-bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E) -2-methyl-2-butenoate (tigroate), o- (methoxycarbonyl) Benzoate, p-poly-ben , Α-naphthonate, nitrate ester, alkyl N, N, N ′, N′-tetramethyl phosphorodiamidate, N-phenylcarbamate, borate ester, dimethylphosphinothioyl, 2,4-dinitrophenyl sulfenate ); And sulfonates (sulfate, methyl sulfonate (mesylate), benzyl sulfonate, tosylate).

  Typical 1,2-diol protecting groups (and therefore generally when two OH groups are combined with protecting functional groups) are described in Greene pages 118-142, which include cyclic Acetals and ketals (methylene, ethylidene, 1-tert-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene , Cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, 2-nitrobenzylidene); cyclic orthoester (methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene) 1-ethoxy Tyridine, 1,2-dimethoxyethylidene, α-methoxybenzylidene, 1- (N, N-dimethylamino) ethylidene derivative, α- (N, N-dimethylamino) benzylidene derivative, 2-oxacyclopentylidene); silyl derivative (Di-t-butylsilylene group, 1,3- (1,1,3,3-tetraisopropyldisiloxanilidene) and tetra-t-butoxydisiloxane-1,3-diylidene), cyclic carbonate, cyclic boronate , Ethyl boronate and phenyl boronate.

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

Here, R ⁹ is C ₁ -C ₆ alkyl.

(Amino protecting group)
Another set of protecting groups includes any of the typical amino protecting groups described in Greene, pages 315-385. They include 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-methoxyphenacyl);
Substituted ethyl: (2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1- Dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- (3,5-di-t-butyl Phenyl) -1-methylethyl, 2- (2′- and 4′-pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl , Cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitroben Le, p- bromobenzyl, p- chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinyl benzyl, 9-anthrylmethyl, diphenylmethyl);
Groups that aid in cleavage: (2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, 4-methylthiophenyl, 2,4-dimethyl Thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (dihydroxybonyl) benzyl, 5-benzisoxazolylmethyl 2- (trifluoromethyl) -6-chromonylmethyl);
Groups capable of photolytic cleavage: (m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl (o-nitrophenyl) methyl); urea type derivatives (pheno Thiazinyl- (10) -carbonyl, N′-p-toluenesulfonylaminocarbonyl, N′-phenylaminothiocarbonyl);
Miscellaneous carbamates: (t-amyl, S-benzylthiocarbamate, 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-furanylmethyl, 2-iodoethyl, Iodobornyl, isobutyl, isonicotinyl, p- (p′-methoxyphenylazo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1- (3,5- Dimethoxyphenyl) Eth 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- (trimethylammonium) benzyl, 2,4,6-trimethylbenzyl);
Amide: (N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl, N-benzoyl, Np-phenylbenzoyl);
Amides that aid in cleavage: (N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) propionyl N-3- (o-nitrophenyl) propionyl, N-2-methyl-2- (o-nitrophenoxy) propionyl, N-2-methyl-2- (o-phenylazophenoxy) propionyl, N-4- Chlorobutyryl, N-3-methyl-3-nitrobutyryl, No-nitrocinnamoyl, N-acetylmethionine, No-nitrobenzoyl, No- (benzoyloxymethyl) benzoyl, 4,5-diphenyl-3 -Oxazolin-2-one);
Cyclic imide derivatives: (N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleyl oil, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilyl Azacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3-5-triazacyclohexane-2- ON, 1-substituted 3,5-dinitro-4-pyridonyl);
N-alkyl and N-arylamines: (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-dibenzosuberyl, N-triphenylmethyl, N- (4- Methoxyphenyl) diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, N-2-picolylamine N′-oxide);
Imine derivatives: (N-1,1-dimethylthiomethylene, N-benzylidene, Np-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl) mesityl] methylene, N, (N ′, N ′ -Dimethylaminomethylene, N, N-isopropylidene, Np-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N- (5-chloro-2-hydroxyphenyl) phenylmethylene, N-cyclohex Silidene);
Enamine derivatives: (N- (5,5-dimethyl-3-oxo-1-cyclohexenyl));
N-metal derivatives (N-borane derivatives, N-diphenylborinic acid derivatives, N- [phenyl (pentacarbonylchromium-or-tungsten)] carbenyl, N-copper or N-zinc chelates);
NN derivatives: (N-nitro, N-nitroso, N-oxide);
NP derivatives: (N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkylphosphoryl, N-dibenzylphosphoryl, N-diphenylphosphoryl);
N-Si derivatives, NS derivatives and N-sulfenyl derivatives: (N-benzenesulfenyl, No-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl, N 2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl, N-3-nitropyridinesulfenyl); and N-sulfonyl derivatives (Np-toluenesulfonyl, N-benzenesulfonyl, N- 2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N- 2,3,5,6-tetramethyl-4-methoxybenzenesulfonate 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-β-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N-4- (4 ', 8'-dimethoxynaphthylmethyl) benzenesulfonyl, N-benzylsulfonyl, N- Trifluoromethylsulfonyl, N-phenacylsulfonyl).

More typically, protected amino groups, carbamates, and amides, still more typically, -NHC (O) OR ¹ or ^{-N = CR 1 N (R 1} ), 2 and the like. Other protecting groups useful as prodrugs for amino or —NH (R ⁵ ) include the following:

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

(Amino acid and polypeptide protecting groups and conjugates)
The amino acid or polypeptide protecting group of the compounds of the invention has the structure R ¹⁵ NHCH (R ¹⁶ ) C (O) —, wherein R ¹⁵ is H, an amino acid or a polypeptide residue, or R ⁵ and R ¹⁶ is defined below.

R ¹⁶ is lower alkyl or lower alkyl (C ₁ -C ₆ ), which is amino, carboxyl, amide, carboxyl ester, hydroxyl, C ₆ -C ₇ aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide and And / or substituted with alkyl phosphate. R ¹⁶ is also taken together with the amino acid α-N to form a proline residue (R ¹⁰ = —CH ₂ ) ₃ —). However, R ¹⁰ is generally a naturally occurring amino acid (eg, 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-C (NH ₂ ) -NH ₂ ) side chain. R ¹⁰ also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.

Other sets of protecting groups include amino-containing compounds, particularly amino acids, polypeptides, protecting groups —NHSO ₂ R, NHC (O) R, —N (R) ₂ , NH ₂ or —NH (R) (H ) Such that, for example, the carboxylic acid is reacted (ie, coupled) with the amine to form an amide, such as C (O) NR ₂ . Phosphonic acid may be reacted with the amine, as in -P (O) (OR) ( NR 2), to form a phosphonamidate,
In general, amino acids have the structure R ¹⁷ C (O) CH (R ¹⁶ ) NH—, where R ¹⁷ is —OH, —OR, an amino acid, or a polypeptide residue. Amino acids are low molecular weight compounds of the order of less than about 1000 MW, which contain at least one amino or imino group and at least one carbonyl group. In general, this amino acid is found in nature, i.e. it can be detected in biological material (e.g. bacteria or other microorganisms, plants, animals or humans). Suitable amino acids are typically characterized by an alpha amino acid, ie, one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom. Compound. Hydrophobic residues (eg mono- or di-alkyl or aryl amino acids, cycloalkyl amino acids, etc.) are particularly important. These residues contribute to the permeability of the cell by increasing the partition coefficient of its parent drug. Typically, this residue does not contain a sulfhydryl or guanidino substituent.

  Naturally occurring amino acid residues include those found in nature in plants, animals or microorganisms, particularly those proteins. Polypeptides are most typically composed essentially of such naturally occurring 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 There is hydroxyproline. In addition, unnatural amino acids such as balanine, phenylglycine and homoarginine are also included. Commonly encountered non-gene encoded amino acids can also be used in the present invention. All of the amino acids used in the present invention can be either the D- or L-optical isomer. In addition, other peptidomimetics are also useful in the present invention. For a general review, see Spatola, A. et al. F. , In Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, B .; By Weinstein, Marcel Dekker, New York, p. 267 (1983).

When the protecting group is a single amino acid residue or polypeptide, it is optionally substituted with R ³ of the substituent A ¹ , A ² or A ³ in formula I. These conjugates are generally generated by forming an amide bond between the carboxyl groups of that amino acid (or, for example, the C-terminal amino acid of a polypeptide). Similarly, a conjugate is formed between R ³ (Formula I) and the amino group of the amino acid or polypeptide. In general, only one of the optional sites in the parent molecule is amidated with an amino acid as described herein, but introducing an amino acid with more than one permissive site is Within the scope of the invention. Usually, the carboxyl group of R ³ is amidated with an amino acid. Generally, the α-amino or α-carboxyl group of the amino acid or the terminal amino or carboxyl group of the polypeptide is attached to the parent functional group, ie the carboxyl group or amino group of the amino acid side chain is generally It is not used to form amide bonds with compounds (though these groups may need to be protected during the synthesis of these conjugates, as further described below).

With respect to the side chain of the amino acid or carboxy-containing polypeptide, it can be seen that this carboxyl group is blocked, eg, by R ¹ , esterified with R ⁵ , or amidated, as appropriate. Similarly, amino side chain R ¹⁶ is optionally blocked with R ¹ or substituted with R ⁵ .

  Such ester or amide linkages with side chain amino groups or carboxyl groups are subject to acidic (pH <3) or basic (pH> 10) conditions as required, such as the ester or amide with its parent molecule. Underneath, it can be hydrolyzed in vivo or in vitro. Alternatively, they are substantially stable in the human gastrointestinal tract, but are enzymatically hydrolyzed in the blood or intracellular environment. These esters or amino acids or polypeptide amidates are also useful as intermediates for preparing 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 conjugates of the invention, for example, by conventional hydrolysis procedures.

  When an amino acid residue contains one or more chiral centers, its D, L, meso, threo or erythro (when appropriate) racemate, scalemate compound or mixtures thereof can be used. In general, the D isomer is useful if these intermediates are hydrolyzed (as is the case when their amides are used as chemical intermediates for organic acids or free amines). On the other hand, the L isomer is more versatile because it is susceptible to both non-enzymatic and enzymatic hydrolysis and is more efficiently transported by the amino acid or dipeptidyl transport system in the gastrointestinal tract.

Examples of suitable amino acids whose residues are represented by R ^x or R ^y include the following:
glycine;
Aminopolycarboxylic acids (eg, 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-aminosuberic acid and 2-aminosebacic acid;
Amino acid amides such as glutamine and asparagine;
Polyamino- or polybasic-monocarboxylic acids (eg arginine, lysine, β-aminoalanine, γ-aminobutyrin, ornithine, citrulline, homoarginine, homocitrulline, hydroxylysine, allohydroxylysine and diaminobutyric acid;
Other basic amino acid residues (eg histidine);
Diaminodicarboxylic acid (for example, α, α'-diaminosuccinic acid, α, α'-diaminoglutaric acid, α, α'-diaminoadipic acid, α, α'-diaminopimelic acid, α, α'-diamino-β- Hydroxypimelic acid, α, α′-diaminosuberic acid, α, α′-diaminoazelineic acid and α, α′-diaminosebacic acid;
Imino acids (eg proline, hydroxyproline, allohydroxyproline, γ-methylproline, pipecolic acid, 5-hydroxypipecolic acid and azetidine-2-carboxylic acid);
Mono- or di-alkyl (typically C ₁ -C ₈ branched or normal) amino acids (eg alanine, valine, leucine, allylglycine, butyrin, norvaline, norleucine, heptillin, α-methylserine, α-amino) -Α-methyl-γ-hydroxyvaleric acid, α-amino-α-methyl-δ-hydroxyvaleric 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- Propyl acetic acid, α-aminoisoamyl acetic acid, α-methyl aspartic acid, α-methyl glutamic acid, - amino cyclopropane-1-carboxylic acid, isoleucine, allo-isoleucine, tert-leucine, beta-methyl tryptophan and α- amino -β- ethyl -β- phenylpropionic acid;
β-phenylselinyl;
Aliphatic α-amino-β-hydroxy acids (eg, serine, β-hydroxyleucine, β-hydroxynorleucine, β-hydroxynorvaline and α-amino-β-hydroxystearic acid);
α-amino, α-, γ-, δ- or ε-hydroxy acids (eg homoserine, δ-hydroxynorvaline, γ-hydroxynorvaline and ε-hydroxynorleucine residues); canabin and canalin; γ-hydroxy Ornithine;
2-hexosamic acid (eg, D-glucosamic acid or D-galactosamic acid);
α-amino-β-thiol (eg penicillamine, β-thionorvaline or β-thiobutyrin);
Other sulfur-containing amino acid residues (cysteine; homocystin, 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 (including, for example, phenyl- or cyclohexyl amino acids, α-aminophenylacetic acid, α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionic acid); phenylalanine analogs and derivatives ( This includes aryl, lower alkyl, hydroxy, guanidino, oxyalkyl ether, nitro, sulfur or halo-substituted phenyl (eg 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); furyl-, thionyl-, pyridyl , Pyrimidinyl-, purinyl- Or naphthyl-alanine; and tryptophan analogs and derivatives (including kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan);
α-amino substituted amino acids (including sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N-benzylvaline) ); And α-hydroxy and substituted α-hydroxy amino acids (including serine, threonine, arosleonine, phosphoserine and phosphothreonine).

  A polypeptide is a polymer of amino acids, where the carboxyl group of one amino acid monomer is linked to the amino or imino group of the next amino acid monomer by an amide bond. Polypeptides include dipeptides, lower polypeptides (about 1500-5000 MW) and proteins. The protein optionally contains 3, 5, 10, 50, 75, 100 or more residues, and suitably with human, animal, plant or microbial proteins. The sequence is substantially homologous. They include not only enzymes (eg, hydrogen peroxide degrading enzymes) but also immunogens (eg, KLH or any type of antibody or protein for which it is desired to enhance the immune response). The nature and identity of this polypeptide can vary widely.

  A polypeptide amidase raises an antibody against either the polypeptide (if not the immunogen in the animal to which it is administered) or an antigenic determinant on the remainder of the compound of the invention. Useful as an immunogen.

  Antibodies capable of binding to the parent non-peptidyl compound are used to separate the parent compound from the mixture, eg, in the diagnosis or manufacture of the parent compound. The conjugate of the parent compound and the polypeptide is generally more immunogenic than the polypeptide in closely homologous animals, and thus the polypeptide is made more effective to promote the induction of antibodies against the polypeptide. Make it immunogenic. Thus, the polypeptide or protein may not need to be immunogenic in animals typically used to raise antibodies (eg, rabbits, mice, horses, or rats), but the final product The substance conjugate should be immunogenic in at least one of such animals. The polypeptide optionally includes a peptide lytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such cleavage sites are flanked by enzyme recognition structures (eg, specific sequences of residues recognized by peptide lytic enzymes).

Peptide lytic enzymes for cleaving the polypeptide conjugates of the present invention are well known and include, in particular, carboxypeptidases. Carboxypeptidases that digest polypeptides by removing C-terminal residues are often specific for a particular C-terminal sequence. Such enzymes and their general substrate requirements are well known. For example, a dipeptide (having a given residue pair and a free carboxy terminus) is covalently bonded to the phosphorus atom or carbon atom of the compounds herein through its α-amino group. In the claims where W ₁ is a phosphonate, the peptide is cleaved by an appropriate peptide lytic enzyme, leaving the carboxyl of the proximal amino acid residue, and the phosphonoamidate bond expected to be autocatalytically cleaved. Is done.

  A suitable dipeptidyl group (indicated by its one letter code) is

There is.

Tripeptide residues are also useful as protecting groups. If the phosphonate is to be protected, the sequence -X ⁴ -pro-X ^5- (X ⁴ is any amino acid residue and X ⁵ is an amino acid residue, a carboxyl ester of proline, or hydrogen ) is is cleaved by luminal carboxypeptidase, produce X ⁴ with a free carboxyl, X ⁴ having the free carboxyl is then expected to autocatalytically cleave the phosphonoamidate bond. Carboxy group of X ⁵ optionally is esterified with benzyl.

  Dipeptide or tripeptide species can be selected based on known transport properties and / or susceptibility to peptidases that can affect transport to intestinal mucosal cell types or other cell types. Dipeptides and tripeptides lacking an α-amino group are transport substrates for peptide transporters found in the brush border membrane of intestinal mucosal cells (Bai, JPF, (1992) Pharm Res. 9: 969- 978). Thus, transport competent peptides can be used to enhance the bioavailability of the amidate compound. Dipeptides or tripeptides having one or more amino acids of form D are also compatible with peptide transport and can be utilized in the amidate compounds of the invention. D-form amino acids can be used to reduce the sensitivity of dipeptides or tripeptides to hydrolysis by proteases common to brush borders (eg, aminopeptidase N). In addition, the dipeptide or tripeptide is alternatively selected based on its relative resistance to hydrolysis by proteases found in the intestinal lumen. For example, a tripeptide or polypeptide lacking asp and / or glu is a poor quality substrate for aminopeptidase A and is an amino acid residue on the N-terminal side of a hydrophobic amino acid (leu, tyr, phe, val, trp) A dipeptide or tripeptide lacking is a poor substrate for endopeptidase, and a peptide lacking the penultimate pro residue at the free carboxyl terminus is a poor substrate for carboxypeptidase P. Similar considerations also apply to the selection of peptides that are either relatively resistant or relatively sensitive to hydrolysis by cytosolic peptidases, kidney peptidases, liver peptidases, serum peptidases, or other peptidases. obtain. Such poorly cleaved polypeptides amidates are immunogens or are useful for binding to proteins to prepare immunogens.

(Specific Embodiments of the Invention)
Not only are the specific values describing radicals, substituents and ranges, but also the specific embodiments of the invention described herein are presented by way of example only; Or other values within the specified range are not excluded.

In one particular embodiment of the invention, the conjugate is a compound substituted with one or more phosphonate groups, either directly or indirectly through a linker, or a pharmaceutically acceptable salt thereof. It is an acceptable salt; it is optionally substituted with one or more A ⁰ groups, where:
A ⁰ is A ¹ , A ² or W ³ ;
A ¹ is:

A ² are the following:

A ³ are the following:

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 a 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 - is;
R ^x is independently 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 with carbon atoms Together, two R ² groups form a ring having 3 to 8 carbons, and the ring can be substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, is a ^{R 3c} or ^{R 3d,} provided that ^{when R 3} is bonded to a heteroatom, ^{R 3 is} a ^{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, 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;
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, alkylene, alkenylene or alkynylene. Any one of 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 _M2 R ⁵ or —SO _M2 W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
W ⁶ is W ³ and W ³ is 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; and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another particular embodiment of the invention, A ¹ is:

In another particular embodiment of the invention, A ¹ is:

In another particular embodiment of the invention, A ¹ is:

In another particular embodiment of the invention, A ¹ is:

In another particular embodiment of the invention, A ¹ is:

W ^5a is a carbocyclic or heterocyclic ring, where W ^5a is independently substituted with 0 or 1 R ² group. The specific value of M12a is 1.

In another particular embodiment of the invention, A ¹ is:

In another particular embodiment of the invention, A ¹ is:

In another particular embodiment of the invention, A ¹ is:

Where: W ^5a is a carbocycle, which is separately substituted with 0 or 1 R ² groups.

In another particular embodiment of the invention, A ¹ is:

Where Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another particular embodiment of the invention, A ¹ is:

Where: W ^5a is a carbocycle, which is separately substituted with 0 or 1 R ² groups.

In another particular embodiment of the invention, A ¹ is:

Here, W ^5a is a carbocyclic or heterocyclic ring, where W ^5a is independently substituted with 0 or 1 R ² groups.

In another particular embodiment of the invention, A ¹ is:

Where Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In certain embodiments of the invention, A ² is:

In another particular embodiment of the invention, A ² is:

In another specific embodiment of the invention each M12b is 1.

In another particular embodiment of the present invention, M12b is 0, Y ² is a bond, and W ⁵ is a carbocycle or heterocycle wherein, W ⁵ is optionally Separately substituted with 1, 2 or 3 R ² groups.

In another particular embodiment of the invention, A ² is:

Here, W ^5a is a carbocyclic or heterocyclic ring, where W ^5a is independently substituted with one, two, or three R ² groups as required.

  In another specific embodiment of the invention M12a is 1.

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

In another particular embodiment of the invention, A ² is:

In another particular embodiment of the invention, A ² is:

In another specific embodiment of the invention M12b is 1.

In another particular embodiment of the invention, A ³ is:

In another particular embodiment of the invention, A ³ is:

In another particular embodiment of the invention, A ³ is:

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

In another particular embodiment of the invention, A ³ is:

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

In another particular embodiment of the invention, A ³ is:

Where Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another particular embodiment of the invention, A ³ is:

Where Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

  In another specific embodiment of the invention M12d is 1.

In another particular embodiment of the invention, A ³ is:

In another particular embodiment of the invention, A ³ is:

In another specific embodiment of the invention W ⁵ is a carbocycle.

In another particular embodiment of the invention, A ³ is:

In another specific embodiment of the invention W ⁵ is phenyl.

In another particular embodiment of the invention, A ³ is:

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

In another particular embodiment of the invention, A ³ is:

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

In another particular embodiment of the invention, A ³ is:

Where Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention R ¹ is H.

In another particular embodiment of the invention, A ³ is:

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

In another particular embodiment of the invention, A ³ is:

In another particular embodiment of the invention, A ³ is:

In another particular embodiment of the invention, A ³ is:

In another particular embodiment of the invention, A ³ is:

In another particular embodiment of the invention, A ³ is:

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

In another particular embodiment of the invention, A ³ is:

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 particular embodiment of the invention, A ³ is:

Where 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.

In another particular embodiment of the invention, A ³ is:

Where Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another particular embodiment of the invention, A ³ is:

Here, Y ^2b is O or N (R ² ).

In another particular embodiment of the invention, A ³ is:

In another particular embodiment of the invention, A ³ is:

In another particular embodiment of the invention, A ³ is:

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

In another particular embodiment of the invention, A ³ is:

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 particular embodiment of the invention, A ³ is:

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.

In another particular embodiment of the invention, A ³ is:

Where Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another particular embodiment of the invention, A ³ is:

Here, Y ^2b is O or N (R ² ).

In another particular embodiment of the invention, A ³ is:

Where Y ^2b is O or N (R ^X ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another particular embodiment of the invention, A ³ is:

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

In another particular embodiment of the invention, A ³ is:

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

In another particular embodiment of the invention, A ³ is:

In another particular embodiment of the invention, A ⁰ is:

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

In other specific embodiments of the invention, R ^x is independently 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 with carbon atoms Together, two R ² groups form a ring having 3 to 8 carbons, and the ring can be substituted with 0 to 3 R ³ groups;
In another particular embodiment of the invention, R ^x is:

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

In another particular embodiment of the invention, R ^x is:

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

In another particular embodiment of the invention, R ^x is:

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

In another particular embodiment of the invention, R ^x is:

In another particular embodiment of the invention, R ^x is:

In another particular embodiment of the invention, R ^x is:

In another specific embodiment of the invention Y ¹ is O or S.

In another specific embodiment of the invention, Y ² is O, N (R ^y ) or S.

In one particular embodiment 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;
However:
If m1a, m12c and m1d are 0, m1b, m1c and m1e are 0;
If m1a and m12c are 0 and m1d is not 0, m1b and m1c are 0;
If m1a and m1d are 0 and m12c is not 0, m1b and at least one of m1c and m1e are 0;
If m1a is 0 and m12c and m1d are not 0, m1b is 0;
If m12c and m1d are 0 and m1a is not 0, at least two of m1b, m1c and m1e are 0;
If m12c is 0 and m1a and m1d are not 0, then at least one of m1b and m1c is 0; and if m1d is 0 and m1a and m12c are not 0, At least one of m1c and m1e is 0.

In another specific embodiment, the invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof:
[DRUG]-(A ⁰ ) _nn
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 comprises at least one A ¹ ;
A ¹ is,

Is;
A ² is,

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 ));
Y ² is independently a 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 - a and;
R ^x is independently H, R ¹ , W ³ , a protecting group, or the formula:

Is;
R ^y is independently 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 R ⁴ , and each R ⁴ is independently substituted with 0 to 3 R ³ groups, or two at both carbon atoms The R ² group can form 3-8 carbocycles, and the ring can be substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , when R ³ is attached 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 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 and each R ⁴ is substituted with 0-3 R ³ groups;
R ^5a is independently an alkylene of 1-18 carbon atoms, an alkenylene of 2-18 carbon atoms, or an alkynylene of 2-18 carbon atoms, of alkylene, alkenylene, or alkynylene Any one 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 ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, W ⁵ is independently substituted with 0-3 R ² groups;
W ⁶ is independently W ³ 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 invention provides compounds of formulas 1-336:

(Where
A ⁰ is A ¹ ;
A ¹ is,

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 ));
Y ² is independently a 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 - a and;
R ^x is independently H, W ³ , a protecting group, or the formula:

Is;
R ^y is independently 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 R ⁴ , and each R ⁴ is independently substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , and when 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 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 and each R ⁴ is substituted with 0 to 3 R ³ groups;
R ^5a is independently an alkylene of 1-18 carbon atoms, an alkenylene of 2-18 carbon atoms, or an alkynylene of 2-18 carbon atoms, of alkylene, alkenylene, or alkynylene Any one 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 ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, W ⁵ is independently substituted with 0-3 R ² groups;
W ⁶ is independently W ³ 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) or a pharmaceutically acceptable salt thereof.

3. Formula 1-336: wherein A ⁰ is A ¹ ;
A ¹ is,

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 ));
Y ² is independently a 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 - a and;
R ^x is independently H, W ³ , a protecting group, or the formula:

Is;
R ^y is independently 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 R ⁴ , and each R ⁴ is independently substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , and when 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 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 and each R ⁴ is substituted with 0 to 3 R ³ groups;
R ^5a is independently an alkylene of 1-18 carbon atoms, an alkenylene of 2-18 carbon atoms, or an alkynylene of 2-18 carbon atoms, of alkylene, alkenylene, or alkynylene Any one 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 ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, W ⁵ is independently substituted with 0-3 R ² groups;
W ⁶ is independently W ³ 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 invention provides a compound of formula:
^{[DRUG] - [L-P} (= Y 1) -Y 2 -R x] nn
Wherein DRUG is any one compound from 500 to 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 a 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 - a and;
R ^x is independently H, W ³ , a protecting group, or the formula:

Is;
R ^y is independently H, W ³ , R ² , or a protecting group;
R ² is independently H, R ³ , or R ⁴ , and each R ⁴ is independently substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , and when 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 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 and 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 a carbocyclic or heterocyclic ring, W ⁵ is independently substituted with 0-3 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) or a pharmaceutically acceptable salt thereof.

In another specific embodiment, the invention provides a compound of formula:
[DRUG]-(A ⁰ ) _nn
Wherein DRUG is any one compound of formula 500-601;
nn is 1, 2, or 3;
When the compound contains at least one A ¹ , A ⁰ is A ¹ , A ² , or W ³ ;
A ¹ is,

Is;
A ² is,

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 ));
Y ² is independently a 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, W ³ , a protecting group, or the formula:

Is;
R ^y is independently H, W ³ , R ² , or a protecting group;
R ² is independently H, R ³ , or R ⁴ , and each R ⁴ is independently substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , and when R ³ is attached 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 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 and 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 a carbocyclic or heterocyclic ring, W ⁵ is independently substituted with 0-3 R ² groups;
W ⁶ is independently W ³ 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) or a pharmaceutically acceptable salt thereof.

In the compounds of the present invention, the W ⁵ carbocycle and the W ⁵ heterocycle can be independently substituted with 0 to 3 R ² groups. W ⁵ can have 3 to 10 (eg, 3 to 7) ring atoms. W ⁵ ring is saturated when it contains 3 atoms, saturated or monounsaturated when it contains 4 ring atoms, saturated, monounsaturated when it contains 5 ring atoms, or It is diunsaturated and saturated, monounsaturated, diunsaturated or aromatic when it contains 6 ring elements.

W ⁵ heterocycle is a single or 7-10 membered ring having 3-7 membered rings (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S) It may be a bicyclic ring having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. W ⁵ heterocycle is 3-6 ring atoms (2-5 carbon atoms and 1-2 heteroatoms selected from N, O, and S) or 5 or 6 ring atoms (3 ˜5 carbon atoms and 1-2 heteroatoms selected from N and S). W ⁵ heterocyclic bicycles are composed of 7 to 10 ring atoms (6 to 6) arranged as a [4,5], [5,5], [5,6], or [6,6] bicyclic system. 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) or 9-10 ring atoms arranged as a [5,6] or [6,6] bicyclic ring system (8-9 carbon atoms and 1-2 heteroatoms selected from N and S). The W ⁵ heterocycle can be attached to Y ² via a carbon, nitrogen, sulfur, or other atom by a stable covalent bond.

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 It is. W ⁵ includes, for example, but is not limited to:

As defined above, the W ⁵ carbocycles and heterocycles, independently, can be substituted with 0-3 R ² groups. For example, substituted W ⁵ carbocycles include the following:

.

  Examples of substituted phenyl carbocycles include the following:

.

Conjugates of Formula I In one embodiment, the present invention provides compounds of formula I:

Wherein 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, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine , 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substitution Triazole, And it is selected from pyrazolo [3,4-D] pyrimidine;
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 substituted Selected from alkynyl,
Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
Y ² is independently a bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N—NR ₂ , S, S—S , 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 to} C ₈ alkyl, C ₁ to C ₈ alkyl halide, carboxyl Rate, sulfate, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl thiols, alkyl sulfones (—SO ₂ R), aryl sulfones (—SO ₂ Ar), aryl sulfoxides (—SOAr), arylthio (—SAr), sulfonamides (—SO ₂ NR ₂ ), alkyl sulfoxides (—SOR) ), Ester (—C (═O) OR), amide (—C (═O) NR ₂ ), 5-7 membered lactam, 5-7 membered lactone, nitrile (—CN), azide (—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, When it is a C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, protecting group (PG), or W ³ or taken together, R ^y forms a carbocycle of 3-7 carbon atoms;
R ^x is independently R ^y , a protecting group, or the formula:

Is;
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 heterocyclic or a protecting group;
When W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ , W ³ is W ⁴ or W ⁵ . Yes; W ⁵ is a carbocyclic or heterocyclic ring, and W ⁵ is independently substituted with 0 to 3 R ^y groups) or a pharmaceutically acceptable salt or solvent thereof Offer Japanese products.

For a conjugate of Formula I, in one specific _embodiment, 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 heterocyclic are independently, F, Cl, Br, I , OH, -NH 2, -NH 3 +, -NHR, -NR 2, -NR 3 +, C 1 ~C 8 alkyl halides , carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl hydroxyl, _{C 1} -C _{8 alkylthio, -SO 2 R, -SO 2 Ar} , -SOAr, -SAr, -SO 2 NR 2, -SOR, -CO 2 R, -C (= O) NR 2, 5~7 -membered ring Lac Arm, 5-7 membered ring _{lactone, -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 Substituted with one or more substituents selected from C ₆ -C ₂₀ aryl, C ₂ -C ₂₀ heterocycle, polyethyleneoxy, phosphonate, phosphate, and prodrug moieties.

  For a conjugate of Formula I, in one particular embodiment, the “protecting group” is selected from carboxyl esters, carboxyamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonate esters, carbonates, and carbamates. .

For a conjugate of Formula I, in one particular embodiment, W ⁵ is selected from the following structures:

.

For the conjugate of Formula I, in one particular embodiment, X is O and R ^y is H.

For the conjugate of Formula I, in one particular embodiment, X is C═CH ₂ and R ^y is H.

For one conjugate of Formula I, Z ¹ is OH.

For the conjugate of Formula I, in one particular embodiment, Z ² is C ₁ -C ₈ alkyl or C ₁ -C ₈ substituted alkyl.

For the conjugate of Formula I, in one particular embodiment, Z ² is CH ₃ .

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

(In a more particular 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 particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

(Wherein R ² is H or C ₁ -C ₈ alkyl).

  In one particular embodiment, the conjugate of formula I has the following formula:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

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

  In one particular embodiment, the conjugate of formula I has the following formula:

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

  For a conjugate of Formula I, in one particular embodiment, the substituted triazole has the following structure:

.

  In one particular embodiment, the conjugate of formula I has the following formula:

.

Wherein 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, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine , 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substitution Triazole, And it is selected from pyrazolo [3,4-D] pyrimidine;
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 substituted Selected from 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 to} C ₈ alkyl, C ₁ to C ₈ alkyl halide, carboxyl Rate, sulfate, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl thiols, alkyl sulfones (—SO ₂ R), aryl sulfones (—SO ₂ Ar), aryl sulfoxides (—SOAr), arylthio (—SAr), sulfonamides (—SO ₂ NR ₂ ), alkyl sulfoxides (—SOR) ), Ester (—C (═O) OR), amide (—C (═O) NR ₂ ), 5-7 membered lactam, 5-7 membered lactone, nitrile (—CN), azide (—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, When it is a C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, protecting group (PG), or W ³ or taken together, R ^y forms a carbocycle of 3-7 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 heterocyclic or a protecting group;
When W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ , W ³ is W ⁴ or W ⁵ . Yes; W ⁵ is a carbocyclic or heterocyclic ring, and W ⁵ is independently substituted with 0 to 3 R ^y groups) or a pharmaceutically acceptable salt or solvent thereof It is a Japanese product.

  In one particular embodiment, the conjugate of formula I has the following formula:

(Wherein PG is an ether-forming group, thioether-forming group, ester-forming group, thioester-forming group, silyl ether-forming group, amide-forming group, acetal-forming group, ketal-forming group, carbonate-forming group, carbamate-forming group, urea-forming group) Protecting groups selected from groups, amino acid conjugates, and polypeptide conjugates).

  In one particular embodiment, the present invention provides the following formula:

Wherein 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, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine , 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substitution Triazole, Providing and pyrazolo [3,4-D] conjugate or a pharmaceutically acceptable salt or solvate of formula I with one pyrimidine a is). In a further embodiment, the compound is isolated and purified.

  In one particular embodiment, the present invention provides the following formula:

One where B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 2,6-diaminopurine, 5-fluorocytosine, or c-propyl-2,6-diaminopurine. Or a pharmaceutically acceptable salt or solvate thereof. In a further embodiment, the compound is isolated and purified.

  In one particular embodiment, the present invention provides the following formula:

Or a pharmaceutically acceptable salt or solvate thereof. In a further embodiment, the compound is isolated and purified.

  In one particular embodiment, the present invention provides the following formula:

Wherein 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, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine , 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substitution Triazole, Providing and pyrazolo [3,4-D] conjugate or a pharmaceutically acceptable salt or solvate of formula I with one pyrimidine a is). In a further embodiment, the compound is isolated and purified.

  In one particular embodiment, the present invention provides the following formula:

One where B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 2,6-diaminopurine, 5-fluorocytosine, or c-propyl-2,6-diaminopurine. Or a pharmaceutically acceptable salt or solvate thereof. In a further embodiment, the compound is isolated and purified.

  In one particular embodiment, the present invention provides the following formula:

Or a pharmaceutically acceptable salt or solvate thereof. In a further embodiment, the compound is isolated and purified.

Conjugates of Formula II In one embodiment, the present invention provides compounds of Formula II:

Wherein 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, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine , 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substitution Triazole, And it is selected from pyrazolo [3,4-D] pyrimidine;
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 substituted Selected from alkynyl,
Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
Y ² is independently a bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N—NR ₂ , S, S—S , 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 to} C ₈ alkyl, C ₁ to C ₈ alkyl halide, carboxyl Rate, sulfate, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl thiols, alkyl sulfones (—SO ₂ R), aryl sulfones (—SO ₂ Ar), aryl sulfoxides (—SOAr), arylthio (—SAr), sulfonamides (—SO ₂ NR ₂ ), alkyl sulfoxides (—SOR) ), Ester (—C (═O) OR), amide (—C (═O) NR ₂ ), 5-7 membered lactam, 5-7 membered lactone, nitrile (—CN), azide (—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, When it is a C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, protecting group (PG), or W ³ or taken together, R ^y forms a carbocycle of 3-7 carbon atoms;
R ^x is independently R ^y , a protecting group, or the formula:

Is;
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 heterocyclic or a protecting group;
When W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ , W ³ is W ⁴ or W ⁵ . Yes; W ⁵ is a carbocyclic or heterocyclic ring, and W ⁵ is independently substituted with 0 to 3 R ^y groups) or a pharmaceutically acceptable salt or solvent thereof Offer Japanese products.

For a conjugate of Formula II, in one particular embodiment, a C ₁ -C ₈ substituted alkyl, a C ₁ -C ₈ substituted alkenyl, a C ₁ -C ₈ substituted alkynyl, a C ₆ -C ₂₀ substituted aryl, and a C ₂ -C ₂₀ substituted heterocyclic are independently, F, Cl, Br, I , OH, -NH 2, -NH 3 +, -NHR, -NR 2, -NR 3 +, C 1 ~C 8 alkyl halides , carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl hydroxyl, _{C 1} -C _{8 alkylthio, -SO 2 R, -SO 2 Ar} , -SOAr, -SAr, -SO 2 NR 2, -SOR, -CO 2 R, -C (= O) NR 2, 5~7 -membered ring La Tam, 5-7 membered ring _{lactone, -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 Substituted with one or more substituents selected from C ₆ -C ₂₀ aryl, C ₂ -C ₂₀ heterocycle, polyethyleneoxy, phosphonate, phosphate, and prodrug moieties.

  For a conjugate of Formula II, in one particular embodiment, the “protecting group” is selected from carboxyl esters, carboxyamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonate esters, carbonates, and carbamates. .

For a conjugate of formula II, in one particular embodiment, W ⁵ is selected from the following structures:

.

For a conjugate of Formula II, in one particular embodiment, X is O and R ^y is H.

  In one particular embodiment, the conjugate of formula II has the following formula:

.

  In one particular embodiment, the conjugate of formula II has the following formula:

(Wherein in a more particular embodiment Z ¹ is OH; Z ² is CH ₃ ).

  In one particular embodiment, the conjugate of formula II has the following formula:

(Wherein, in a more particular embodiment, Z ² is C ₁ -C ₈ alkyl or C ₁ -C ₈ substituted alkyl).

  In one particular embodiment, the conjugate of formula II has the following formula:

.

  In one particular embodiment, the conjugate of formula II has the following formula:

.

  In one particular embodiment, the conjugate of formula II has the following formula:

.

  In one particular embodiment, the conjugate of formula II has the following formula:

.

  In one particular embodiment, the conjugate of formula II has the following formula:

.

  In one particular embodiment, the conjugate of formula II has the following formula:

.

  In one particular embodiment, the conjugate of formula II has the following formula:

Wherein R ² is H or C ₁ -C ₈ alkyl.
In one particular embodiment, the conjugate of formula II has the following formula:

.

  In one particular embodiment, the conjugate of formula II has the following formula:

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

  In one particular embodiment, the conjugate of formula II has the following formula:

(In a more particular embodiment, Y ^2c is O; Y ^2c is N (CH ₃ )).

  In one particular embodiment, the substituted triazole has the following structure:

.

  In one particular embodiment, the conjugate of formula II has the following formula:

Wherein 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, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine , 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substitution Triazole, And it is selected from pyrazolo [3,4-D] pyrimidine;
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 substituted Selected from 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 to} C ₈ alkyl, C ₁ to C ₈ alkyl halide, carboxyl Rate, sulfate, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl thiols, alkyl sulfones (—SO ₂ R), aryl sulfones (—SO ₂ Ar), aryl sulfoxides (—SOAr), arylthio (—SAr), sulfonamides (—SO ₂ NR ₂ ), alkyl sulfoxides (—SOR) ), Ester (—C (═O) OR), amide (—C (═O) NR ₂ ), 5-7 membered lactam, 5-7 membered lactone, nitrile (—CN), azide (—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, When it is a C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, protecting group (PG), or W ³ or taken together, R ^y forms a carbocycle of 3-7 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 heterocyclic or a protecting group;
When W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ , W ³ is W ⁴ or W ⁵ . Yes; W ⁵ is a carbocyclic or heterocyclic ring, and W ⁵ is independently substituted with 0-3 R ^y groups).

  In one particular embodiment, the conjugate of formula II has the following formula:

(Wherein PG is an ether-forming group, thioether-forming group, ester-forming group, thioester-forming group, silyl ether-forming group, amide-forming group, acetal-forming group, ketal-forming group, carbonate-forming group, carbamate-forming group, urea-forming group) Protecting groups selected from groups, amino acid conjugates, and polypeptide conjugates).

Conjugates of Formula III In one embodiment, the present invention provides compounds of Formula III:

Wherein 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, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine , 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substitution Triazole, And it is selected from pyrazolo [3,4-D] pyrimidine;
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, S—S, S (O) or S (O) 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 Alkyl halides, carboxylates DOO, sulfate, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl thiols, alkyl sulfones (—SO ₂ R), aryl sulfones (—SO ₂ Ar), aryl sulfoxides (—SOAr), arylthio (—SAr), sulfonamides (—SO ₂ NR ₂ ), alkyl sulfoxides (—SOR) ), Ester (—C (═O) OR), amide (—C (═O) NR ₂ ), 5-7 membered lactam, 5-7 membered lactone, nitrile (—CN), azide (—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 _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} heterocyclic, _{C 2} -C ₂₀ substituted heterocycle, polyethyleneoxy, a protecting group (PG), or a ^{W 3,} when taken together, ^{R y} form a carbocyclic ring having 3 to 7 carbon atoms;
R ^x is independently R ^y , a protecting group, or the formula:

Is;
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 heterocyclic or a protecting group;
When W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ , W ³ is W ⁴ or W ⁵ . Yes; W ⁵ is a carbocyclic or heterocyclic ring, and W ⁵ is independently substituted with 0 to 3 R ^y groups) or a pharmaceutically acceptable salt or solvent thereof Offer Japanese products.

For a conjugate of Formula II, in one particular embodiment, a C ₁ -C ₈ substituted alkyl, a C ₁ -C ₈ substituted alkenyl, a C ₁ -C ₈ substituted alkynyl, a C ₆ -C ₂₀ substituted aryl, and a C ₂ -C ₂₀ substituted heterocyclic are independently, F, Cl, Br, I , OH, -NH 2, -NH 3 +, -NHR, -NR 2, -NR 3 +, C 1 ~C 8 alkyl halides , carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl hydroxyl, _{C 1} -C _{8 alkylthio, -SO 2 R, -SO 2 Ar} , -SOAr, -SAr, -SO 2 NR 2, -SOR, -CO 2 R, -C (= O) NR 2, 5~7 -membered ring La Tam, 5-7 membered ring _{lactone, -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 Substituted with one or more substituents selected from C ₆ -C ₂₀ aryl, C ₂ -C ₂₀ heterocycle, polyethyleneoxy, phosphonate, phosphate, and prodrug moieties.

  For a conjugate of Formula II, in one particular embodiment, the “protecting group” is selected from carboxyl esters, carboxyamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonate esters, carbonates, and carbamates. .

In one particular embodiment, for the conjugate of formula III, W ⁵ is selected from the following structures:

.

In one particular embodiment, for the conjugate of formula III, X is O and each R ^y is H.

  In one particular embodiment, the conjugate of formula III is a resolved enantiomer having the formula:

.

  In one particular embodiment, the conjugate of formula III is a resolved enantiomer having the formula:

.

  In one particular embodiment, the conjugate of formula III has the following formula:

.

  In one particular embodiment, the conjugate of formula III has the following formula:

.

  In one particular embodiment, the conjugate of formula III has the following formula:

.

  In one particular embodiment, the conjugate of formula III has the following formula:

.

  In one particular embodiment, the conjugate of formula III has the following formula:

.

  In one particular embodiment, the conjugate of formula III has the following formula:

(Wherein R ² is H or C ₁ -C ₈ alkyl).

  In one particular embodiment, the conjugate of formula III has the following formula:

.

  In one particular embodiment, the conjugate of formula III has the following formula:

.

  (Wherein in a more particular embodiment Z is H and B is adenine).

  In one particular embodiment, the conjugate of formula III has the following formula:

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

  In one particular embodiment, the conjugate of formula III has the following formula:

.

^Wherein Y ^2c is O or N (CH ₃ ) in a more particular embodiment.

  In one particular embodiment, for a conjugate of formula III, the substituted triazole has the following formula:

.

  In one particular embodiment, the conjugate of formula III has the following formula:

Wherein 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, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine , 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substitution Triazole, And it is selected from pyrazolo [3,4-D] pyrimidine;
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, S—S, S (O) or S (O) 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 Alkyl halides, carboxylates DOO, sulfate, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl thiols, alkyl sulfones (—SO ₂ R), aryl sulfones (—SO ₂ Ar), aryl sulfoxides (—SOAr), arylthio (—SAr), sulfonamides (—SO ₂ NR ₂ ), alkyl sulfoxides (—SOR) ), Ester (—C (═O) OR), amide (—C (═O) NR ₂ ), 5-7 membered lactam, 5-7 membered lactone, nitrile (—CN), azide (—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 _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} heterocyclic, _{C 2} -C ₂₀ substituted heterocycle, polyethyleneoxy, a protecting group (PG), or a ^{W 3,} when taken together, ^{R y} form a carbocyclic ring having 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 heterocyclic or a protecting group;
PG is a protecting group selected from ether-forming groups, ester-forming groups, silyl ether-forming groups, amide-forming groups, acetal-forming groups, ketal-forming groups, carbonate-forming groups, carbamate-forming groups, amino acids, and polypeptides) .

Binding Groups and Linkers The present invention provides conjugates comprising an anti-cancer compound attached to one or more phosphonate groups directly (eg, covalently) or via a linking group (ie, linker). The nature of the linker is not critical as long as it does not interfere with the ability of the phosphate containing compound to function as a therapeutic agent. The compound (e.g., any synthesizeable moiety on the compound by removal of hydrogen or any part of the compound to obtain an open valence for the phosphonate group or linker bond to the phosphonate group or linker (e.g. Compounds of formula 500-601).

In one embodiment of the invention, the linking group or linker (which may be denoted as “L”) includes an A ⁰ group, an A ¹ group, an A ² group, or a W ³ group as described herein. All or part may be included.

  In another embodiment of the invention, the molecular weight of the linking group or linker is from about 20 daltons to about 400 daltons.

  In another embodiment of the invention the length of the linking group or linker is from about 5 to about 300 mm.

In another embodiment of the invention, the linking group or linker separates DRUG and P (= Y ¹ ) residues from about 5 to about 200 cm in length.

In another embodiment of the invention, the linking group or linker has one or more (eg, 1, 2, 3, or 4) carbon atoms optionally substituted with (—O—) and the chain is , Optionally on carbon, (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, azide, cyano, nitro, halo, hydroxy, oxo (═O), carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy A divalent branched or unbranched saturated or unsaturated hydrocarbon chain having from 2 to 25 carbon atoms, substituted with one or more (eg 1, 2, 3, or 4) substituents A.

In another embodiment of the invention, the linking group or linker is of the 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 (═O) —, —C (═O) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -N (R) -, - C (= O) -, or a direct bond; each R is independently, but H or _(C 1 -C ₆₎ alkyl).

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

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

  In another embodiment of the 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-L- A divalent radical formed from threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine, or poly-L-lysine-L-tyrosine .

In another embodiment of the invention, the linking group or linker has the formula: W— (CH ₂ ) _n , wherein n is between about 1 and about 10; W is —N (R) C (= O)-, -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. )belongs to.

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

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

Intracellular targeting The phosphonate groups of the compounds of the invention can be cleaved stepwise in vivo after they reach the desired site of action (ie, intracellular). One mechanism of action in the cell can yield a negatively charged “locked-in” intermediate, for example by initial cleavage by esterase. Thus, cleavage of the terminal ester group in the compounds of the invention results in an unstable intermediate that releases a negatively charged “fixed” intermediate.

  Following intracellular passage, cleaved or modified compounds can accumulate in the cell by a “trapping” mechanism by intracellular enzymes or modifications of the phosphate or prodrug compound. The cleaved or modified compound is then given to the cell by a change in charge, polarity, or other physical property that reduces the rate at which the cleaved or modified compound can exit the cell compared to the rate of penetration of the phosphate prodrug. Can be “fixed”. Other mechanisms that provide a therapeutic effect can be similarly operated. Enzymes that are capable of enzyme activation using the phosphate prodrug compounds of the present invention include, but are not limited to, amidase, esterase, microbial enzyme, phospholipase, chlorinesterase, and phosphatase.

  In selected examples where the drug is a nucleoside type such as zidovudine and many other antiretroviral drugs, it is known that the drug is activated by phosphorylation in vivo. This can be achieved in the system of the present invention by enzymatic conversion of the “fixed” intermediate to the active phosphonate diphosphate using phosphokinase and / or phosphorylation of the drug itself after its release from the above “fixed” intermediate. Such activation can occur. In either case, the original nucleoside drug is converted to an active phosphorylated species via a derivative of the invention.

  From the above it is clear that a number of different drugs can be derivatized by the present invention. A number of such drugs are noted herein. However, it should be understood that the discussion of the drug family and its specific members for derivatization of the present invention is not exhaustive and is merely exemplary.

Anticancer compounds The compounds of the present invention include compounds having anticancer activity. In particular, the compounds include anticancer compounds. The compounds of the present invention have one or more (eg, 1, 2, 3, or 4) phosphonate groups that can be glo-drug moieties.

  Typically, the molecular weight of the compounds of the invention is from about 400 amu to about 10,000 amu, and in certain embodiments of the invention the molecular weight of the compound is less than about 5000 amu, In a form, the molecular weight of the compound is less than about 2500 amu, in another specific embodiment of the invention, the molecular weight of the compound is less than about 1000 amu, and in another specific embodiment of the invention, the molecular weight of the compound is about In another specific embodiment of the invention, the molecular weight of the compound is less than about 600 amu, and in another specific embodiment of the invention, the molecular weight of the compound is less than about 600 amu, and about 400 amu. It is super.

  The log D (polarity) of the compounds of the present invention is also typically less than about 5. In one embodiment, the invention provides a compound with a log D of less than about 4, and in another one embodiment, the invention provides a compound with a log D of less than about 3, and another one embodiment. Thus, the present invention provides compounds with a logD greater than about −5, and in another embodiment, the present invention provides compounds with a logD greater than about −3, and in another embodiment, The present invention provides compounds having a log D of greater than about 0 and less than about 3.

  In one particular embodiment, the present invention is within the general definition of the term “anticancer compound”, but is a phosphonate group (eg, phosphodiester, phosphonamidate ester prodrug, or phosphondamidate). Esters) are further provided (Jiang et al., US 2002/0173490 A1).

Selected substituents within the compounds of the present invention are present in a recursive degree. In this context, “repeat substituent” means that the substituent can by itself enumerate another instance. Because of the repeatability of such substituents, in theory, a large number can be present in any given claim. For example, R ^x includes a R ^y substituent. R ^y may be R ² or R ³ . If R ³ is selected to be R ^3c , a second example of R ^x can be selected. Those skilled in the medicinal chemistry field understand that the total number of such substituents is reasonably limited by the desired properties of the intended compound. Examples of such properties include, but are not limited to, physical properties such as molecular weight, solubility, or logP, applicability such as activity against the intended target, and practicality such as ease of synthesis. Not.

By way of example, W ³ , R ^y , and R ³ are all repeating substituents in certain claims, but are not limited thereto. Typically, these are each independently 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6 in the given claims. Can occur 5, 4, 3, 2, 1, or 0 times. More typically, each of these can occur independently 12 times or less in a given claim. More typically, in a given claim, W ³ occurs 0 to 8 times, R ^y occurs 0 to 6 times, and R ³ occurs 0 to 10 times. Even more typically, in a range of a given claims, ^{W 3} occurs 0-6 times, ^{R y} will occur 0 to 4 times, ^{R 3} will occur 0 to 8 times.

  Repeating substituents are an intended aspect of the invention. Those skilled in the field of medicinal chemistry understand the versatility of such substituents. The total number is determined as described above to the extent that repeated substituents are present in the claims of this invention.

Whenever a compound described herein is substituted with more than one identical designated group (eg, “R ¹ ” or “R ^6a ”), the groups may be the same or different (ie, each The groups are independently selected). The wavy line indicates a covalent bond site to an adjacent group, moiety, or atom.

  The term “anticancer compound” includes not only the general disclosure cited above, but also all species contained therein. The phosphonate group can be a phosphonate prodrug moiety. Prodrug moieties may be sensitive to hydrolysis, such as, but not limited to, pivaloyloxymethyl (POC) or POM groups. Alternatively, the prodrug moiety may be sensitive to enzyme-enhanced cleavage such as lactate or phosphonamidate ester groups.

  The term `` anticancer compound '' includes gefitinib, imatinib, erlotinib, batalanib, fostearbin, camptosar, irinotecan, hicamtine, femara, letrozole, fadrozole, temozolomide, etopophos, anastrozole, arimidex, carboplatin, paraplatin, exemestane, exemestane , Epirubicin, adriamycin, taxotere, taxol, vinorelbine, osperifene, troglitazone, etoposide, everolimus, vincristine, sirolimus, raltitrexide (tomudex), aminopterin, arbocidib, bortezomib, VX-148, vinblastine, tipifine Ronafarib, Merimeposibu, Brekinar, Amsacrine CEP-701, decitabine, teniposide, midostaurine, MLN-518, PD-184352, emetrexide (ALIMTA), 10-propargyl-10-deaza-aminopterin (PDX), tasedinarine, thalidomide, TLK-286, pixanthrone, pentostatin, Enocitabine, clofarabin, BCX-1777, rubitecan, suberilohydroxamic acid, levimide, MS-275, dexamethasone, LAQ-824, fludarabine, pirarubicin, teriflunomide, servidin hydrochloride, idarubicin hydrochloride, exatecan, saldomozide, adriamycin, metopetulin, Tamoxifen citrate / toremifine citrate, raloxifene hydrochloride, mycophenolate, dexamethasone, methotrexe GLEEVEC, PNP-405, MDL-74428, 9- (3,3-dimethyl-5-phosphonopentyl) guanine, DADMe-IMMG, camptosar, idarubicin, leflunomide, BAY-43-9006, bicyclonucleobase compound Also included are 2-fluoro, 2 ', 3' didehydro, 4 'phosphonate nucleoside compounds, gemcitabine, cladribine, rofecoxib, ANA-245, and halobetasol propionate.

  In one embodiment of the invention, the compound is not a kinase inhibitor, IMPDH, PMP, antiviral agent, or autoimmune system enhancer. In another embodiment of this invention, the compound has 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 512 compound.

Cell accumulation In one embodiment, the present invention provides compounds that can accumulate in human PBMC (peripheral blood mononuclear cells). PBMC refers to hair balls having circular lymphocytes and monocytes. Physiologically, PBMC is an important component of infectious function. PBMCs are isolated from normal healthy donor heparinized whole blood or buffy coats by standard density gradient centrifugation and border recovery, washed (eg, phosphate buffered saline) and stored in cryogen can do. PBMC can be cultured in multiwell plates. After various culture times, the supernatant can be removed for evaluation or the cells can be harvested and analyzed (Smith R. et al (2003) Blood 102 (7): 2532-2540). The claimed compounds may further comprise a phosphonate or phosphonate prodrug. More typically, the phosphonate or phosphonate prodrug can have the structure A ³ as described herein.

  Typically, compounds of the present invention have improved intracellular half-life of compound compounds or intracellular metabolites in human PBMC when compared to phosphonates or analogs of compounds without phosphonate prodrugs. Show. Typically, the improvement is at least about 50%, more typically in the range of at least 50-100%, even more typically at least about 100%, more typically more than 100%.

  In one embodiment of the invention, the intracellular half-life of the metabolite of the compound in human PBMC is improved when compared to a phosphonate or an analog of the compound that does not contain a phosphonate prodrug. In such claims, metabolites can be produced intracellularly (eg, within human PBMC). The metabolite can be a cleavage product of a phosphonate prodrug in human PBMC. The phosphonate prodrug can be cleaved to form a metabolite with at least one negative charge at physiological pH. Phosphonate prodrugs can be enzymatically cleaved within human pH to form phosphonates having at least one active hydrogen of formula P-OH.

Stereoisomers The compounds of the present invention may have chiral centers (eg, chiral carbon or phosphorous atoms). Accordingly, the compounds of the present invention include racemic mixtures of all stereoisomers (including enantiomers, diastereomers, and atropisomers). Furthermore, the compounds of the present invention include optical isomers enriched or resolved with any or all asymmetric chiral atoms. In other words, the chiral centers apparent from the depictions are provided as chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures substantially free of their enantiomers or diastereomeric partners are within the scope of the invention, as are the individual optical isomers isolated or synthesized. For example, the racemic mixture can be separated into its individual substantially optically isolated by well-known techniques such as separation of diastereomeric salts formed with optically active additives (eg, acids or bases) and subsequent back conversion to optically active materials. To the pure isomer. In most cases, the desired optical isomer is synthesized by a stereospecific reaction starting from the appropriate stereoisomer of the desired starting material.

  The compounds of the invention may also exist as tautomers in certain cases. All such forms are intended to be within the scope of the present invention, although only one delocalized resonance structure can be shown. For example, purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole can exist as ene-amine tautomers, and all possible tautomeric forms thereof are of the present invention. Within range.

Salts and Hydrates Compositions of the present invention are optionally pharmaceutically acceptable, including salts of the compounds described herein, in particular, for example, Na +, Li +, K +, Ca + 2, and Mg + 2. Contains possible non-toxic salts. Such salts are derived by a combination of suitable cations such as alkali metal ions and alkaline earth metal ions or ammonium ions and quaternary amino ions with acid anion moieties (typically carboxylic acids). Salt may be included. When water-soluble salts are desired, monovalent salts are preferred.

  Typically, a metal salt is prepared by reaction of 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 +. A less soluble metal can be precipitated from a more soluble salt solution by the addition of a suitable metal compound.

  In addition, salts are formed from acid additions of certain organic and inorganic acids (eg, HCl, HBr, H 2 SO 4, H 3 PO 4) or organic sulfonic acids to basic centers (typically amines) or acidic groups. be able to. Ultimately, the compositions described herein are understood to include the compounds of the invention in combination with their non-ionized forms as well as zwitterionic forms and stoichiometric amounts of water as hydrates. .

  Also included within the scope of the invention are salts of the parent compound with one or more amino acids. Any of the above amino acids are suitable, particularly naturally occurring amino acids found as protein components, but the amino acids typically are basic or acidic groups (eg, glycine, serine, etc. , Threonine, alanine, isoleucine, or leucine).

Another embodiment of the present invention relates to a method for treating cancer. The compositions of the invention can treat cancer and can act as an intermediate for such treatment or other uses described below. The anticancer compound binds to a position on the surface of the cancer cell or in the cavity having a shape unique to the anticancer compound. Compositions that bind to anti-cancer compounds can bind in various reversible ways. Compounds that bind substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, compositions that bind substantially irreversibly are useful as cancer detection probes. Accordingly, the present invention provides a method for treating cancer comprising treating a sample suspected of containing cancer with a composition comprising a compound of the invention conjugated to a label and observing the effect of the sample on the activity of the label. The present invention relates to a method for detecting cancer in a sample suspected of containing. Suitable labels are well known in the diagnostic art and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups, and chromogens. The compounds described herein are labeled in a conventional manner using functional groups such as hydroxyl groups or amino groups.

  Within the context of the present invention, samples suspected of containing cancer include artificial materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid) , Tears, sputum, saliva, and tissue samples); experimental samples; food, water, or air samples; and byproduct samples such as cell extracts (especially recombinant cells that synthesize the desired glycoprotein) It is. Typically, the sample is suspected of containing cancer. The sample can be contained in any solvent, including water and organic solvent / water mixtures. Samples include living organisms such as humans and man-made materials such as cell cultures.

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

  If desired, the activity of the cancer after application of the composition can be observed by any method, including methods for direct or indirect detection of cancer activity. Quantitative, qualitative, and semi-quantitative methods for measuring cancer activity are all contemplated. Typically, one screening method described above is applied, but any other method is also applicable, such as observing the physiological properties of living organisms.

  Living organisms containing cancer include mammals such as humans. The compounds of the present invention are useful in the treatment or prevention of animal or human cancer.

  However, it should be noted that in screening for compounds that can treat cancer, enzyme assay results may not correlate with cell culture assays. Cell-based assays should therefore be primary screening tools.

Screening for anti-cancer compounds The compositions of the invention are screened for activity against cancer by any conventional enzyme activity assessment technique. Within the context of the present invention, compositions are typically screened for activity against cancer in vitro, and then compositions that show activity are screened for activity in vivo. Useful in vitro screens have been described in detail and are not detailed here. However, suitable in vitro assays are described in the Examples.

Pharmaceutical Formulations The compounds of the present invention are formulated using conventional carriers and excipients selected on a routine basis. Tablets contain excipients, glidants, fillers, binders and the like. When aqueous formulations are prepared in sterile form and are intended for delivery by other than oral administration, they are generally isotonic. All formulations optionally contain excipients such as those described in Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulation ranges from about 3 to about 11, but is usually about 7-10.

  While it is possible for the active ingredients to be administered alone, it is preferable to present them as pharmaceutical formulations. The formulations of the present invention for both animals and humans comprise at least one active ingredient together with one or more acceptable carriers and optionally other therapeutic ingredients. The carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient.

  Formulations include those suitable for the above route of administration. The formulation can be present in unit dosage form and can be prepared by any method known in the pharmaceutical arts. Techniques and formulations are generally found at Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which is comprised of one or more accessory ingredients. In general, the active ingredients are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

  Formulations of the present invention suitable for oral administration are individual units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; aqueous or non-aqueous liquid solutions or suspensions; or oil-in-water or It can be present as an irrigated emulsion. The active ingredient can also be administered as a bolus, electuary or paste.

  A tablet optionally comprising one or more accessory ingredients is made by compression or molding. By compression in a free-flowing form such as powders or granules containing the active ingredient optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant in a suitable machine Compressed tablets can be prepared. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored, optionally formulated to give sustained or controlled release of the active ingredient.

  For administration to the eye or other external tissue (e.g. oral cavity and skin), the formulation is for example 0.075-20% w / w (0.1% in units of 0.1% w / w) Between 20 and 20% (0.6% w / w, 0.7% w / w, etc.), preferably 0.2-15% w / w, most preferably 0.5-10% w It is preferably applied as a topical ointment or cream containing the active ingredient in an amount of / w. When used in ointments, the active ingredient can be used with either paraffinic or water-miscible ointment bases. Alternatively, the active ingredient can be formulated with an oil-in-water cream base.

  If desired, the aqueous phase of the cream may be, for example, at least 30% w / w polyhydric alcohol (ie, propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400)). And alcohols having two or more hydroxyl groups, as well as mixtures thereof. Topical formulations may desirably include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

  The oily phase of the emulsion of the present invention may be composed of known ingredients in a known manner. This phase may contain only an emulsifier (also known as an emulgent), but preferably contains at least one emulsifier and a fat or oil or a mixture of both fat and oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Preferably it contains both oil and fat. In summary, an emulsifier with or without a stabilizer makes a so-called emulsified wax, which creates a so-called emulsified ointment base that forms an oily dispersed phase of the cream formulation with oil and fat.

  Suitable emulsions and emulsion stabilizers for use in 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 selection of the appropriate oil or fat for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable firmness to avoid leakage from tubes or other containers. Straight chain such as diisoadipic acid, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP Chain or branched chain, monobasic, or dibasic alkyl esters can be used, the last three being the preferred esters. Depending on the properties required, these can be used alone or in combination. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are used.

  The pharmaceutical formulations of the present invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. A pharmaceutical formulation comprising the active ingredient may be in any form suitable for the intended method of administration. For oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can be used to obtain palatable preparations. One or more agents (including sweeteners, flavoring substances, colorants, and preservatives) can be included. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients that are suitable for tablet manufacture are acceptable. These excipients include, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulation such as corn starch or alginic acid Agents and disintegrants; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets can be uncoated or they can be coated by known techniques, including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby obtain a sustained release action over an extended period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or in combination with a wax can be used.

  Oral formulations include hard gelatin capsules in which the active ingredient is mixed with an inert diluent (eg, calcium phosphate or kaolin) or soft gelatin capsules in which the active ingredient is mixed with water or an oily solvent such as peanut oil, liquid paraffin, or olive oil. Can also exist.

  Aqueous suspensions of the present invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspensions such as sodium carboxycellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, dispersions such as naturally occurring phospholipids (eg, lecithin) Agent or wetting agent, condensation product of alkylene oxide and fatty acid (eg, polyoxyethylene stearate), condensation product of ethylene oxide and long chain aliphatic alcohol (eg, heptadecaethyleneoxysetanol), ethylene oxide and fatty acid and Condensation products (eg, polyoxyethylene sorbitan monooleate) with partial esters derived from anhydrous hexitol are included. The aqueous suspension is one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more colorants, one or more flavoring substances, and one such as sucrose or saccharin. Alternatively, multiple sweeteners can be included.

  Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions may contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. In order to obtain a palatable oral preparation, sweeteners and flavoring substances such as those mentioned above can be added. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

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

  The pharmaceutical composition of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a mixture of these. Suitable emulsifiers include naturally occurring gums such as acacia gum and tragacanth gum, naturally occurring phospholipids such as soy lecithin, fatty acids such as sorbitan monooleate and esters or partial esters derived from anhydrous hexitol, monooleic acid poly Condensation products of these partial esters such as oxyethylene sorbitan with ethylene oxide are included. The emulsion may also contain sweetening and flavoring substances. Syrups and elixirs can be formulated with sweetening agents, such as glycerol, sorbitol, or sucrose. Such formulations may also contain protective agents, preservatives, flavoring substances, or coloring agents.

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

  The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans is about 1 mg with an appropriate and convenient amount of carrier material that can vary from about 5% to about 95% (weight: weight) of the total composition. It may contain ˜1000 mg of active substance. The pharmaceutical composition can be prepared to provide an easily measurable dose. For example, an aqueous solution intended for intravenous infusion may contain from about 3 μg to 500 μg of active ingredient so that a suitable amount can be infused at a rate of about 30 mL / hour.

  Formulations suitable for administration to the eye include carriers suitable for the active ingredient, in particular eye drops wherein the active ingredient is dissolved or suspended in an aqueous solvent. The active ingredient is preferably present in such formulations at 0.5-20% w / w, advantageously 0.5-10% w / w, especially about 1.5% w / w.

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

  Rectal administration formulations may exist as suppositories with a suitable base comprising for example cocoa butter or a salicylate.

  The particle size of the formulation suitable for intrapulmonary or intranasal administration is, for example, 0.1 to 500 microns administered by rapid inhalation through the nasal passage or inhalation through the oral cavity to reach the alveolar sac. (Including range particle sizes between 0.1 and 500 microns in 1 micron increments (including 0.5, 1, 30, 35 microns, etc.). Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and delivered with other therapeutic agents such as conventional compounds used in the treatment or prevention of cancerous infections described below. it can.

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

  Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient. As well as aqueous and non-aqueous sterile suspensions which may contain suspending and thickening agents.

  The formulation should be stored in freeze-dried conditions that exist in single-dose or multi-dose containers (eg, sealed ampoules and vials) and require only the addition of a sterile liquid carrier just prior to use. Can do. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets as previously described. Preferred unit dosage formulations are those containing a daily dose or sub-dose of an active ingredient as described herein, or an appropriate fraction.

  In particular, in addition to the components described above, the formulations of the present invention may include other conventional agents that take into account the formulation type in question, eg, those suitable for oral administration may include flavoring substances. Should be understood.

  The invention further provides a veterinary formulation comprising at least one active ingredient as defined above together with a veterinary carrier.

  Animal carriers are materials useful for composition administration purposes, and can be solid, liquid, or gaseous materials that are inert or acceptable in the veterinary field and that are compatible with the active ingredients. These veterinary compositions can be administered orally, parenterally, or by any other desired route.

  The compounds of the invention can also be formulated to control release of the active ingredient to reduce the frequency of administration or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the present invention also provides compositions comprising one or more compounds of the present invention formulated for sustained or controlled release.

  The effective amount of the active ingredient depends at least on the nature of the therapeutic condition, toxicity, whether the compound is used against prophylactic (low dose) or active cancer infections, the delivery method, and the pharmaceutical formulation, traditionally Determined by a clinician using a dose escalation study. About 0.0001-100 mg / kg body weight / day can be expected. Typically about 0.01 to about 10 mg / kg body weight. More typically from about 0.01 to about 5 mg / kg body weight / day. More typically, about 0.05 to 0.5 mg / kg body weight / day. For example, a candidate daily dose for an adult human of about 70 kg ranges from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and can take the form of a single dose or multiple doses.

Route of administration One or more compounds of the invention (referred to herein as active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes are oral, rectal, intranasal, topical (including buccal and sublingual), vaginal, and parenteral (subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural Is included). It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.

Combination Therapy The active ingredients of the present invention are also used in combination with other active ingredients. Such combinations are selected based on therapeutic conditions, component cross-reactivity, and the pharmacological properties of the combination. For example, when treating cancer, the compositions of the invention can be combined with other chemotherapeutic agents. The second chemotherapeutic agent can be any suitable compound that has biological activity against one or more cancer types.

  It is also possible to combine any compound of the invention with one or more other active ingredients in a unit dosage form for simultaneous or sequential administration to a cancer patient. Combination therapy can be performed as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered by two or more administrations. The second and third active ingredients in the combination can have chemotherapeutic activity and include any additional chemotherapeutic agents described herein. Examples of active ingredients to be administered in combination with the compounds of the present invention are described below.

  Suitable additional chemotherapeutic agents include, for example, anthracyclines (eg, doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone); (b) other DNA interfering agents (eg, actinomycin C, D, B, etc.); Podophyllotoxin, and epipodophyllatoxin (etoposide, teniposide, cloposide); (c) alkylating agents (eg, mechloretamine, melphalan, cyclophosphamide, chlorambucil, ifosfamide, carmustine, lomustine, busulfan) , Dacarbazine, cisplatin, carboplatin, oxaliplatin, iproplatin, and tetraplatin); (d) hormonal drugs (eg, antiestrogens, estrogen antagonists (tamoxife And other SERMs); LHRH agonists and antagonists (leuprolide acetate, goserelin, abarelix); aromatase inhibitors; and antiandrogens; (e) chemopreventive drugs (eg, NSAIDs and cis-retinoids); and (f) cell cycle chemistry Contains prophylactic drugs.

  Alternatively, additional chemotherapeutic agents can include, for example, antineoplastic agents. Representative anti-neoplastic agents include, for example, adjuvants (eg, levamisole, gallium nitrate, granisetron, salgramostine, strontium chloride-89, filgrastim, pilocarpine, dexrazoxane, and ondansetron); androgen inhibitors (eg, Flutamide and leuprolide acetate); antibiotic derivatives (eg, doxorubicin, bleomycin sulfate, daunorubicin, dactinomycin, and idarubicin); antiestrogens (eg, tamoxifen citrate, analogs thereof, toremifene, droloxifene, and rofoxifene) Steroidal antiestrogens); antimetabolites (eg fludarabine phosphate, interferon α-2b recombinant, methotrexate sodium, piricamai Cytotoxic drugs (eg, doxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramtin sodium phosphate, altretamine, hydroxyurea, ifosfamide, procarbazine, Mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplati, cisplatin, cisplatin, interferon alpha-2a recombinant, paclitaxel, teniposide, and streptozocin); hormones (eg, medroxyprogesterone acetate, estradiol, megest acetate) Rolls, octreotide acetate, diethylstilbestrol diphosphate, test lactone, and goserelin acetate); Desuroikin); nitrogen mustard derivatives (e.g., melphalan, chlorambucil, mechlorethamine, and thiotepa), and steroids (betamethasone sodium and betamethasone acetate phosphoric acid).

  Suitable additional chemotherapeutic agents include, for example, alkylating agents, anti-mitotic agents, plant alkaloids, biologics, topoisomerase I inhibitors, topoisomerase II inhibitors, and synthetic substances.

  Representative alkylating agents include, for example, asaley, AZQ, BCNU, busulfan, bisulfan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cisplatin, chromozone, Morpholinodoxorubicin, cyclodison, cyclophosphamide, dianhydrogalactitol, fluorodopan, hepsulfam, hicanton, ifosfamide, melphalan, methyl CCNU, mitomycin C, mitozolamide master , PCNU, piperazine, piperazinedione, piperobro Emissions, porfiromycin machine, spirohydantoin mustard, streptozotocin, teroxirone, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogen mustard, and Yoshi-864, are included.

  Representative anti-mitotic drugs include, for example, arocolchicine, halichondrin B, colchicine, colchicine derivatives, dolastatin 10, maytansine, lysoxine, paclitaxel derivatives, paclitaxel, thiocolchicine, tritylcysteine, vinblastine sulfate, and vincristine sulfate. included.

  Exemplary plant alkaloids include, for example, actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, mitramycin, mitomycin, daunorubicin, VP-16-213, VM-26, navelbine, and taxotia. included.

  Exemplary biologics include, for example, alpha interferon, BCG, G-CSF, GM-CSF, and interleukin-2.

  Exemplary topoisomerase I inhibitors include, for example, camptothecin, camptothecin derivatives, and morpholinodoxorubicin.

  Representative topoisomerase II inhibitors include, for example, mitoxantrone, amonafide, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine, bisantrene hydrochloride, daunorubicin, deoxyxorubicin, menogalyl, N, N-dibenzyldaunomycin, oxanthrazole (Oxanthrazole), ruvidazone, VM-26, and VP-16.

  Representative synthetic materials include, for example, hydroxyurea, procarbazine, o, p′-DDD, dacarbazine, CCNU, BCNU, cis-diamine dichloroplatin, mitoxantrone, CBDCA, levamisole, hexamethylmelamine, all-trans retinoic acid , Gliadel, and porfimer sodium.

  Alternatively, additional chemotherapeutic agents can include tubulin binding agents and drugs that affect tubulin dynamics and function. This includes a variety of drugs that are chemically unrelated to vinca alkaloids and taxanes, such as CP-248 (exisulind derivatives) and ILX-651). These drugs have special effects on G2M phase cells and may have functionally independent effects on G1 and / or S phase cells.

  Alternatively, additional chemotherapeutic agents include selective apoptotic anticancer drugs (SAANDs) (including sulindac, aptosine, CP-461, CP-248) and one or more of the following cyclic GMP phosphodiesterases (cGMP PDEs) Related sulindac-inducing compounds that inhibit the isoenzyme (1, 2, 5) can be included.

  Alternatively, additional chemotherapeutic agents can include drugs that inhibit the proteosome (bortezomib or velcade). Proteosomes degrade a large number of ubiquitous proteins made for active destruction. The ubiquitous proteins include a number of important cell cycle regulatory molecules and molecules that regulate apoptosis at specific stages of the cell cycle. Although proteosomes can degrade proteins throughout the cell cycle, proteins that are degraded by the proteosomes include some of the most important cell cycle regulatory proteins. The so-called “cell cycle active relational” is applied to various categories of diseases (including cancers involved in disordered cell cycle and / or apoptosis, inflammatory diseases / autoimmune diseases, nervous system diseases) Can be provided for treatment.

  Alternatively, additional chemotherapeutic agents may include drugs that inhibit heat shock protein 90 (HSP90) (“chaperonins” involved in the degradation of “client proteins” in the ubiquitin-mediated proteosome pathway). Some drugs appear to exert their anti-tumor effects by inhibiting the intrinsic ATPase activity of HSP90 and degrade HSP90 “client protein” via the ubiquitin proteosome pathway. Examples include geldanamycin, 17-allylaminogeldanamycin, 17-demethoxygeldanamycin, and radicicol.

  Suitable cell cycle-dependent or schedule-dependent biological factors include cell cycle progression at the G1, G1 / S boundary, S, G2 / M boundary, or M phase of the cell cycle Drugs, proteins, or other molecules that block, delay, or interfere with. These drugs are cell cycle dependent or schedule dependent.

  Specifically, suitable cell cycle-dependent or schedule-dependent biological factors include the following.

  (1) Uridine nucleoside analogs, thymidine nucleoside analogs, and uridine and thymidine nucleoside analogs. These compounds act at the S phase of tumor cells, possibly angiogenic endothelial cells. These compounds include, for example, 5-fluorodeoxyuridine (furoxyuridine, FUDR); 5-fluorouracil (5-FU); 5-FU prodrugs (eg, capecitabine, 5′-deoxy-5-fluorouridine, ftoflaur , Flucytosine); bromodeoxyuridine; and iododeoxyuridine.

  (2) A modulator of fluoropyrimidine. These compounds act at the S phase of tumor cells, possibly angiogenic endothelial cells. These compounds include, for example, leuovorin, methotrexate, and other folates; levamisole; acivicin; phosphonacetyl-L-aspartate (PALA); brequinar; 5-ethynyluracil; and uracil .

  (3) Cytidine analogs and cytidine nucleoside analogs. These compounds act at the S phase of tumor cells, possibly angiogenic 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 of tumor cells, possibly angiogenic endothelial cells. These compounds include, for example, 6-thioguanine; 6-mercaptopurine; azathioprine; adenosine arabinoside (Ara-A); 2 ′, 2′-difluorodeoxyguanosine; deoxycorphomycin (pentostatin); cladribine ( 2-chlorodeoxyadenosine); and inhibitors of adenosine deaminase.

  (5) Antifolate drugs. These compounds act at the S phase of tumor cells, possibly angiogenic endothelial cells. These compounds include, for example, methotrexate; aminopterin; trimethotrexate; edatrexate; N10-propargyl-5,8-dideazafolate (CB3717); ZD1694, 5,8-dideazaisofolate (IAHQ); 5,10-dideaza Tetrahydrofolic acid (DDATHF); 5-deazafolic acid (an effective substrate for FPGS); PT523 (Nα- (4-amino-4-deoxypteroyl) -Nδ-hemiphthaloyl-L-ornithine); 10-ethyl-10-dea Zaminopterin (DDATHF, romatrexol); Pyrtrexime; 10-EDAM; ZD1694; GW1843; PDX (10-propargyl-10-deazaaminopterin); Multitargeting folate (ie, LY231514, pemetriexe) Do); any folate-based inhibitor of thymidylate synthase (TS); any folate-based inhibitor of dihydrofolate reductase (DHFR); any folate-based inhibitor of glycinamide ribonucleotide transferase (GARTF); Any inhibitor of polyglutamate synthetase (FPGS); and any folate-based inhibitor of GAR formyltransferase (AICAR transformylase) are included.

  (6) Other antimetabolite substances. These compounds act at the S phase of tumor cells, possibly angiogenic endothelial cells. These compounds include, for example, hydroxyurea and polyamines.

  (7) S phase specific radiotoxin (deoxythymidine analog). These compounds act in the S phase of all cells that synthesize DNA. This compound is integrated into the S phase chromosomal DNA. These compounds include, for example, [125I] -iododeoxyuridine; [123I] -iododeoxyuridine; [124I] -iododeoxyuridine; [80mBr] -iododeoxyuridine; [131I] -iododeoxyuridine; 211At] -Astatine-deoxyuridine.

  (8) Inhibitors of enzymes involved in deoxynucleoside / deoxynucleotide metabolites. These compounds act at the S phase of tumor cells, possibly angiogenic endothelial cells. These compounds include, for example, inhibitors of thymidylate synthetase (TS); inhibitors of dihydrofolate reductase (DHFR); inhibitors of glycinamide ribonucleotide transformylase (GARTF); inhibitors of folylpolyglutamate synthetase (FPGS); Inhibitors of GAR formyltransferase (AICAR transformylase); inhibitors of DNA polymerase (DNA Pol; eg, aphidocholine); inhibitors of ribonucleotide reductase (RNR); inhibitors of thymidine kinase (TK); and inhibitors of topoisomerase I enzyme (eg. , Camptothecin, Iritothecan (CPT-11, Camptosar), Topotecan, NX-211 (Lurto) Kang (lurtotecan)), such as rubitecan) are included.

  (9) DNA chain terminating nucleoside analog. These compounds in particular act on S phase cells and are integrated into chromosomal DNA in S phase. These compounds include, for example, acyclovir; abacavir; valacyclovir; zidovudine (AZT); didanosine (ddI, dideoxycytidine); sarcitabine (ddC); stavudine (D4T); lamivudine (3TC); any 2'3'-dideoxy Nucleoside analogs; and any 2'3'-dideoxy nucleoside analog that terminates DNA synthesis are included. These compounds include, for example, inhibitors of growth factor receptor tyrosine kinases that regulate progression through the G1, G1 / S borderline, or S phase of the cell cycle (eg, EGF receptor, HER-2 neu / c-erbB2 receptor, PDGF receptor, etc. (eg, trastuzumab, Iressa, Erbitux, Tarceva)); inhibitors of non-receptor tyrosine kinases (eg, c-src family of tyrosine kinases; (eg, Gleevec)) Inhibitors of serine-threonine kinases that regulate progression through the G1, G1 / S borderline or S phase of the cell cycle (eg, G1 cyclin dependent kinases, G1 / S cyclin dependent kinases, and S cyclin dependent) Kinase (eg, CDK2, CDK4, CDK5, CDK6) Mitogencassica kinase; MAP kinase signaling pathway); inhibitors of G1, G1 / S borderline or S phase cyclins (eg, cyclins D1, D2, D3, E, and A)); G1 phase of cell cycle, G1 Inhibitors of G protein and cGMP phosphodiesterase that positively regulate cell cycle progression at / S boundary phase or S phase; drugs that inhibit induction of early response transcription factors (eg, N-terminal c-jun kinase, c-myc And drugs that inhibit proteosomes that degrade “negative” cell cycle regulatory molecules (eg, p53, p27 / Kip1; (eg, bortezomib)).

  (10) Cytokines, growth factors, anti-angiogenic factors, and other proteins that inhibit cell cycle progression at the G1 phase or G1 / S boundary phase of the cell cycle. These compounds act at the G1, G1 / S, or S phase of the cell cycle in tumor cells, and in some cases, angiogenic endothelial cells. These compounds include, for example, interferons; interleukins; somatostatin, and somatostatin analogs (octreotide, sanostatin LAR); and a number of antivascular vessels that inhibit cell proliferation of endothelial cells in the G1 or G1 / S phase of the cell cycle. Protogenic factor.

  (11) Drugs and compounds that inhibit cell cycle progression at the G2 / M boundary phase or M phase of the cell cycle. These compounds act at the G2 / M boundary or M phase of the cell cycle in tumor cells, in some cases angiogenic endothelial cells. These compounds include, for example: (a) microtubule targeting agents—taxanes (eg, taxol, taxotere, epothilone, and other taxanes and derivatives); (b) microtubule targeting agents—vinca alkaloids (eg, vinblastine, vincristine). (Vin), vindesine; vinflunine, vinorelbine, vinzolidine, nocadazole, and colchicine); (c) microtubule targeting agents—others (eg, estramustine, CP-248, and CP-461); (d) G2 / M in the cell cycle Inhibitors of serine-threonine kinases (eg, inhibitors of G2 / M cyclin dependent kinases (eg, CDC2)) that modulate progression through the borderline or M phase; inhibitors of M phase cyclins (eg, cyclin B) And blocking cell cycle progression at G2 / M boundary or M phase of the cell cycle include delayed or interfere with any of the drug.

  (12) Radiopharmaceuticals useful in radiotherapy and / or diagnosis. A suitable radioisotope class decays by a nuclear decay process known as the “Auger process” or “Auger cascade”. Auger electron emitting isotopes generate short acting electrons that effectively cleave double stranded DNA. Suitable Auger electron emitting radionuclides include, for example, 125-iodine, 123-iodine, and 80m-bromine. Suitable corresponding halogenated pyrimidines and purine nucleosides include, for example, 5-125 iodo-2'-deoxyuridine, 5-123 iodo-2'-deoxyuridine, 5-80mbromo-2'-deoxyuridine, and 8 -80m bromo-2'-guanidine is included.

Growth factors Many growth factors and cytokines have the ability to interfere with malignant cells at specific points in the cell cycle. For example, G-CSF or GM-CSF can stimulate leukemic blasts of acute myeloid leukemia and interfere with the G1 / S boundary phase. This increases the sensitivity of the cells to cell cycle specific drugs such as cytarabine. Similar strategies using EGF and cytotoxic drugs have been tested for solid tumors. In order to respond to growth factors, the cell must be at a specific stage of the cell cycle (eg, the G1 / S boundary phase). Since only a subset of blasts are in the G1 / S phase at a given time, the continuous presence of growth factors may be advantageous. 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 thrombocytopenia.

  Thus, peptide / protein growth factors can be used in the present invention to promote the survival of normal non-malignant cell lines. One advantage of 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 within this category include, for example, hematopoietic growth factors: G-CSF, GM-CSF, erythropoietin, thrombopoietin, and biologically active derivatives of these peptides; mucositis keratinocyte growth Factor (KGF); B lymphocyte stimulating peptide (BLys); platelet derived growth factor (PDGF), epidermal growth factor (EGF), TGF-α and related growth factors; interleukins (eg, IL-2, IL-6) Other cytokines, growth factors, and peptides that stimulate the proliferation of non-malignant cells necessary for protection.

Therapeutic growth factors / cytokines Some therapeutic growth factors / cytokines can inhibit cell proliferation of cancer cells and / or angiogenic cells at specific stages of the cell cycle. For example, interferon, somatostatin, octreotide and its analogs, thrombospondin, and troponin I inhibit angiogenic endothelial cell proliferation by reducing the rate at which cells enter S phase. Thus, any one or more of these materials can be used in the present invention.

  Combination therapy can provide a “synergy” and “synergistic effect” (ie, an effect that is higher than the sum of the effects of individual use of the compound when used with an active ingredient). When the active ingredients are (1) co-delivered in a co-formulation and administration or combination formulation, (2) delivered alternately or in parallel in separate formulations, or (3) some other dosing regimen You can get a cooperative effect. When delivered in alternation therapy, a synergistic effect can be obtained when the compound is administered or delivered sequentially, for example by different injections in individual tablets, pills, or capsules or individual syringes. In general, during alternation therapy, each active ingredient in an effective dosage is administered sequentially (ie, continuously), whereas in combination therapy, two or more active ingredients in an effective dosage are administered together To do.

Metabolites of the compounds of the invention In vivo metabolites of the compounds described herein are also within the scope of the invention. Such products can result from, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, both by enzymatic processes. Accordingly, the present invention includes compounds produced by a process comprising contacting a compound of the present invention with a mammal for a time sufficient to obtain its metabolite. Such products are typically prepared by preparing a radiolabeled (eg, C ¹⁴ or H ³ ) compound of the invention, detectable doses (eg, about approximately 1) to a rat, mouse, guinea pig, monkey, or human. Parenteral administration (greater than 0.5 mg / kg), metabolism in sufficient time (typically about 30 seconds to 30 hours), and its conversion products from urine, blood, or other biological samples Identify by isolation. Since these products are labeled, they are easily isolated (isolating others by the use of antibodies capable of binding epitopes that survive in the metabolite). The structure of the metabolite is determined in a conventional manner, for example by MS or NMR analysis. In general, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. The conversion products are useful in diagnostic assays for therapeutic administration of the compounds of the invention, unless they are found in other forms in vivo, even if they do not exhibit anticancer activity.

  Recipes and methods for determining the stability of compounds in gastrointestinal secretions are known. A compound is defined herein as stable in the gastrointestinal tract when less than about 50 mol% of the protecting group is deprotected in surrogate intestinal fluid or gastric fluid upon 1 hour incubation at 37 ° C. This is simply because the compounds are stable to the gastrointestinal tract and does not mean that they cannot be hydrolyzed in vivo. The phosphonate prodrugs of the present invention are typically stable in the lumen of the gastrointestinal tract, but are substantially hydrolyzed to the parent drug in the lumen of the gastrointestinal tract, liver, or other metabolic organs, or generally cells. Disassembled.

  In one embodiment of the invention, the compound is in isolated and purified form. In general, the term “isolation and purification” means that the compound is substantially free of biological material. In one particular embodiment of the invention, the term means that the compound or conjugate of the invention does not contain at least about 50% by weight biological material, and in another particular embodiment of the invention, this The term means that the compound or conjugate of the invention is free of at least about 75% biological material, and in another specific embodiment, the term is at least about 90% by weight of the compound or conjugate of the invention. In another specific embodiment, the term means that the compound or conjugate of the invention does not contain at least about 98% by weight of the biological material, It means that the compound or conjugate of the invention is free of at least about 99% by weight of biological material. In another specific embodiment, the present invention provides a compound or conjugate of the present invention prepared synthetically (eg, ex vivo).

Exemplary Methods for Making the Compounds of the Invention The invention also relates to methods for making the compositions of the invention. The composition is prepared by any applicable organic synthesis technique. Many such techniques are well known in the art. However, a number of known techniques are described in Compendium of Organic Synthetic Methods (John Wiley & Sons, New 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.B. Smith; and March, J. et al. , Advanced Organic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985), Comprehensive Organic Synthesis. Selectivity, Strategie & Efficiency in Modern Organic Chemistry. In 9 Volumes, Barry M. et al. See, Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing).

  A number of exemplary methods for preparing the preparations of the present invention are shown below. These methods are intended to illustrate the lipids of such preparations and are not intended to limit the applicable methods.

  In general, reaction conditions such as temperature, reaction time, solvents, and operating procedures are common in the art for the particular reaction to be performed. The cited reference material, along with the cited material, contains a detailed description of such conditions. Typically, the temperature is -100 ° C to 200 ° C, the solvent is aprotic or protic, and the reaction time is 10 seconds to 10 days. The operation typically consists of quenching any unreacted reagents and subsequent partitioning (extraction) between the aqueous / organic phase system and separation of the phase containing the product.

  The redox reaction is typically performed at a temperature close to room temperature (about 20 ° C.), but for metal hydride reactions, the temperature is reduced to 0 ° C. to −100 ° C. and the solvent is typically The reduction reaction is aprotic, and the oxidation reaction may be either protic or aprotic. The reaction time is adjusted to achieve the desired conversion.

  The condensation reaction is typically conducted near room temperature, but an unbalanced kinetically controlled condensation reduction temperature (0 ° C. to −100 ° C.) is also common. The solvent can be either protic (common in equilibrium reactions) or aprotic (common in kinetically controlled reactions).

  Standard synthetic techniques such as azeotropic removal of reaction byproducts and the use of anhydrous reaction conditions (eg, inert gas environments) are common in the art and apply where appropriate.

Schemes and Examples General aspects of these exemplary methods are described below and in the Examples. Each product of the following process is optionally separated, isolated, and / or purified prior to use in subsequent processes.

  In general, reaction conditions such as temperature, reaction time, solvents, and operating procedures are common in the art for the particular reaction to be performed. The cited reference material, along with the cited material, contains a detailed description of such conditions. Typically, the temperature is -100 ° C to 200 ° C, the solvent is aprotic or protic, and the reaction time is 10 seconds to 10 days. The operation typically consists of quenching any unreacted reagents and subsequent partitioning (extraction) between the aqueous / organic phase system and separation of the phase containing the product.

  The redox reaction is typically performed at a temperature close to room temperature (about 20 ° C.), but for metal hydride reactions, the temperature is reduced to 0 ° C. to −100 ° C. and the solvent is typically The reduction reaction is aprotic, and the oxidation reaction may be either protic or aprotic. The reaction time is adjusted to achieve the desired conversion.

  The condensation reaction is typically conducted near room temperature, but an unbalanced kinetically controlled condensation reduction temperature (0 ° C. to −100 ° C.) is also common. The solvent can be either protic (common in equilibrium reactions) or aprotic (common in kinetically controlled reactions).

  Standard synthetic techniques such as azeotropic removal of reaction byproducts and the use of anhydrous reaction conditions (eg, inert gas environments) are common in the art and apply where appropriate.

  The terms “treated”, “treating”, “treatment” and the like, when used in combination with a chemical synthesis operation, contact, mixing, reacting, making it responsive, contact And other terms common in the art that indicate that the treatment is such as converting one or more chemicals to one or more other chemicals. This means that “treatment of compound 1 with compound 2” is synonymous with “treating compound 1 with compound 2”, “contact of compound 1 with compound 2”, “reaction of compound 1 with compound 2”. And other expressions common in the field of organic synthesis reasonably indicate that Compound 1 is “treated”, “reacted”, “reacted”, etc. with Compound 2. For example, treatment shows a reasonable and useful manner in which organic compounds are reacted. Unless otherwise indicated, standard concentrations (0.01 M to 10 M, typically 0.1 M to 1 M), temperatures (−100 ° C. to 250 ° C., typically −78 ° C. to 150 ° C., more typically Is −78 ° C. to 100 ° C., even more typically 0 ° C. to 100 ° C.), reaction vessel (typically made of glass, plastic, metal), solvent, pressure, atmosphere (typically For reactions that are not sensitive to oxygen and water, air or oxygen or nitrogen or argon for reactions sensitive to water or the like. Similar reaction knowledge known in the field of organic synthesis is used to select conditions and equipment for “treatment” in a given process. In particular, one skilled in the art of organic synthesis selects conditions and equipment that are reasonably expected to successfully carry out the chemical reactions of the described processes based on knowledge in the art.

  Modifications of each exemplary scheme (hereinafter “exemplary scheme”) and examples produce various analogs of particular exemplary materials. The above cited references describing suitable organic synthesis methods are applicable to such modifications.

  In each exemplary scheme, it may be advantageous to separate reaction products from each other and / or starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter “separated”) to the desired homogeneity by techniques common in the art. Typically such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography includes, for example, numerous methods (eg, reverse and normal phase chromatography; size exclusion chromatography; ion exchange chromatography; high speed, medium speed, and low speed liquid chromatography methods and equipment; small scale analytical chromatography; simulated moving bed (SMB) Chromatography, and preparative thin layer or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques).

  Another class of separation methods involves the treatment of the mixture with the reactants with reagents, unreacted starting materials, or products selected to allow binding or separation to the desired product. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, or ion exchange media. Alternatively, the reagent can be an acid in the case of a basic substance, a base in the case of an acidic substance, a reagent such as an antibody, a binding protein, a selective chelator such as a crown ether, or a liquid / liquid ion extraction reagent (LIX). .

  The selection of an appropriate separation method depends on the nature of the materials involved. For example, boiling point and molecular weight in distillation and azeotropy, presence or absence of polar functional groups in chromatography, and stability of acidic and basic media in multiphase extraction. One skilled in the art will apply techniques most likely to achieve the desired separation.

  Resolution of racemic mixtures using methods such as the formation of diastereomers using a single stereoisomer (eg, an enantiomer substantially free of the stereoisomer) using an optically active resolving agent (Stereochemistry of Carbon Compounds, (1962) by EL Liel, McGraw Hill; Lochmuller, CH, (1975) J. Chromatgr., 113: (3) 283-302). Racemic mixtures of the chimeric compounds of the present invention can be prepared by any suitable method ((1) formation of ionic diastereomeric salts with the chimeric compounds and separation by fractional crystallization or other methods, (2) with chiral derivatization reagents. Separated by formation of diastereomeric compounds, separation of diastereomers, and conversion to pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers under chiral conditions) And can be isolated.

  According to method (1), diastereomeric salts can be obtained from enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and α-methyl-β-phenylethylamine (amphetamine) and carboxylic acids and sulfonic acids, etc. It can be formed by reaction with an asymmetric compound that exhibits acidic functionality. Diastereomeric salts can be derived for separation by fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds, diastereomeric salts can be formed by the addition of chiral carboxylic or sulfonic acids (such as camphorsulfonic acid), tartaric acid, mandelic acid, or lactic acid.

  Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of the chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p.322). Diastereomeric compounds can be formed by reaction of asymmetric compounds with enantiomerically pure chiral derivatizing reagents such as menthyl derivatives, followed by enantiomer enrichment by separation and hydrolysis of diastereomers The formed free xanthene is obtained. Determination of optical purity can be accomplished by chiral esters (such as menthyl esters of racemic mixtures (such as menthyl (-) chloroformate in the presence of a base) or Mosher esters (α-methoxy-α (trifluoromethyl) phenyl acetate)). Jacob III. (1982) J. Org. Chem. 47: 4165) and analyzing the NMR spectrum for the presence of diastereomers of the two atropisomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal and reverse phase chromatography and subsequent methods of separation of the atropisomer naphthylisoquinoline (Hoye, T., WO 96/15111). According to method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) WJ Lough, Ed. Chapman and Hall, New York. Okamoto, (1990) J. of Chromatogr. 513: 375-378). Enriched or purified enantiomers can be distinguished by the methods used to distinguish other chiral molecules with asymmetric carbon atoms (such as optical rotation and circular dichroism).

(Example General section)
Numerous exemplary methods for preparing the compounds of the invention are provided herein (eg, in the Examples below). These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of applicable methods. Certain compounds of the present invention can be used as intermediates for the preparation of multiple compounds of the present invention. For example, the interchange of various phosphonate compounds of the present invention is illustrated below.

(Interconversion of phosphonate R-link-P (O) (OR ¹ ) ₂ , R-link-P (O) (OR ¹ ) (OH) and R-link-P (O) (OH) ₂ )
Schemes 32-38 below depict the preparation of phosphonate esters of the general structure R-link-P (O) (OR ¹ ) _2, where the R ¹ groups can be the same or different. The R ¹ group attached to the phosphonate ester or precursor thereof can be altered using established chemical transformations. The phosphonate interconversion reaction is illustrated in Scheme S32. The R group of Scheme 32 represents the substructure (ie, the drug “scaffold”) in any of the compounds of the invention or their precursors, where the substituent Link—P (O) (OR ¹ ₂ is bonded. During synthetic pathways that effect phosphonate interconversion, certain functional groups within R can be protected. The method used for a given phosphonate transformation depends on the nature of the substituent R ^{1 and} the nature of the substrate to which the phosphonate group is attached. The preparation and hydrolysis of phosphonate esters is described in Organic Phosphorus Compounds, G. et al. M.M. Kosolapoff, L.M. Maair, eds, Wiley, 1976, p. It is described in 9ff.

  In general, the synthesis of phosphonate esters is accomplished by coupling a nucleophilic amine or alcohol with the corresponding activated phosphonate electrophilic precursor, for example, chlorophosphonate addition of a nucleoside to the 5′-hydroxy It is a well-known method for preparing nucleoside phosphonic acid monoesters. This activated precursor can be prepared by several well-known methods. Chlorophosphonates useful for synthesizing these prodrugs are prepared from substituted 1,3-propanediol (Wissner et al. (1992) J. Med Chem. 35: 1650). Chlorophosphonates are prepared by oxidation of the corresponding chlorophosphorane (Anderson et al. (1984) J. Org. Chem. 49: 1304), which is obtained by reaction of a substituent diol with phosphorus trichloride. . Alternatively, the chlorophosphonate reagent is prepared by treating a substituted 1,3-diol with phosphorous oxychloride (Patois et al. (1990) J. Chem. Soc. Perkin Trans. 1, 1577). Chlorophosphonate species can also be generated in situ from the corresponding cyclic phosphites, which in turn can be prepared from either chlorophosphorane or phosphoramidate intermediates (Silverburg, et al. (1996) Tetrahedron. lett., 37: 771-774). Phosphorfluoridate intermediates prepared from either pyrophosphate or phosphoric acid can also act as precursors in the preparation of cyclic prodrugs (Watanabe et al. (1988) Tetrahedron lett., 29: 5763-66). .

  The phosphonate prodrugs of the present invention can also be prepared from its free acid by the Mitsunobu reaction (Mitsunobu, (1981) Synthesis, 1; Campbell, (1992) J. Org. Chem., 57: 6331), and others These include carbodiimides (Alexander et al., (1994) 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 benzotriazolyloxytris- (dimethylamino) phosphonium salt (Campagne et al., (1993) Tetrah. dron Lett, 34:. 6743) include, but are not limited to.

Aryl halides undergo Ni ⁺² catalyzed reaction with phosphite derivatives to give arylphosphonate-containing compounds (Balthazar et al. (1980) J. Org. Chem. 45: 5425). Phosphonates can also be prepared from this chlorophosphonate using aromatic triflates in the presence of a palladium catalyst (Petrakis et al., (1987) J. Am. Chem. Soc. 109: 2831; Lu et al., ( 1987) Synthesis, 726). In other methods, phosphonic acid aryl esters are prepared from aryl phosphates under anionic rearrangement conditions (Melvin (1981) Tetrahedron Lett. 22: 3375; Casteel et al. (1991) Synthesis, 691). N-alkoxyaryl salts with alkali metal derivatives of cyclic alkyl phosphonates provide a general synthesis of heteroaryl-2-phosphonate linkers (Redmore (1970) J. Org. Chem. 35: 4114). The above method can also be extended to compounds whose W ⁵ group is a heterocycle. Cyclic-1,3-propanyl prodrugs of phosphonates can also be prepared using a coupling reagent (eg, 1,3-dicyclohexylcarbodiimide (DCC)) in the presence of a base (eg, pyridine). Synthesized from acid and substituted propane-1,3-diol. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), another carbodiimide-based coupling reagent such as 1,3-diisopropylcarbodiimide or a water-soluble reagent, is also a cyclic phosphonate prodrug. Can be used for synthesis.

Conversion of the phosphonate diester S32.1 to the corresponding phosphonate monoester S32.2 (Scheme 32, Reaction 1) is accomplished by a number of methods. For example, ester S32.1 (where R ¹ is an aralkyl group (eg, benzyl)) is described in J. Org. Org. Chem. , 1995, 60: 2946, can be converted to the monoester compound S32.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine. This reaction is carried out at about 110 ° C. in an inert hydrocarbon solvent (eg, toluene or xylene). Conversion of the diester S32.1 (where R ¹ is an aryl group (eg, phenyl) or an alkenyl group (eg, allyl)) to the monoester S32.2 may result in the ester S32.1 being a base (eg, This is accomplished by treatment with aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran. The phosphonate diester S32.1, where one of the R ¹ groups is aralkyl (eg benzyl) and the other is alkyl is converted to the monoester by hydrogenation using, for example, palladium over a carbon catalyst. Can be converted to S32.2, where R ¹ is alkyl. Phosphonate diesters in which both R ₁ groups are alkenyl (eg allyl) are described, for example, in J.C. Org. Chem. , 38: 3224 1973, using chlorotris (triphenylphosphine) rhodium (Wilkinson catalyst), optionally in the presence of diazabicyclooctane in refluxing aqueous ethanol. ) To give the monoester S32.2 where R ¹ is alkenyl.

Conversion of phosphonate diester S32.1 or phosphonate monoester S32.2 to the corresponding phosphonic acid S32.3 (Scheme 32, reactions 2 and 3) is described in J. Am. Chem. Soc. , Chem. Comm. 739, (1979) by reacting the diester or monoester with trimethylsilyl bromide. This reaction is carried out in an inert solvent (eg, dichloromethane), optionally in the presence of a silylating agent (eg, bis (trimethylsilyl) trifluoroacetamide) at room temperature. The phosphonate monoester S32.2 (where R ¹ is aralkyl (eg benzyl)) is hydrogenated with a palladium catalyst or treated with hydrogen chloride in an ether-containing solvent (eg dioxane). Can be converted to the corresponding phosphonic acid S32.3. Phosphonate monoester S32.2 (where R ¹ is alkenyl (eg allyl)) is described, for example, in Helv. Chim. Acta. , 68: 618, 1985, is converted to phosphonic acid S32.3 by reaction with a Wilkinson catalyst in an aqueous organic solvent (eg, 15% aqueous acetonitrile or aqueous ethanol). The Palladium catalyzed hydrogenolysis of the phosphonate ester S32.1 (where R ¹ is benzyl) is described in J. Am. Org. Chem. 24: 434, 1959. Platinum catalyzed hydrogenolysis of phosphonate ester S32.1 (where R ¹ is phenyl) is described in J. Am. Am. Chem. Soc. 78: 2336, 1956.

Conversion of phosphonate monoester S32.2 to phosphonate diester S32.1 (Scheme 32, Reaction 4) (wherein the newly introduced R ¹ group is alkyl, aralkyl, haloalkyl (eg chloroethyl) or aralkyl) Is achieved by a number of reactions in which the substrate S32.2 is reacted with the hydroxy compound R ¹ OH in the presence of a coupling agent. Typically, the second phosphonate ester group is different from the initially introduced phosphonate ester group, ie, R ² is introduced following R ¹ , where each of R ¹ and R ² is an alkyl , Aralkyl, haloalkyl (eg, chloroethyl) or aralkyl (Scheme 32, Reaction 4a), whereby S32.2 is converted to S32.1a. Suitable coupling agents include those used to prepare carboxylate esters, which include carbodiimides (eg, dicyclohexylcarbodiimide, in which case the reaction is preferably a basic organic Carried out in a solvent (eg pyridine)) or (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma) (in this case the reaction is carried out with a tertiary organic base (eg Carried out in a polar solvent (eg dimethylformamide) in the presence of diisopropylethylamine), or Aldrithiol-2 (Aldrich) (in this case the reaction is triarylphosphine (For example, tonophenylphosphine In the presence of emissions), a basic solvent (e.g., in pyridine) is performed) and the like. Alternatively, conversion of the phosphonate monoester S32.2 to the diester S32.1 is accomplished by using a Mitsunobu reaction as described above. The substrate is reacted with the hydroxy compound R ¹ OH in the presence of diethyl azodicarboxylate and a triarylphosphine (eg triphenylphosphine). Alternatively, the phosphonate monoester S32.2 can be converted to the phosphonate diester S32.1 where the R ¹ group introduced by reacting the monoester with the halide R ¹ Br is alkenyl or aralkyl, where And R ¹ is alkenyl or aralkyl. This alkylation reaction is carried out in a polar organic solvent (eg dimethylformamide or acetonitrile) in the presence of a base (eg cesium carbonate). Alternatively, the phosphonate monoester is converted to the phosphonate diester in a two step procedure. In the first step, the phosphonate monoester S32.2 is prepared from Organic Phosphorus Compounds, G.M. M.M. Kosolapoff, L.M. Maair, eds, Wiley, 1976, p. 17 can be converted to the chloro analog RP (O) (OR ¹ ) Cl by reaction with thionyl chloride or oxalyl chloride, etc., and the resulting product RP (O ) (OR ¹ ) Cl is then reacted with the hydroxy compound R ¹ OH in the presence of a base (eg triethylamine) to give the phosphonate diester S32.1.

Phosphonate R-Link-P (O) (OH) ₂ is a phosphonate diester R-Link-P (O) (OR ¹ ), except that only one molar proportion of component R ¹ OH or R ¹ Br is used. ₂ Converted to the phosphonate monoester RP (O) (OR ¹ ) (OH) (Scheme 32, Reaction 5) by the method described above to prepare S32.1. Dialkyl phosphonates can be prepared according to the following method: Quast et al. (1974) Synthesis 490; Stowell et al. (1990) Tetrahedron Lett. 3261; US 5663159.

Phosphonic acid R-link-P (O) (OH) ₂ S32.3 is coupled with a hydroxy compound R ¹ OH in the presence of a coupling agent (Aldrithiol-2 (Aldrich) and triphenylphosphine). Can be converted to phosphonate diester R-link-P (O) (OR ¹ ) ₂ S32.1 (Scheme 32, Reaction 6). This reaction is performed in a basic solvent (eg, pyridine). Alternatively, phosphonic acid S32.3 is converted to phosphonic acid ester S32.1 (where R ¹ is aryl) by coupling reaction in pyridine at about 70 ° C., for example using dicyclohexylcarbodiimide. Can be converted. Alternatively, phosphonic acid S32.3 can be converted to a phosphonic acid ester S32.1 (where R ¹ is alkenyl) by an alkylation reaction. This phosphonic acid is reacted with an alkenyl bromide R ¹ Br in a polar organic solvent (eg acetonitrile solution) at reflux temperature in the presence of a base (eg cesium carbonate) to give the phosphonic acid ester S32 .1 is obtained.

(Preparation of phosphonate carbamate)
The phosphonate ester may contain carbamate linkages. The preparation of carbamate is described in Comprehensive Organic Functional Group Transformations, A.M. R. Katritzky, ed. Pergamon, 1995, Vol. 6, p. 416ff and Organic Functional Group Preparations, by S. R. Sandler and W.M. Karo, Academic Press, 1986, p. It is described at 260ff. The carbamoyl group can be formed by reaction of a hydroxyl group according to methods known in the art, including the teachings of Ellis, US 2002/0103378 A1 and Hajima, US 6018049.

  Scheme 33 illustrates various methods for synthesizing this carbamate chain. As shown in Scheme 33, in a general reaction to generate carbamate, alcohol S33.1 is converted to activated derivative S33.2 as described herein, where Lv is Leaving groups (eg, halo, imidazolyl, benzotriazoyl, etc.). The activated derivative S33.2 is then reacted with amine S33.3 to give the carbamate product S33.4. Examples 1-7 of Scheme 33 depict how to perform this general reaction. Examples 8-10 illustrate an alternative reaction to prepare carbamate.

  Scheme 33, Example 1 illustrates the preparation of carbamate using a chloroform derivative of alcohol S33.5. In this procedure, alcohol S33.5 is obtained from Org. Syn. Coll. Vol. 3,167,1965, reacted with phosgene in an inert solvent (eg, toluene) at about 0 ° C., or Org. Syn. Coll. Vol. Reacted with an equivalent reagent (eg, trichloromethoxychloroformate) to give chloroformate S33.6, as described in US Pat. The latter compound is then reacted with an amine component S33.3 in the presence of an organic or inorganic base to give carbamate S33.7. For example, chloroformyl compound S33.6 is obtained from Org. Syn. Coll. Vol. 3,167,1965, reacted with amine S33.3 in a water miscible solvent (eg, tetrahydrofuran) in the presence of aqueous sodium hydroxide to give carbamate S33.7. It is done. Alternatively, this reaction is carried out in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine.

  Scheme 33, Example 2, depicts the reaction of the chloroformate compound S33.6 with imidazole to produce imidazolide S33.8. This imidazolide product is then reacted with amine S33.3 to give carbamate S33.7. The preparation of the imidazolide is carried out at 0 ° C. in an aprotic solvent (eg dichloromethane) and the preparation of the carbamate is described in J. Am. Med. Chem. 1989, 32, 357 in a similar solvent at room temperature, optionally in the presence of a base (eg, dimethylaminopyridine).

  Scheme 33, Example 3, depicts the reaction of chloroformate S33.6 with activated hydroxyl compound R ″ OH to give mixed carbonate S33.10. This reaction can be accomplished using an inert organic solvent (eg, , Ether or dichloromethane) in the presence of a base (eg, dicyclohexylamine or triethylamine). The hydroxyl component R ″ OH can be converted to compounds S33.19-S33.24 and similar compounds shown in Scheme 33. Selected from the group of For example, if component R ″ OH is hydroxybenzotriazole S33.19, N-hydroxysuccinimide S33.20 or pentachlorophenol S33.21, it is described in Can. J. Chem., 1982, 60, 976. As shown, the reaction of this chloroformate with a hydroxyl compound in the presence of dicyclohexylamine in an ether-containing solvent gives mixed carbonate S33.10. Component R ″ OH is pentafluorophenol S33. A similar reaction which is 22 or 2-hydroxypyridine S33.23 is described in Syn. , 1986, 303, and Chem. Ber. 118, 468, 1985, in an ether-containing solvent in the presence of triethylamine.

Scheme 33, Example 4, illustrates the preparation of carbamates using alkyloxycarbonylimidazole S33.8. In this procedure, alcohol S33.5 is reacted with an equimolar amount of carbonyldiimidazole S33.11 to prepare intermediate S33.8. This reaction is performed in an aprotic organic solvent (eg, dichloromethane or tetrahydrofuran). Acyloxyimidazole S33.8 is then reacted with an equimolar amount of amine R′NH ₂ to give carbamate S33.7. This reaction is described in Tet. Lett. , 42, 2001, 5227, in aprotic organic solvent (eg dichloromethane) to give carbamate S33.7.

Scheme 33, Example 5 illustrates the preparation of carbamate with the intermediate alkoxycarbonylbenzotriazole S33.13. In this procedure, alcohol ROH is reacted with an equimolar amount of benzotriazole carbonyl chloride S33.12 at room temperature to give alkoxycarbonyl product S33.13. This reaction is described in Synthesis. 1977, 704 in an organic solvent (eg benzene or toluene) in the presence of a tertiary organic amine (eg triethylamine). The product is then reacted with amine R′NH ₂ to give carbamate S33.7. This reaction is described in Synthesis. 1977, 704 in toluene or ethanol at room temperature to about 80 ° C.

Scheme 33, Example 6, illustrates the preparation of carbamate, where carbonate (R ″ O) ₂ CO S33.14 is reacted with alcohol S33.5 to yield the intermediate alkyloxycarbonyl S33.15. The latter reagent is then reacted with amine R′NH ₂ to give carbamate S33.7 The procedure by which reagent S33.15 is derived from hydroxybenzotriazole S33.19 is described in Synthesis, 1993, The procedure by which reagent S33.15 is derived from N-hydroxysuccinimide S33.20 is described in Tet.Lett., 1992, 2781; reagent S33.15 is 2-hydroxypyridine S33. The procedure derived from .23 is Tet.Lett., 1991, 4251. The procedure by which reagent S33.15 is derived from 4-nitrophenol S33.24 is described in Synthesis, 1993, 103. Between equimolar amounts of alcohol ROH and carbonate S33.14. The reaction is carried out at room temperature in an inert organic solvent.

Scheme 33, Example 7, illustrates the preparation of carbamate from alkoxycarbonyl azide S33.16. In this procedure, alkyl chloroformate S33.6 is reacted with an azide (eg, sodium azide) to give alkoxycarbonyl azide S33.16. The latter compound is then reacted with an equimolar amount of amine R′NH ₂ to give carbamate S33.7. This reaction is described, for example, in Synthesis. , 1982, 404 at room temperature in a polar aprotic solvent such as dimethyl sulfoxide.

  Scheme 33, Example 8 illustrates the preparation of carbamate by reaction between alcohol ROH and the chloroformyl derivative of amine S33.17. In this procedure (which is described in Synthetic Organic Chemistry, RB Wagner, HD Zoo, Wiley, 1953, p. 647), the reactants are reacted at room temperature with an aprotic solvent (eg, , Acetonitrile) in the presence of a base (eg triethylamine) to give carbamate S33.7.

  Scheme 33, Example 9, illustrates the preparation of carbamate by reaction between alcohol ROH and isocyanate S33.18. In this procedure (which is described in Synthetic Organic Chemistry, RB Wagner, HD Zoo, Wiley, 1953, p.645), the reactants are reacted at room temperature with an aprotic solvent (eg, , Ether or dichloromethane, etc.) to give carbamate S33.7.

Scheme 33, Example 10 illustrates the preparation of carbamate by reaction between alcohol ROH and amine R′NH ₂ . In this procedure (which is described in Chem. Lett. 1972, 373), the reaction is performed at room temperature in an aprotic organic solvent (eg, tetrahydrofuran) with a tertiary base (eg, triethylamine). And in the presence of selenium. Carbon monoxide is passed through the solution, and the reaction proceeds to obtain carbamate S33.7.

Preparation of carboalkoxy substituted phosphonate bisamidates, monoamidates, diesters and monoesters
Numerous methods for converting phosphonic acids to amidates and esters are available. In one group of methods, the phosphonic acid is converted to an isolated and activated intermediate (eg, phosphoryl chloride) or activated in situ for reaction with an amine or hydroxy compound, Either.

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

  Phosphonic acid is described in J. Am. Chem. Soc. , Chem. Comm. (1991) 312 or Nucleosides & Nucleotides (2000) 19: 1885, which is converted to the activated imidazolyl derivative by reaction with carbonyldiimidazole. Activated sulfonyloxy derivatives can be obtained by reacting phosphonic acid with trichloromethylsulfonyl chloride or by Tet. Lett. (1996) 7857 or Bioorg. Med. Chem. Lett. (1998) 8: 663, obtained by reaction with triisopropylbenzenesulfonyl chloride. The activated sulfonyloxy derivative is then reacted with an amine or hydroxy compound to give an amidate or ester.

  Alternatively, the phosphonic acid and amine or hydroxy reactant are combined in the presence of a diimide coupling agent. The preparation of phosphonate amidates and esters by coupling reactions in the presence of dicyclohexylcarbodiimide is described, for example, in J. Am. Chem. Soc. , Chem. Comm. (1991) 312 or Coll. Czech. Chem. Comm. (1987) 52: 2792. The use of ethyldimethylaminopropylcarbodiimide to activate and couple phosphonic acids is described in Tet. Lett. (2001) 42: 8841 or Nucleosides & Nucleotides (2000) 19: 1885.

  A number of additional coupling reagents have been described for the preparation of amidates and esters from phosphonic acids. These reagents include aldolthiol-2, and PYBOP and BOP (which are described in J. Org. Chem., 1995, 60, 5214 and J. Med. Chem. (1997) 40: 3842. ), Mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT) (which are described in J. Med. Chem. (1996) 39: 4958), diphenylphosphoryl azide (these J. Org. Chem. (1984) 49: 1158), 1- (2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT) ( This is described in Bioorg. Med. Chem. Lett. (1998) 8: 1013), Motris (dimethylamino) phosphonium hexafluorophosphate (BroP) (which is described in Tet. Lett., (1996) 37: 3997), 2-chloro-5,5-dimethyl-2-oxo-1, 3,2-dioxaphosphinan (which is described in Nucleosides Nucleotides 1995, 14, 871), and diphenyl chlorophosphate (which is described in J. Med. Chem., 1988, 31, 1305). Is).

  Phosphonic acid is converted to amidate and ester by Mitsunobu reaction, where the phosphonic acid and amine or hydroxy reactant are combined in the presence of triarylphosphine and dialkyl azodicarboxylate. The procedure is described in Org. Lett. , 2001, 3, 643, or J.A. Med. Chem. 1997, 40, 3842.

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

  Schemes 34-37 show phosphonate esters and phosphonic acids to carboalkoxy substituted phosphorobisamidates (Scheme 34), phosphoramidates (Scheme 35), phosphonate monoesters (Scheme 36) and phosphonate diesters (Scheme 37). The conversion is illustrated. Scheme 38 illustrates the synthesis of gemi-dialkylaminophosphonate reagents.

Scheme 34 illustrates various methods for converting phosphonate diester S34.1 to phosphorobisamidate S34.5. Diester S34.1 (prepared as described above) is hydrolyzed to either monoester S34.2 or phosphonic acid S34.6. The method used for these transformations is described above. Monoester S34.2 is converted to monoamidate S34.3 by reaction with aminoester S34.9, wherein R ² group is H or alkyl; R ^4b group is divalent alkylene A moiety (eg, CHCH ₃ , CHCH ₂ CH ₃ , CH (CH (CH ₃ ) ₂ ), CH (CH ₂ Ph), etc.), or a side chain group present in a natural or modified amino acid; and R ^5b The groups are C ₁ -C ₁₂ alkyl (eg methyl, ethyl, propyl, isopropyl or isobutyl); C ₆ -C ₂₀ aryl (eg phenyl or substituted phenyl); or C ₆ -C ₂₀ arylalkyl (eg benzyl Or benzhydryl). These reactants are optionally prepared in the presence of an activator (eg, hydroxybenzotriazole) in J. Am. Chem. Soc. (1957) 79: 3575, and mixed in the presence of a coupling agent (eg, carbodiimide (eg, dicyclohexylcarbodiimide)) to give the amidate product S34.3. This amidate formation reaction is also similar to BOP (which is described in J. Org. Chem. (1995) 60: 5214), Aldrithiol, PYBOP, and similar coupling agents used in the preparation of amides and esters. In the presence of Alternatively, reactants S34.2 and S34.9 are converted to monoamidate S34.3 by Mitsunobu reaction. Preparation of amidate by Mitsunobu reaction is described in J. Am. Med. Chem. (1995) 38: 2742. Equimolar amounts of these reactants are combined in an inert solvent (eg, tetrahydrofuran) in the presence of triarylphosphine and dialkylazodicarboxylate. The monoamidate ester S34.3 so obtained is then converted to amidate phosphonic acid S34.4. The conditions used for this hydrolysis reaction depend on the nature of the R ¹ group, as described above. The phosphonate amidate S34.4 is then reacted with the amino ester S34.9 as described above to give the bisamidate product S34.5, where the amino substituents are the same or different. Alternatively, phosphonic acid S34.6 can be treated simultaneously with two different aminoester reagents (ie, S34.9 with different R ² , R ^4b or R ^5b ). The resulting mixture of bisamidate products S34.5 may then be separable, for example by chromatography.

An example of this procedure is shown in Scheme 34, Example 1. In this procedure, dibenzyl phosphonate S34.14 Org. Chem. , 1995, 60, 2946, reacted with diazabicyclooctane (DABCO) in toluene at reflux to give monobenzyl phosphonate S34.15. The product is then reacted with equimolar amounts of ethyl alaninate S34.16 and dicyclohexylcarbodiimide in pyridine to give the amidate product S34.17. The benzyl group is then removed, for example, by hydrogenolysis over a palladium catalyst to give the monoacid product S34.18, which is Med. Chem. (1997) 40 (23): 3842 can be destabilized. This compound S34.18 was then Med. Chem. , 1995, 38, 2742 in a Mitsunobu reaction with ethyl leucine S34.19, triphenylphosphine and diethyl azodicarboxylate to give the bisamidate product S34.20.

  Using the above procedure, but using different aminoesters S34.9 instead of ethyl leucine S34.19 or ethyl alaninate S34.16, the corresponding product S34.5 is obtained.

  Alternatively, phosphonic acid S34.6 is converted to bisamidate S34.5 by using the above coupling reaction. This reaction is carried out in one stage (in this case the nitrogen-related substituents present in the product S34.5 are the same) or in two stages (in which case the nitrogen-related substituents can be different) The

  An example of this method is shown in Scheme 34, Example 2. In this procedure, phosphonic acid S34.6 is described, for example, in J. Org. Chem. Soc. , Chem. Comm. , 1991, 1063, is reacted with an excess of ethyl phenylalanate S34.21 and dicyclohexylcarbodiimide in a pyridine solution to give the bisamidate product S34.22.

  Using the above procedure, but using the different amino ester S34.9 instead of ethyl phenylalaninate, the corresponding product S34.5 is obtained.

  As a further alternative, phosphonic acid S34.6 is converted to a mono or bis-active derivative S34.7, where Lv is a leaving group (eg, chloro, imidazolyl, triisopropylbenzenesulfonyloxy, etc.). Conversion of phosphonic acid to chloride S34.7 (Lv = Cl) is described in Organic Phosphorus Compounds, G .; M.M. Kosolapoff, L.M. Maair, eds, Wiley, 1976, p. As described in 17, it is carried out by reaction with thionyl chloride or oxalyl chloride. Conversion of phosphonic acid to monoimidazolide S34.7 (Lv = imidazolyl) is described in J. Am. Med. Chem. , 2002, 45, 1284 and J.A. Chem. Soc. Chem. Comm. 1991, 312. Alternatively, the phosphonic acid is activated by reaction with triisopropylbenzenesulfonyl chloride as described in Nucleosides and Nucleotides, 2000, 10, 1885. The activated product is then reacted with amino ester S34.9 in the presence of a base to give bisamidate S34.5. This reaction can be performed in one step (in this case the nitrogen substituent present in the product S34.5 is the same) or in two steps via the intermediate S34.11 (in this case the nitrogen substituent is Can be different).

  Examples of these methods are shown in Scheme 34, Examples 3 and 5. In the procedure illustrated in Scheme 34, Example 3, the phosphonic acid S34.6 is prepared according to Zh. Obschei Khim. , 1958, 28, 1063 and reacted with 10 molar equivalents of thionyl chloride to give the dichloro compound S34.23. This product is then reacted with butyl selenate S34.24 in the presence of a base (eg triethylamine) in a polar aprotic solvent (eg acetonitrile) at reflux temperature to give the bisamidate product. S34.25 is obtained.

  Using the above procedure, but using a different amino ester S34.9 instead of butyl serinate S34.24, the corresponding product S34.5 is obtained.

  In the procedure illustrated in Scheme 34, Example 5, phosphonic acid S34.6 is prepared according to J. Am. Chem. Soc. Chem. Comm. , 1991, 312 and reacted with carbonyldiimidazole to give imidazolide S34.32. This product is then reacted with 1 molar equivalent of ethyl alaninate S34.33 in acetonitrile solution at room temperature to give the mono-substituted product S34.34. The latter compound is then reacted with carbonyldiimidazole to produce the activated intermediate S34.35, which is then reacted with ethyl N-methylalaninate S34.33a under the same conditions. Thus, the bisamidate product S34.36 is obtained.

  Using the above procedure, but using a different amino ester S34.9 instead of ethyl alaninate S34.33 or ethyl N-methylalaninate S34.33a, the corresponding product S34.5 is obtained.

The intermediate monoamidate S34.3 can also first convert the monoester S34.2 to the activated derivative S34.8 using the above procedure (where Lv is a leaving group (eg halo , Imidazolyl and the like)). Product S34.8 is then reacted with amino ester S34.9 in the presence of a base (eg, pyridine) to give intermediate monoamidate product S34.3. The latter compound is then converted to bisamidate S34.5 by removing its R ¹ group and coupling the product with amino ester S34.9 as described above.

  An example of this procedure, where the phosphonic acid is activated by conversion to the chloro derivative S34.26, is shown in Scheme 34, Example 4. In this procedure, phosphonic acid monobenzyl ester S34.15 was prepared according to Tet. Letters. , 1994, 35, 4097, reacted with thionyl chloride in dichloromethane to give phosphoryl chloride S34.26. This product is then reacted with 1 molar equivalent of ethyl 3-amino-2-methylpropionate S34.27 in acetonitrile solution at room temperature to give the monoamidate product S34.28. The latter compound is hydrogenated in ethyl acetate with 5% palladium on carbon catalyst to give the monoacid product S34.29. This product was subjected to the Mitsunobu coupling procedure with equimolar amounts of butyl alaninate S34.30, triphenylphosphine, diethylazodicarboxylate and triethylamine in tetrahydrofuran to give the bisamidate product S34.31. It is done.

  Using the above procedure, but replacing the ethyl 3-amino-2-methylpropionate S34.27 or butyl alaninate S34.30 with a different amino ester S34.9, the corresponding product S34.5 is can get.

The activated phosphonic acid derivative S34.7 is also converted to the bisamidate S34.5 via the diamino compound S34.10. Conversion of activated phosphonic acid derivatives (eg, phosphoryl chloride) to the corresponding amino analog S34.10 by reaction with ammonia is described in Organic Phosphorus Compounds, G .; M.M. Kosolapoff, L.M. It is described by Maair, Wiley, 1976. The bisamino compound S34.10 is then converted to the haloester in the presence of a base (eg 4,4-dimethylaminopyridine (DMAP) or potassium carbonate) in a polar solvent (eg dimethylformamide) at elevated temperature. Reaction with S34.12 (Hal = halogen, ie F, Cl, Br, I) gives bisamidate S34.5. Alternatively, S34.6 can be treated simultaneously with two different aminoester reagents (ie, S34.12 with different R ^4b or R ^5b ). The resulting mixture of bisamidate products S34.5 may then be separable, for example by chromatography.

  An example of this procedure is shown in Scheme 34, Example 6. In this method, dichlorophosphonate S34.23 is reacted with ammonia to give diamide S34.37. This reaction is carried out at reflux temperature in an aqueous solution, aqueous alcohol solution or alcohol solution. The resulting diamino compound is then reacted in a polar organic solvent (eg, N-methylpyrrolidinone) at about 150 ° C. in the presence of a base (eg, potassium carbonate), and optionally as a catalyst. Reaction with 2 molar equivalents of ethyl 2-bromo-3-methylbutyrate S34.38 in the presence of an amount of potassium iodide gives the bisamidate product S34.39.

  Using the above procedure, but using a different haloester S34.12 instead of ethyl 2-bromo-3-methylbutyrate S34.38, the corresponding product S34.5 is obtained.

  The procedure shown in Scheme 34 is also applicable to the preparation of bisamidates, where the aminoester moiety incorporates different functional groups. Scheme 34, Example 7 illustrates the preparation of bisamidates derived from tyrosine. In this procedure, monoimidazolide S34.32 is reacted with propyl tyrosine S34.40 as described in Example 5 to yield monoamidate S34.41. This product is reacted with carbonyldiimidazole to give imidazolide S34.42, which is reacted with an additional molar equivalent of propyl tyrosine to produce the bisamidate product S34.43.

  Using the above procedure, but using the different amino ester S34.9 instead of propyl tyrosine S34.40, the corresponding product S34.5 is obtained. The amino ester used in the two steps of the above procedure can be the same or different, so that bisamidates with the same or different amino substituents are prepared.

  Scheme 35 illustrates a method for preparing phosphonate monoamidate.

  In one procedure, the phosphonate monoester S34.1 is converted to the activated derivative S34.8 as described in Scheme 34. This compound is then reacted with the amino ester S34.9 in the presence of a base as described above to give the monoamidate product S35.10.

  This procedure is illustrated in Scheme 35, Example 1. In this method, monophenyl phosphonate S35.7 is described, for example, in J. Org. Gen. Chem. USSR. , 1983, 32, 367 and reacted with thionyl chloride to give the chloro product S35.8. This product is then reacted with ethyl alaninate S35.9 as described in Scheme 34 to yield amidate S35.1.

  Using the above procedure, but using the different amino ester S34.9 instead of ethyl alaninate S35.9, the corresponding product S35.1 is obtained.

Alternatively, phosphonate monoester S34.1 is coupled with aminoester S34.9 as described in Scheme 34 to give amidate S35.1. If necessary, the R ¹ substituent is then changed by initial cleavage to give the phosphonic acid S35.2. The procedure for this transformation depends on the nature of the R ¹ group and is described above. This phosphonic acid is then synthesized using the same coupling procedure described in Scheme 34 for the coupling of amine and phosphonic acid (carbodiimide, aldolthiol-2, PYBOP, Mitsunobu reaction, etc.) using the hydroxy compound R ³ OH ( Wherein the R ³ group is converted to the ester amidate product S35.3 by reaction with aryl, heterocycle, alkyl, cycloalkyl, haloalkyl, and the like.

Examples of this method are shown in Scheme 35, Examples 2 and 3. In the sequence shown in Example 2, monobenzyl phosphonate S35.11 is converted to monoamidate S35.12 by reaction with ethyl alaninate using one of the methods described above. The benzyl group is then removed by catalytic hydrogenation with 5% catalyst on carbon in ethyl acetate solution to give phosphonate amidate S35.13. The product is then obtained, for example, from Tet. Lett. , 2001, 42, 8841 and reacted with equimolar amounts of 1- (dimethylaminopropyl) -3-ethylcarbodiimide and trifluoroethanol S35.14 in dichloromethane solution at room temperature. The amidate ester S35.15.

  In the sequence shown in Scheme 35, Example 3, monoamidate S35.13 is coupled with equimolar amounts of dicyclohexylcarbodiimide and 4-hydroxy-N-methylpiperidine S35.16 in tetrahydrofuran solution at room temperature. To produce the amidate ester product S35.17.

The above procedure is used, but instead of the ethyl alaninate product S35.12, a different monoacid S35.2 is used and trifluoroethanol S35.14 or 4-hydroxy-N-methylpiperidine S35.16 is used. Instead, a different hydroxy compound R ³ OH is used to give the corresponding product S35.3.

Alternatively, activated phosphonate ester S34.8 is reacted with ammonia to yield amidate S35.4. This product is then reacted with the haloester S35.5 in the presence of a base as described in Scheme 34 to produce the amidate product S35.6. If appropriate, the nature of the R ¹ group is altered using the above procedure to give product S35.3. This method is illustrated in Scheme 35, Example 4. In this order, monophenyl phosphoryl chloride S35.18 is reacted with ammonia as described in Scheme 34 to give the amino product S35.19. This material is then reacted in N-methylpyrrolidinone solution at 170 ° C. with butyl 2-bromo-3-phenylpropionate S35.20 and potassium carbonate to give the amidate product S35.21.

  Using these procedures, but using a different haloester S35.5 instead of butyl 2-bromo-3-phenylpropionate S35.20, the corresponding product S35.6 is obtained.

The monoamidate product S35.3 is also prepared from a doubly activated phosphonate derivative S34.7. In this procedure, an example is Synlett. , 1998, 1, 73, and intermediate S34.7 is reacted with a limited amount of amino ester S34.9 to give mono-substituted product S34.11. The latter compound is then reacted with the hydroxy compound R ³ OH in the presence of a base (eg diisopropylethylamine) in a polar organic solvent (eg dimethylformamide) to give the monoamidate ester S35.3. Occurs.

  This method is illustrated in Scheme 35, Example 5. In this method, phosphoryl dichloride S35.22 is reacted with 1 molar equivalent of ethyl N-methyltyrosinate S35.23 and dimethylaminopyridine in dichloromethane solution to yield monoamidate S35.24. This product is then reacted with phenol S35.25 in dimethylformamide containing potassium carbonate to yield the ester amidate product S35.26.

Using these procedures, but using the amino ester S34.9 and / or the hydroxy compound R ³ OH in place of the ethyl N-methyltyrosinate S35.23 or phenol S35.25, the corresponding product S35. 3 is obtained.

Scheme 36 illustrates a method of preparing carboalkoxy substituted phosphonate diesters, where one of those ester groups incorporates a carboalkoxy substituent.

In one procedure, the phosphonate monoester S34.1 (prepared as described above) is prepared using one of the methods described above, where the hydroxy ester S36.1 (where the R ^4b and R ^5b groups are As described in Scheme 34). For example, equimolar amounts of these reactants can be obtained from Aust. J. et al. Chem. , 1963, 609, in the presence of carbodiimide (eg, dicyclohexylcarbodiimide) as required, as described in Tet. , 1999, 55, 12997, in the presence of dimethylaminopyridine. This reaction is carried out in an inert solvent at room temperature.

  This procedure is illustrated in Scheme 36, Example 1. In this method, monophenyl phosphonate S36.9 was coupled with ethyl 3-hydroxy-2-methylpropionate S36.10 in the presence of dicyclohexylcarbodiimide in dichloromethane solution to produce phosphonate mixed diester S36. 11 is produced.

  Using this procedure, but using a different hydroxy ester 33.1 instead of ethyl 3-hydroxy-2-methylpropionate S36.10, the corresponding product 33.2 is obtained.

Conversion of phosphonate monoester S34.1 to mixed diester S36.2 is also described in Org. Lett. , 2001, 643, by Mitsunobu reaction with hydroxy ester S36.1. In this method, reactants S34.1 and S36.1 are combined in a polar solvent (eg, tetrahydrofuran) in the presence of a triarylphosphine and a dialkylazodicarboxylate to give mixed diester S36.2. can get. The R ¹ substituent is changed by cleavage using the method described above to give the monoacid product S36.3. This product is then coupled with the hydroxy compound R ³ OH, eg, using the method described above, to give the diester product S36.4.

  This procedure is illustrated in Scheme 36, Example 2. In this method, monoallyl phosphonate S36.12 is coupled with ethyl lactate S36.13 in tetrahydrofuran in the presence of triphenylphosphine and diethyl azodicarboxylate to give mixed diester S36.14. It is done. This product is reacted with tris (triphenylphosphine) rhodium chloride (Wilkinson catalyst) in acetonitrile as described above to remove the allyl group and the monoacid product S36.15 is Generate. The latter compound is then coupled in pyridine solution at room temperature in the presence of dicyclohexylcarbodiimide with 1 molar equivalent of 3-hydroxypyridine S36.16 to give the mixed diester S36.17.

Using the above procedure, but using different hydroxy ester S36.1 and / or different hydroxy compound R ³ OH instead of ethyl lactate S36.13 or 3-hydroxypyridine, the corresponding product S36.4 is obtained. It is done.

  Mixed diester S36.2 is also obtained from monoester S34.1 via activated monoester S36.5. In this procedure, monoester S34.1 can be prepared, for example, according to J. Org. Chem. , 2001, 66, 329 by reaction with phosphorus pentachloride or in pyridine as described by Nucleosides and Nucleotides, 2000, 19, 1885 (thionyl chloride or oxalyl chloride ( Lv = Cl) or by reaction with triisopropylbenzenesulfonyl chloride, or J. Org. Med. Chem. , 2002, 45, 1284, which is converted to the activated compound S36.5 by reaction with carbonyldiimidazole. The resulting activated monoester is then reacted with the hydroxy ester S36.1 as described above to give the mixed diester S36.2.

  This procedure is illustrated in Scheme 36, Example 3. In this sequence, monophenyl phosphonate S36.9 is reacted with 10 equivalents of thionyl chloride in an acetonitrile solution at 70 ° C. to produce phosphoryl chloride S36.19. This product is then reacted with ethyl 4-carbamoyl-2-hydroxybutyrate S36.20 in dichloromethane containing triethylamine to give the mixed diester S36.21.

  Using the above procedure, but using different hydroxy ester S36.1 instead of ethyl 4-carbamoyl-2-hydroxybutyrate S36.20, the corresponding product S36.2 is obtained.

These mixed phosphonate diesters are also obtained by an alternative route of incorporating the R ³ O group into intermediate S36.3, where the hydroxy ester moiety has already been incorporated. In this procedure, the monoacid intermediate S36.3 is converted to the activated derivative S36.6 (where Lv is a leaving group (eg, chloro, imidazole, etc.)) as previously described. The The activated intermediate is then reacted with the hydroxy compound R ³ OH in the presence of a base to give the mixed diester product S36.4.

  This method is illustrated in Scheme 36, Example 4. In this order, the phosphonate monoacid S36.22 is Med. Chem. , 1995, 38, 4648, is reacted with trichloromethanesulfonyl chloride in tetrahydrofuran containing collidine to produce the trichloromethanesulfonyloxy product S36.23. This compound is reacted with 3- (morpholinomethyl) phenol S36.24 in dichloromethane containing triethylamine to give the mixed diester product S36.25.

Using the above procedure, but substituting a different alcohol R ³ OH for 3- (morpholinomethyl) phenol S36.24, the corresponding product S36.4 is obtained.

  The phosphonate ester S36.4 is also obtained by an alkylation reaction carried out on the monoester S34.1. The reaction between the monoacid S34.1 and the haloester S36.7 can be carried out in a polar solvent in a base (eg diisopropylethylamine, as described in Anal. Chem., 1987, 59, 1056, or J Chem., 1995, 38, 1372, in the presence of triethylamine) or in a non-polar solvent such as benzene. Comm. , 1995, 25, 3565, in the presence of 18-crown-6.

  This method is illustrated in Scheme 36, Example 5. In this procedure, monoacid S36.26 is reacted with ethyl 2-bromo-3-phenylpropionate S36.27 and diisopropylethylamine in dimethylformamide at 80 ° C. to give the mixed diester product S36.28. can get.

  Using the above procedure, but using the different haloester S36.7 instead of ethyl 2-bromo-3-phenylpropionate S36.27, the corresponding product S36.4 is obtained.

Scheme 37 illustrates a method for preparing phosphonate diesters, where both ester substituents incorporate a carboalkoxy group.

  These compounds are prepared directly or indirectly from phosphonic acid 34.6. In one alternative, the phosphonic acid is hydroxylated using conditions previously described in Schemes 34-36 (eg, coupling reactions using dicyclohexylcarbodiimide or similar reagents) or under Mitsunobu reaction conditions. Coupling with ester S37.2 yields diester product S37.3, where their ester substituents are the same.

  This method is illustrated in Scheme 37, Example 1. In this procedure, phosphonic acid S34.6 is reacted with 3 molar equivalents of butyl lactate S37.5 in pyridine at about 70 ° C. in the presence of Aldrithiol-2 and triphenylphosphine to give the diester S37. 6 is obtained.

  Using the above procedure, but using a different hydroxy ester S37.2 instead of butyl lactate S37.5, the corresponding product S37.3 is obtained.

  Alternatively, diester S37.3 is obtained by alkylating phosphonic acid S34.6 with haloester S37.1. This alkylation reaction is carried out as described in Scheme 3 for the preparation of ester S36.4.

  This method is illustrated in Scheme 37, Example 2. In this procedure, phosphonic acid S34.6 was prepared in Anal. Chem. , 1987, 59, 1056 are reacted with excess ethyl 3-bromo-2-methylpropionate S37.7 and diisopropylethylamine to produce the diester S37.8.

  Using the above procedure, but using the different haloester S37.1 instead of ethyl 3-bromo-2-methylpropionate S37.7, the corresponding product S37.3 is obtained.

  The diester S37.3 is also obtained by reaction of displacing the activated derivative S34.7 of this phosphonic acid with the hydroxy ester S37.2. This substitution reaction is performed as described in Scheme 6 in the presence of a suitable base in a polar solvent. This substitution reaction is carried out in the presence of excess hydroxy ester to give the diester product S37.3 (wherein the ester substituents are the same) or a limited amount of different hydroxy esters. To prepare diester S37.3, where their ester substituents are different.

  These methods are illustrated in Scheme 37, Examples 3 and 4. As shown in Example 3, phosphoryl dichloride S35.22 was reacted with 3 molar equivalents of ethyl 3-hydroxy-2- (hydroxymethyl) propionate S37.9 in tetrahydrofuran containing potassium carbonate. The diester product S37.10 is thus obtained.

  Using the above procedure, but using different hydroxy ester S37.2 instead of ethyl 3-hydroxy-2- (hydroxymethyl) propionate S37.9, the corresponding product S37.3 is obtained.

  Scheme 37, Example 4 depicts that a substitution reaction between equimolar amounts of phosphoryl chloride S35.22 and ethyl 2-methyl-3-hydroxypropionate S37.11 yields the monoester product S37.12. ing. This reaction is carried out in acetonitrile at 70 ° C. in the presence of diisopropylethylamine. Product S37.12 is then reacted with 1 molar equivalent of ethyl lactate S37.13 under the same conditions to give diester product S37.14.

  Using the above procedure, but using a continuous reaction with different hydroxy esters S37.2 instead of ethyl 2-methyl-3-hydroxypropionate S37.11 and ethyl lactate 4,13, the corresponding product S37 .3 is obtained.

The 2,2-dimethyl-2-aminoethylphosphonic acid intermediate can be prepared by the route of Scheme 5. Condensation of 2-methyl-2-propanesulfinamide with acetone gives sulfinyl imine S38.11 (J. Org. Chem. 1999, 64, 12). Addition of lithium dimethylmethylphosphonate to S38.11 yields S38.12. S38.12 is decomposed with acidic methanol to give amine S38.13. Protection of the amine with a Cbz group and removal of the methyl group yields phosphonic acid S38.14, which can be converted to the desired S38.15 (Scheme 38a) using previously reported methods. An alternative synthesis of compound S38.14 is also shown in Scheme 38b. Commercially available 2-amino-2-methyl-1-propanol is converted to aziridine S38.16 according to literature methods (J. Org. Chem. 1992, 57, 5813; Syn. Lett. 1997, 8, 893). . Opening the phosphite with aziridine yields S38.17 (Tetrahedron Lett. 1980, 21, 1623). Reprotecting S38.17 gives S38.14.

The invention is illustrated herein by the following non-limiting examples.

(Example)
Example 1: Preparation of exemplary compounds of the invention (Scheme 1.1)

Schemes 1.1-1.3 illustrate the synthesis of target molecules of type 1-12 and 1-56 (where the bond is a heteroatom and a carbon chain). The preparation of 1-1 is described in U.S. Pat. S. Patent No. 5,770,596. Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Wuts, Wiley, Third Edition (1999) p. 246 or U.V. S. Patent No. Diether 1-1 is converted to monoether 1-2 by the method described in US Pat. Preferably, methanesulfonic acid containing diester 1-1 is treated with L-methionine at reflux to give phenol 1-2. Phenol 1-2 is then protected as acetyl compound 1-3 and converted to chloride 1-4. Then, U. S. Patent No. As described in US Pat. No. 5,770,596, an acetoxy compound is treated with aniline 1-5 to give amine 1.6, followed by deprotection of the acetyl group to give 1-7. Treatment of 1-7 with epibromohydrin 1-8 in DMF containing potassium carbonate provides epoxide 1-9. Treatment of epoxide 1-9 with morpholine in an aprotic solvent by refluxing in the presence of a base such as triethylamine provides alcohol 1-10. 1 equivalent of a phosphonate alkylating agent (where Lv is mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc.) in DMF in the presence of a base (eg, potassium carbonate or cesium carbonate) To give ether 1-12 (bonds are oxygen and carbon chains). Alternatively, Comprehensive Organic Transformations, by R.C. C. ^{Larock, 2 nd Edition, (1999} ), p. Alcohol 1-10 is oxidized to give ketone 1-13 as described in 1234ff. Preferably, alcohol 1-10 is treated with Dess-Martin periodinane to give ketone 1-13. The ketone 1-13 is then treated with an amino chain alkyl phosphonate 1-14 under reductive amination conditions to give the phosphonate 1-56 (the linkage is a nitrogen and carbon chain). For example, the preparation of amines by reductive amination procedures is described in Comprehensive Organic Transformations, by R. C. ^Larock, 2 nd ^edition, p. 835. In this procedure, an amine component and an aldehyde component are reacted together in the presence of a reducing agent (such as borate, sodium cyanoborohydride, or diisobutylaluminum hydride) to obtain an amine product.

  (Scheme 1.2)

For example, alcohol 1-10 in TMF was added to Tetrahedron Lett. Treatment with triflate 1-15 and potassium carbonate prepared as described in 1986, 27, 1497 provides ether 1-16. Alternatively, ketone 1-13 is treated with amine 1-17 (Acros) in methanol and after a certain time sodium borohydride is added to give amine 1-18. Using the above procedure, but using phosphonates 1-11 and 1-14 respectively instead of triflate 1-15 or amine 1-17, the corresponding products 1-12 and 1-56 are obtained.

  (Scheme 1.4)

(Scheme 1.5)

The reactions shown in Schemes 1.4-1.5 illustrate the preparation of compound 1-22 (phosphonates are attached via a carbon chain and a heteroatom). Treatment of phenol 1-7 (Scheme 1.1-1.3) with dibromide 1-19 using the conditions described in Schemes 1.1-1.3 for the preparation of 1-7 to 1-9 Thus, bromide 1-20 is obtained. Bromide 1-20 is then treated with dialkylhydroxy, thio, or amino substituted alkyl phosphonate 1-21 to give product 1-22. The reaction is carried out in the presence of a base, a polar aprotic solvent such as dioxane, or N-methylpyrrolidinone. The base used in the reaction depends on the nature of the reactant 1-21. For example, when X is O, a strong base (such as lithium hexamethyldisilylazide or potassium tert. Butoxide) is used. When X is S, NH, or N-alkyl, an inorganic base such as cesium carbonate is used.

  For example, treatment of 1-7 with dibromoethane 1-23 as described in Schemes 1.1-1.3 provides bromide 1-24. Then bromide 1-24 was prepared in J.F. Org. Chem. Treatment with amine 1-25 prepared as described in 2000, 65,676 gives phosphonate 1-26. Alternatively, bromide 1-24 is then refluxed in the presence of sodium carbonate with an equimolar amount of dialkyl 2-mercaptoethylphosphonate 1-27 (preparation as described in Aust. J. Chem., 1990, 43, 1123). Upon heating, the thioether product 1-28 is obtained. Using the above procedure but using a different dibromo compound 1-19 instead of dibromoethane 1-23 and / or using a different alkyl phosphonate 1-21 instead of 1-25 or 1-27 The product 1-22 is obtained.

Scheme 1.6 illustrates the synthesis of target molecule 1-32 (A is Br, Cl, [OH], [NH], or a group bond —P (O) (OR ¹ ) ₂ ). The preparation of 1-4 is illustrated in Scheme 1.1. Treatment of chloride 1-4 with amine 1-29 in refluxing isopropanol provides amine 1-30. The preparation of 1-29 (A is a group bond —P (O) (OR ¹ ) ₂ ) is described in Schemes 1.8-1.12. Below. Then, U. S. Patent No. Treatment of amine 1-30 according to the conditions described in 5,770,599 gives the final product 1-31.

The reaction shown in Scheme 1.6 is performed using compound 1-31 (substituent A is a group bond —P (O) (OR ¹ ) ₂ or a precursor such as [OH], [SH], [NH], or Br. The preparation of any) is illustrated. Scheme 1.7 shows the conversion of compound 1-31 (substituent A is [OH], [SH], [NH], Br, etc.) to phosphonate ester 1-32. This procedure converts compound 1-31 to compound 1-32, using the procedures described in Schemes 1.1-1.6.

  Schemes 1.8-1.12. Describe the preparation of the phosphonate-containing derivative 1-29 used in the preparation of the phosphonate ester intermediate 1-32.

  (Scheme 1.8)

Schemes 1.8 to 1.10 illustrate the preparation of 1-29 in which the phosphonate is attached via a heteroatom (eg, O, S, or N and a carbon linker). In this procedure, an optionally protected aniline is reacted with an alkyl phosphonate 1-34 (Lv is a free radical such as triflate, Br, Cl, mesyl, etc.) in the presence of a suitable base. The base required for this transformation depends on the nature of the heteroatom X. For example, when X is N or S, an excess of an inorganic base (such as potassium carbonate) in the presence of an organic solvent such as dimethylformamide is suitable. The reaction proceeds from ambient temperature to about 80 ° C. to give the substituted product 1-35. When X is O, an equal amount of strong base (eg, lithium hexamethyldisilylazide) is used in the presence of a solvent such as tetrahydrofuran. Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Deprotection of the amine group described in Wuts, Wiley, Third Edition (1999), chapter 7 gives amine 1-36.

  (Scheme 1.9)

For example, diamine 1-37 (Aldrich) protected with CBZ carbamate (Protective Groups in Organic Synthesis, by TW Greene and PGM Wuts, Wiley, Third Edition (1999), page 531ff), etc. Treatment with an equimolar amount of triflate (the preparation is described in Tetrahedron Lett. 1986, 27, 1497) in dimethylformamide containing excess potassium carbonate at about 60 ° C. gives the phosphonate product 1-39. Is obtained. Subsequent deprotection by reduction using a palladium on carbon catalyst in the presence of hydrogen affords amine 1-40.

  (Scheme 1.10)

Alternatively, aminophenol 1-41 protected with CBZ carbamate as described above is reacted with 1 equivalent of triflate 1-38 to give phosphonate 1-42. Subsequent removal of the CBZ group by catalytic reduction using a palladium carbon catalyst in the presence of hydrogen provides amine 1-43.

  Using the above procedure, but using a different aniline 1-33 instead of aniline 1-37 or phenol 1-41 and / or using a different alkyl phosphonate 1-34 instead of 1-38, the corresponding production Product 1-36 is obtained.

  (Scheme 1.11)

Schemes 1.11-1.12 illustrate the preparation of 1-29 with phosphonate attached through an unsaturated or saturated carbon linker. In this procedure, a halo-substituted aniline 1-44 optionally protected by a palladium catalyzed Heck reaction is coupled with a dialkylalkenyl phosphonate 1-45 to give the coupling product 1-46. Coupling of aryl halides and olefins by the Heck reaction is described, for example, in Advanced Organic Chemistry, by F.M. A. Carey and R.C. J. et al. Sundberg, Plenum, (2001), p. 503ff and Acc. Chem. Res. 1979, 12, 146. Dimethylformamide 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 optionally a base such as triethylamine or potassium carbonate Alternatively, coupling of aryl bromide and olefin in a polar solvent such as dioxane provides coupling product 1-46. Deprotection of aniline is described in Protective Groups in Organic Synthesis, by T .; W. Greene and P.M. G. M.M. Wuts, Wiley, Third Edition (1999), chapter 7. Preferably, the aniline is treated with a BOC reagent such as BOC chloride or anhydrous BOC in the presence of a base such as DMAP and triethylamine to give the protected aniline. Optionally, product 1-46 is reduced to give saturated phosphonate 1-47. The method for reducing a carbon-carbon double bond is described in, for example, Comprehensive Organic Transformations, by R.C. C. Larock, VCH, (1989), page 6. This method includes catalytic reduction and chemical reduction (the latter using, for example, diborane or diimide).

  (Scheme 1.12)

For example, J. et al. Med. Chem. BOC-protected 3-chloro-4-fluoroaniline 1-50 (Aldrich) in the presence of bis (triphenylphosphine) palladium (II) chloride as described in U.S. Pat. (The preparation is described in J. Med. Chem., 1996, 39, 949) to give the coupling product 1-52. BOC protection of the aniline is performed by treatment of the corresponding aniline with anhydrous BOC in the presence of DMAP. For example, J. et al. Org. Chem. The product 1-52 is reacted with the diimide described in 1965, 30, 3965 to give the saturated product 1-53. Removal of BOC by treatment of 1-52 and 1-53 with TFA in THF or dioxane gives the products 1-54 and 1-55, respectively. Using the above procedure, but using different aniline 1-44 and / or different phosphonate 1-45 instead of haloaniline compound 1-50, the corresponding products 1-48 and 1-49 are obtained.

  The procedures described for the introduction of phosphonate moieties with appropriate modifications known to those skilled in the art (Schemes 1.1 to 1.12) are applicable to different chemical substrates. Thus, the above method for introduction of phosphonate groups into 1-12, 1-56, and 1-22 is also applicable to the introduction of phosphonate moieties into aniline 1-29, or vice versa.

  Example 2: Preparation of exemplary compounds of the invention

Scheme 2.1 illustrates the preparation of compound 2-4, where A is Br, I, [SH], [NH], etc. or a group bond —P (O) (OR ¹ ) ₂ . U. S. Patent No. Amine 2-1 is prepared as described in 5,521,84. Coupling of amine 2-1 and acid 2-2 gives amide 2-3. Preparation of amides from carboxylic acids and derivatives is described, for example, in Organic Functional Group Preparations, by S .; R. Sandler and W.M. Karo, Academic Press, 1968, page 274. In an aprotic solvent such as longitudinal aunt, pyridine, DMF, or dichloromethane, in the presence of an activator, such as, for example, dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally, for example, in the presence of hydroxybenztriazole. To react the carboxylic acid with an amine to give an amide.

  Alternatively, the carboxylic acid can be first converted to an activated derivative such as an acid chloride or anhydride and then reacted with an amine in the presence of an organic base such as pyridine to give an amide.

  Treatment of the carboxylic acid with thionyl chloride or oxalyl chloride in an inert solvent such as dichloromethane converts the carboxylic acid to the corresponding acid chloride. Preferably, acid 2-2 is treated with oxalyl chloride in an inert solvent such as dichloromethane followed by treatment with amine 2-1 to give amide 2-3. Acid 2-2 is prepared according to Schemes 2.7-2.8 shown below.

The reaction shown in Scheme 2.1 is performed using compound 2-3 (substituent A is a group bond —P (O) (OR ¹ ) ₂ or a precursor such as [OH], [SH], [NH], or Br. The preparation of Scheme 2.2 shows the conversion of compound 2-3 (A is [OH], [SH], [NH], Br, etc.) to the phosphonate ester 2-4. In this procedure, compound 2-3 is converted to compound 2-4 using the following procedure (Scheme 2.7-2.12).

Scheme 2.3 illustrates the preparation of compound 2-6, where A is Br, I, [SH], [NH], etc. or a group bond —P (O) (OR ¹ ) ₂ . Treatment of amine 2-1 with acid 2-5 as described in Scheme 2.1 above provides amide 2-6. The preparation of acid 2-5 is described in Schemes 2.9-2.10 below.

The reaction shown in Scheme 2.3 is performed using compound 2-6 (substituent A is a group bond —P (O) (OR ¹ ) ₂ or a precursor such as [OH], [SH], [NH], or Br. The preparation of any) is illustrated. Scheme 2.4 shows conversion of compound 2-6 (A is [OH], [SH], [NH], Br, etc.) to phosphonate ester 2-7. In this procedure, compound 2-6 is converted to compound 2-7 using the following procedure (Scheme 2.7-2.12).

Scheme 2.5-2.6 illustrates the preparation of compound 2-10, where A is Br, I, [SH], [NH], etc. or a group bond —P (O) (OR ¹ ) _2. To do. Treatment of amine 2-1 with acid 2-8 as described in Scheme 2.1 above provides amide 2-9. The preparation of acid 2-8 is described in Schemes 2.11-2.12 below.

The reactions shown in Schemes 2.5 to 2.6 are performed using compound 2-9 (substituent A is group-bonded —P (O) (OR ¹ ) ₂ or [OH], [SH], [NH], Br, etc. Of the precursor of any of the above. Scheme 2.6 shows the conversion of compound 2-9 (A is [OH], [SH], [NH], Br, etc.) to phosphonate ester 2-10. In this procedure, compound 2-9 is converted to compound 2-10 using the following procedure (Scheme 2.7-2.12).

Schemes 2.7 to 2.8 are phosphonate-containing derivatives 2-2 used for the preparation of phosphonate ester intermediate 2-4 (A is Br, Cl, [OH], [NH], or group-bonded-P (O ) (Which is OR ¹ ) ₂ ) is described. Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Wuts, Wiley, Third Edition (1999) p. Piperazine 2-11 is protected with a BOC group according to the method described in 518ff. Preferably, piperazine is treated with 1 equivalent of BOC in methanol or DMF or with 1 equivalent of triethylamine to give BOC amine 2-12. Treatment of 2-12 with an alkyl phosphonate 2-13 (Lv is a free radical such as triflate, Br, Cl, mesyl, etc.) in the presence of a suitable base gives the product 2-14. The base required for this conversion is typically an inorganic base such as potassium carbonate in the presence of an organic solvent such as dimethylformamide. The reaction is allowed to proceed from ambient temperature to about 80 ° C. to give the substituted product 2-14. Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Deprotection of the BOC-amine group described in Wuts, Wiley, Third Edition (1999) p520ff provides amine 2-15. The amine 2-15 is then reacted with the acid 2-16 (Aldrich) in the presence of a base to give the acid product 2-17. For example, 2-12 prepared from piperazine as described above was prepared from Syn. Treatment with bromophosphonate 2-18 and potassium carbonate prepared as described in 1999, 9, 909 gives amine 2-19. The BOC amine 2-19 is then deprotected to give amine 2-20 by treatment with trifluoroacetic acid in dichloromethane. The amine 2-20 is then reacted with bromomethylbenzoic acid 2-16 in THF or dioxane in the presence of triethylamine or potassium carbonate to give the acid 2-21. Using the above procedure, but using a different phosphonate 2-13 instead of the bromophosphonate compound 2-18, the corresponding product 2-17 is obtained.

  (Scheme 2.9)

Schemes 2.9-2.10 show the preparation of acid 2-5 with the phosphonate attached to the scaffold via a heteroatom and a carbon linker. Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Wuts, Wiley, Third Edition (1999), p. Treatment of benzyl protected ketone 2-22 prepared from the corresponding acid by treatment with benzyl alcohol in the presence of DCC and DMAP in DMF as described in 373ff with brominating agent gives bromoketone 2-23 . T. T. W. Greene and P.M. G. M.M. Wuts, Wiley, Third Edition (1999), p. Protection of the ketone as a cyclic dioxalone described in 312ff gives 2-24. Dioxane 2-24 is then treated with a dialkyl hydro group, thio, or amino substituted alkyl phosphonate 2-25 to give dioxalone 2-26. The reaction is carried out in a polar aprotic solvent such as dioxane or N-methylpyrrolidinone in the presence of a base. The base used in the reaction depends on the nature of the reactant 2-25.

For example, when X is O, a strong base (such as lithium hexamethyldisilylazide or potassium tert. Butoxide) is used. When X is S, NH, or N-alkyl, an inorganic base such as cesium carbonate is used. T. T. W. Greene and P.M. G. M.M. Wuts, Wiley, Third Edition (1999), p. Deprotection of the dioxalone described in 317ff gives ketone 2-27, followed by treatment with N-methylpiperazine under reductive amination conditions to give amine 2-28. Preparation of amines by reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R.C. C. ^Larock, 2 nd ^edition, p. 835. In this procedure, an amine component and an aldehyde component are reacted together in the presence of a reducing agent (such as borate, sodium cyanoborohydride, or diisobutylaluminum hydride) to obtain an amine product. T. W. Greene and P.M. G. M.M. Wuts, Wiley, Third Edition (1999) p. Deprotection of the ester group described in 373ff gives acid 2-29.

  (Scheme 2.10)

For example, treatment of 4-acetylbenzoic acid with benzyl bromide in the presence of potassium carbonate in an aqueous THF solution provides benzyl ester 2-22. Treatment of ester 2-22 with bromide in acetic acid or NBS and AIBN in CCl ₄ gives bromide 2-23. The bromide 2-23 is then reacted with 1,2-ethanediol in toluene at reflux under a Dean-Stark head containing a catalytic amount of p-TsOH in the presence of a catalytic amount to give the dioxalone 2-24. It is done. Dioxalone 2-24 was prepared according to the procedure described in J. Am. Org. Chem. Reaction with dialkyl 2-aminoethylphosphonate 2-30 prepared as described in U.S., 2000, 65,676. Distillation of dioxalone 2-31 with 1N hydrochloric acid in THF gives ketone 2-32. Ketone 2-32 is reacted with N-methylpiperazine in the presence of triethylamine and after 30 minutes sodium cyanoborohydride is added to give amine 2-33. Removal of the benzyl ester by hydrolysis using sodium hydroxide in aqueous THF provides the acid 2-34. Using the above procedure, but using a different phosphonate 2-25 in place of the aminophosphonate compound 2-30, the corresponding product 2-29 is obtained.

  (Scheme 2.11)

Schemes 2.11-1.12 illustrate the preparation of 2-8 with phosphonate attached through an unsaturated or saturated carbon linker. In this procedure, acid 2-16 (Aldrich) is treated with the group cyano N-methylpiperazine in Schemes 2.7-2.8 for the preparation of 2-17 to give acid 2-35. The acid 2-35 is then brominated with bromine or MBS to give bromide 2-36. Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. As described in Wuts, Wiley, Third Edition (1999), page 373ff, bromide 2-36 is optionally protected with benzyl or t-butyl ester to give 2-37. The ester 2-37 is then reacted with a dialkylalkenyl phosphonate 2-38 by a palladium catalyzed Heck reaction to give the coupling product 2-39. Coupling of alkyl halides and tail hints by the Heck reaction is described, for example, in Advanced Organic Chemistry, by F.M. A. Carey and R.C. J. et al. Sundberg, Plenum, (2001), p. 503ff. And Acc. Chem. Res. 1979, 12, 146. Palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) or palladium (II) catalyst such as palladium (II) acetate, and optionally dimethylformamide in the presence of a base such as triethylamine or potassium carbonate Alternatively, coupling of aryl bromide and olefin in a polar solvent such as dioxane provides coupling product 2-39. Optionally, product 2-39 can be reduced to give saturated phosphonate 2-40. The method for reducing a carbon-carbon double bond is described in, for example, Comprehensive Organic Transformations, by R.C. C. Larock, VCH, (1989), page 6. This method includes catalytic reduction and chemical reduction (the latter using, for example, diborane or diimide).

  (Scheme 2.12)

For example, amine 2-35 is then treated with NBS and AIBN at reflux in carbon tetrachloromethane to give bromide 2-43. The bromide 2-43 is then reacted with DCC and DMAP in t-butanol to give the t-butyl ester 2-44. Then, J.H. Med. Chem. , 1992, 35, 1371 in the presence of bis (triphenylphosphine) palladium (II) chloride and dialkylpropenyl phosphonate 2-45 (prepared by J. Med. Chem., 1996). , 39, 949) to give the coupled product 2-46. The product 2-46 is then treated with aqueous hydrochloric acid in dioxane to give the acid 2-48. Optionally, J.M. Org. Chem. 1965, 30, 3965, the alkene 2-46 can be reduced by reaction with diimide to give the saturated product 2-47. Hydrolysis of the ester through treatment with aqueous hydrochloric acid in dioxane provides acid 2-49. Using the above procedure, but using a different phosphonate 2-38 instead of the phosphonate compound 2-45, the corresponding products 2-41 and 2-42 are obtained.

Example 3: Exemplary compounds of the present invention (Scheme 3.1)

Scheme 3.1 illustrates exemplary compounds of the present invention in which the phosphonate group can be attached via either a carbon atom or a heteroatom, respectively.

Schemes 3.2-3.3 show a target molecule of type 3-11 (A is Br, Cl, [OH], [NH], or a group bond —P (O) (OR ¹ ) ₂ ). Illustrates synthesis. The preparation of 3-4 (A is phosphonate) is described below. The conversion of 3-4 to 3-9 (A is methoxymethyl) is described in EP 0817775 B1 and using similar conditions 3-9 (A is a group bond —P (O) (OR ¹ ) ₂ ) can be prepared. Diether 3-4 nitro provides compound 3-5, which is then converted to Comprehensive Organic Transformations, by R.C. C. Reduction under standard reducing conditions as described in Larock, 2 ^nd Edition, (1999), p821, gives amine 3-6.

  For example, 3-4 is treated with nitric acid, for example, in acetic acid, followed by catalytic hydrogenolysis of the nitro product in acidic ethanol with a platinum oxide catalyst at high pressure to give amine 3-6. The isolated hydrochloride salt is then heated with ammonium formate and formamide at about 160 ° C. to give quinazoline 3-7. 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. Substitution of this chloride with amine 3-10 then gives product 3-9. For example, heating of chloride 3-8 with 3-ethynyl-aniline in isopropanol at reflux provides 3-9.

The reaction shown in Scheme 3.2 is performed using compound 3-9 (substituent A is a group bond —P (O) (OR ¹ ) ₂ or a precursor such as [OH], [SH], [NH], or Br. The preparation of any) is illustrated. Scheme 3.3 shows the conversion of compound 3-9 (A is [OH], [SH], [NH], Br, etc.) to phosphonate ester 3-11. In this procedure, compound 3-9 is converted to compound 3-11 using the following procedure (Schemes 3.10 to 3.21).

Schemes 3.4-3.5 are for type 3-14 target molecules where A is Br, Cl, [OH], [NH], or a group bond —P (O) (OR ¹ ) ₂ . Illustrates synthesis. The above conditions for the conversion of 3-4 to 3-9 (Scheme 3.2) are used to complete the conversion of 3-12 to 3-13. The preparation of 3-12 (A is a phosphonate) is described in Schemes 3.14-3.17 below.

The reaction shown in Scheme 3.4 is performed using compound 3-13 (substituent A is a group bond —P (O) (OR ¹ ) ₂ or a precursor such as [OH], [SH], [NH], or Br. The preparation of any) is illustrated. Scheme 3.5 shows the conversion of compound 3-13 (substituent A is [OH], [SH], [NH], Br, etc.) to the phosphonate ester 3-14. This procedure converts compound 3-13 to compound 3-14 using the following procedure (Schemes 3.10 to 3.13).

Schemes 3.6-3.7 show a target molecule of type 3-20 where A is Br, Cl, [OH], [NH], or a group bond —P (O) (OR ¹ ) ₂ . Illustrates synthesis. The preparation of 3-15 is described in EP 0817775 B1. The diester 3-15 is converted to the chloride 3-16 using the conditions described in EP 0817775 B1 or scheme 3.2 above. Treatment of chloride 3-16 with amine 3-18 at reflux in isopropanol gives 3-17. The preparation of 3-18 (A is a group bond —P (O) (OR ¹ ) ₂ ) is shown in Schemes 3.18 to 3.19 below.

The reaction shown in Scheme 3.6 is performed using compound 3-17 (substituent A is a group bond —P (O) (OR ¹ ) ₂ or a precursor such as [OH], [SH], [NH], or Br. The preparation of any) is illustrated. Scheme 3.7 shows the conversion of compound 3-17 (substituent A is [OH], [SH], [NH], Br, etc.) to the phosphonate ester 3-20. This procedure converts compound 3-17 to compound 3-20 using the procedure described in Schemes 3.10 to 3.21 below.

Schemes 3.8-3.9 are for type 3-24 target molecules where A is Br, Cl, [OH], [NH], or a group bond —P (O) (OR ¹ ) ₂ . Illustrates synthesis. The preparation of 3-16 is described in Scheme 3.6. The preparation of 3-22 (A is a group bond —P (O) (OR ¹ ) ₂ ) is shown in Schemes 3.20 to 3.21 below.

The reaction shown in Scheme 3.8 is performed using compound 3-23 (substituent A is a group bond —P (O) (OR ¹ ) ₂ or a precursor such as [OH], [SH], [NH], or Br. The preparation of any) is illustrated. Scheme 3.9 shows conversion of compound 3-23 (substituent A is [OH], [SH], [NH], Br, etc.) to phosphonate ester 3-24. This procedure converts compound 3-23 to compound 3-24 using the procedure described in Schemes 3.10 to 3.21 below.

Schemes 3.10-3.13 describe 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). To do. With 3 equivalents of phosphonate alkylating agent (Lv is a free radical such as mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl) in the presence of a base as described in EP 0817775 B1 Treatment gives ether 3-26. The ether is then subjected to the same alkyl conditions in the presence of 2-bromoethyl methyl ether (Aldrich) to give diethers 3-19, 3-30, 3-69, and 3-70. For example, the ester 3-25 prepared from the corresponding acid (Aldrich) by refluxing in acetone with concentrated hydrochloric acid and ethanol can be synthesized according to Syn. Treatment with dialkyl 4-bromobutylphosphonate 3-28, potassium carbonate, and tetrabutylammonium iodide prepared as described in 1999, 9, 909 provides ether 3-29. Ether 3-29 is then treated with 2-bromoethyl methyl ether (Aldrich), potassium carbonate, and tetrabutylammonium iodide to give diether 3-30. Using the above procedure, but using different phosphonates 3-27 and 3-37 instead of bromobutylphosphonate 3-28, the corresponding products 3-4, 3-19, 3-69, 3-70 were obtained. It is done.

  (Scheme 3.12)

Schemes 3.12-3.13 also describe the preparation of phosphonate-containing derivatives 3-69, 3-70 used in the preparation of phosphonate ester intermediate 3-11 (Scheme 3.3). Treatment of dihydroxybenzoic acid 3-25 with 1 equivalent of alcohol 3-31 provides ether 3-32 as described in Schemes 3.10-3.11. This ether 3-32 was then treated with 1 equivalent of 2-bromoethyl methyl ether (Aldrich) and 1 equivalent of base as described in Schemes 3.10-3.11 to give diether 3-33. It is done. Treatment with a phosphonate alkylating agent 3-27 (Lv is a group such as mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc.) in the presence of a base provides ether 3-69.

  (Scheme 3.13)

For example, treatment of 3-25 with 2-bromoethanol in acetone provides 3-35 as described in Scheme 3.10 for the preparation of 3-25 to 3-26. Reaction with 2-bromoethyl methyl ether (Aldrich) and 1 equivalent of sodium hydroxide in DMF provides the diester 3-36. Diether 3-36 in DMF and Tetrahedron Lett. Reaction with triflate 3-37 and potassium carbonate prepared as described in 1986, 27, 1497 gives ether 3-70. Using the above procedure, but using a different phosphonate 3-27 instead of bromobutylphosphonate 3-28 and a different alcohol 3-31 instead of alcohol 3-34, the corresponding product 3-69 is obtained.

  Schemes 3.14-3.17 describe 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).

Dihydroxybenzoic acid 3-25 is first treated with 2-bromoethyl methyl ether (Aldrich) as described in Schemes 3.10-3.11 to give ether 3-38. The ether 3-38 is then treated with 1 equivalent of a phosphonate alkylating agent (Lv is a group such as mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc.) in the presence of a base as described in EP 0817775 B1. To give ether 3-75. For example, ether 3-38 was added to Tetrahedron Lett. Treatment with triflate 3-37 and potassium carbonate prepared as described in 1986, 27, 1497 gives ether 3-39. Using the above procedure, but using a different phosphonate 3-27 instead of phosphonate 3-37, the corresponding product 3-75 is obtained.

Schemes 3.16-3.17 describe the preparation of phosphonate-containing derivative 3-76 used in the preparation of phosphonate ester intermediate 3-13 (Scheme 3.4). As described in Scheme 3.13 above for the preparation of 3-25 to 3-35, 3 ether 3-38 (Scheme 3.14-3.15) was treated with 2-bromoethanol to give 3- 40 is obtained. Treatment of diether 3-40 with phosphonate alkylating agent 3-27 (Lv is a group such as mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc.) in the presence of a base yields ether 3-76. can get. For example, as described in Scheme 3.13 above for the preparation of 3-25 to 3-35, treating 3-38 with 2-iodoethanol (3-66) in acetone yields 3-41 can get. Subsequent reaction with bromobutylphosphonate 3-28 affords 3-42 as described above (Schemes 3.10 to 3.11). Using the above procedure, but using a different phosphonate 3-27 instead of bromobutylphosphonate 3-28 and a different alcohol 3-63 instead of alcohol 3-66, the corresponding product 3-76 was obtained. It is done.

Schemes 3.18-3.19 describe the preparation of phosphonate-containing derivatives used in the preparation of phosphonate ester intermediate 3-20 (Schemes 3.6-3.7). Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. The aniline 3-43 is first protected using the method described in Wuts, Wiley, Third Edition (1999), chapter 7. Bromination of 3-44 by treatment with acetic acid containing bromine or tetrachloromethane containing NBS at reflux in the presence of AIBN then gives bromophenol 3-34. Alkylation with phosphonate alkylating agent 3-77 then provides phosphonate 3-46 as described in Schemes 3.10 to 3.11 above. Alkyne 3-47 was obtained by coupling with TMS via a palladium mediated reaction. W. Greene and P.M. G. M.M. Deprotection can be achieved using conditions described in Wuts, Wiley, Third Edition (1999), chapter 7 to give amine 3-48. Coupling of aryl halides with alkynes is described, for example, in Comprehensive Organic Synthesis, 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 bromide 3-51. Alkylation of bromide 3-51 with 3-37 as described above (Scheme 3.12-3.13) provides phosphonate 3-52. 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 optionally a base such as triethylamine or potassium carbonate and copper iodide ( Treatment of 3-52 with TMS-acetylene in a polar solvent such as dimethylformamide or acetonitrile in the presence of I) provides the coupled product 3-53. Deprotection of the mesyl group by treatment with potassium hydroxide in THF and water provides the amine 3-54. Using the above procedure, but using a different phosphonate 3-77 instead of phosphonate 3-37 and a different alcohol 3-43 instead of alcohol 3-49, the corresponding product 3-48 is obtained.

  (Scheme 3.20)

Schemes 3.20-3.21 describe the preparation of phosphonate-containing derivative 3-58 used in the preparation of phosphonate ester intermediate 3-24 (Scheme 3.9). Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. The 3-iodoaniline is first protected using the method described in Wuts, Wiley, Third Edition (1999), chapter 7. Coupling with propargyl alcohol by palladium mediated reaction as described above (Schemes 3.18-3.19) provides alkyne 3-56. Subsequent alkylation with the phosphonate alkylating agent 3-27 in Schemes 3.10 to 3.11 above gives phosphonate 3-57. Finally, Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Deprotection using the conditions described in Wuts, Wiley, Third Edition (1999), chapter 7 gives amine 3-58.

  (Scheme 3.21)

For example, 3-iodoaniline (Aldrich) is treated with anhydrous BOC in the presence of pyridine and DMAP to give 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 optionally a base such as triethylamine or potassium carbonate and copper iodide ( Treatment of 3-59 with propargyl alcohol in a polar solvent such as dimethylformamide or acetonitrile in the presence of I) provides the coupled product 3-60. Alkylation of 3-60 with triflate 3-37 provides phosphonate 3-61 as described in Schemes 3.12-3.13 above. Deprotection of the BOC group by treatment with TFA in THF or dioxane provides amine 3-62. Using the above procedure, but using a different phosphonate 3-27 instead of phosphonate 3-37 and a different aniline 3-55 instead of iodoaniline 3-59, the corresponding product 3-58 is obtained. .

  The procedures described for the introduction of phosphonate moieties with appropriate modifications known to those skilled in the art (Schemes 3.10 to 3.21) are applicable to different chemical substrates. Thus, for example, the above method for introduction of phosphonate groups into 3-18 and 3-48 aryl rings is also applicable to introduction of phosphonate moieties into alkynes 3-22 and 3-58, or vice versa.

Example 4: Exemplary compounds of the present invention (Scheme 4.1)

Scheme 4.1 illustrates the preparation of compound 4-52 (A is Br, I, [SH], [NH], etc. or a group bond —P (O) (OR ¹ ) ₂ ). The preparation of these compounds is described in J. Am. Med. Chem. The procedure described in 2000, 43, 12, 2310 is followed. Phthalic anhydride 4-1 is melted at high temperature with methylpyridine 4-2 (A is Br, I, [SH], [NH] etc. or a group bond —P (O) (OR ¹ ) ₂ ). 4-3 is obtained. The synthesis of 4-2 is described below. Treatment of product 4-3 with water and optionally hydrazine in ethanol and subsequent rearrangement provides 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 50 ° C. Incorporation of amine 4-7 by heating of chloride 4-5, optionally in the presence of an amine, in a high boiling solvent such as xylene or DMF provides amine 4-6. Alternatively, J. Org. Med Chem. Direct conversion of pyridinone 4-4 in a one-step procedure involving the melting of aniline 4-7 with pyridinone in the presence of a dehydrating agent such as phosphorus pentoxide as described in 2000, 43, 12, 2310. The product 4-6 is obtained.

  (Scheme 4.2)

The reaction shown in Scheme 4.1 is performed using compound 4-6 (substituent A is a group bond —P (O) (OR ¹ ) ₂ or a precursor such as [OH], [SH], [NH], Br. The preparation of Scheme 4.2 shows the conversion of compound 4-6 (A is [OH], [SH], [NH], Br, etc.) to the phosphonate ester 4-52. This procedure converts compound 4-6 to compound 4-52 using the following procedure (Schemes 4.5-4.15).

Scheme 4.3 illustrates the preparation of compound 4-12, where A is Br, I, [SH], [NH], etc. or a group bond —P (O) (OR ¹ ) ₂ . As described in Scheme 4.1 above, J.M. Med. Chem. The chloride 4-8 described in 2000, 43, 12, 2310 is converted to aniline 4-9 (A is Br, I, [SH], [NH] or the like or a group bond -P (O) (OR ¹ ) _2. To give amine 4-10. Alternatively, as described in Scheme 4.1 above, J.M. Med. Chem. Pyridinone 4-11 described in 2000, 43, 12, p2310 is converted to aniline 4-9 (A is Br, I, [SH], [NH] or the like or a group bond —P (O) (OR ¹ ) ₂ To give amine 4-10.

  (Scheme 4.4)

The reaction shown in Scheme 4.3 is performed using compound 4-10 (substituent A is a group bond —P (O) (OR ¹ ) ₂ or a precursor such as [OH], [SH], [NH], or Br. The preparation of any) is illustrated. Scheme 4.4 shows the conversion of compound 4-10 (A is [OH], [SH], [NH], Br, etc.) to the phosphonate ester 4-12. In this procedure, compound 4-10 is converted to compound 4-12 using the following procedure (Schemes 4.5-4.15).

Schemes 4.5-4.10 show the phosphonate-containing derivatives 4-2 (A is Br, Cl, [OH], [NH], and the group bond -P ( The preparation of O) (which is OR ¹ ) ₂ is described.

Schemes 4.5-4.6 describe the preparation of 4-2 (Scheme 4.1) with the phosphonate directly attached to the ring. Treatment of halopyridine 4-13 with dialkyl phosphite 4-14 provides phosphonate 4-15. For example, J. et al. Med. Chem. , 1992, 35, 1371, the coupling reaction is carried out in the presence of a palladium (0) catalyst. For example, 2-bromo-4-methylpyridine (Aldrich) 4-16 is converted to equimolar amounts of dialkylsodium phosphite 4-toluene at reflux in toluene in the presence of tetrakis (triphenylphosphine) palladium (0) and triethylamine. Treatment with 14a gives phosphonate 4-17. Using the above procedure, but using different pyridine 4-13 and / or different dialkyl sodium phosphite 4-14 instead of halopyridine compound 4-16, the corresponding product 4-15 is obtained.

Schemes 4.7-4.8 illustrate the preparation of 4-2 with phosphonate attached through an unsaturated or saturated carbon linker. In this procedure, a halo-substituted pyridine 4-13 is coupled with a dialkylalkenyl phosphonate 4-18 by a palladium catalyzed Heck reaction. Coupling of aryl halides and olefins by the Heck reaction is described, for example, in Advanced Organic Chemistry, by F.M. A. Carey and R.C. J. et al. Sundberg, Plenum, (2001), p. 503ff and Acc. Chem. Res. 1979, 12, 146. Dimethylformamide 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 optionally a base such as triethylamine or potassium carbonate Alternatively, coupling of aryl bromide and olefin in a polar solvent such as dioxane provides coupling product 4-19. Optionally, product 4-19 can be reduced to give saturated phosphonate 4-20. The method for reducing a carbon-carbon double bond is described in, for example, Comprehensive Organic Transformations, by R.C. C. Larock, VCH, (1989), p. 6. This method includes catalytic reduction and chemical reduction (the latter using, for example, diborane or diimide).

  For example, J. et al. Med. Chem. , 1992, 35, 1371 in the presence of bis (triphenylphosphine) palladium (II) chloride in the presence of 2-bromo-4-methylpyridine 4-16 (prepared by dialkylbutenylphosphonate 4-21). , J. Med. Chem., 1996, 39, 949) to give the coupled product 4-22. Optionally, J.M. Org. Chem. 1965, 30, 3965, reduction of product 4-22, for example by reaction with diimide, yields saturated product 4-23. Using the above procedure, but using a different pyridine 4-13 and / or a different phosphonate 4-18 in place of the halopyridine compound 4-16, the corresponding products 4-19 and 4-20 are obtained.

Schemes 4.9-4.10 illustrate the preparation of 4-2 in which the phosphonate is attached via a heteroatom (eg, O, S, or N) and a carbon chain. In this procedure, a halo-substituted pyridine 4-13 is reacted with a dialkylhydroxy- or thio-alkyl phosphonate 4-24. Preparation of alkoxypyridines by reaction of alkoxides with halopyridines is described, for example, in J. Am. Am. Chem. Soc. 1960, 82, 4414. Preparation of pyridine thioethers by reaction of halopyridines with thiols is described, for example, in Chemistry of Heterocyclic Compounds, Pyridine and its derivatives, E.M. Klingsberg, Ed. , Part 4, page 358. Alcohols and thiols are converted to metal salts (eg, sodium or potassium salts) and then reacted with a halopyridine substrate, optionally in the presence of a copper powder catalyst, at elevated temperatures to give ether or thioether products 4-25. can get. For example, a solution of 3-bromo-4-methylpyridine 4-26 (Aldrich) in tetrahydrofuran is dissolved in an equimolar amount of dialkyl 2-mercaptoethylphosphonate 4-27 (prepared by Aust. J. Chem. , 43, 1123 (1990)) to give the thioether product 4-28. Using the above procedure, but using a different halopyridine 4-13 and / or a different hydroxy or thioalkyl phosphonate 4-24 instead of halopyridine 4-26, the corresponding product 4-25 is obtained.

Schemes 4.11 to 4.15 are phosphonate-containing derivatives 4-10 (A is Br, Cl, [OH], used in the preparation of phosphonate ester intermediate 4-12 (Schemes 4.3 to 4.4), [NH], and it describes the preparation of group bonded -P _(O) ^(oR 1) a _2).

  (Scheme 4.11)

Schemes 4.11-4.13 illustrate the preparation of 4-9 (Scheme 4.3) in which the phosphonate is attached via a heteroatom (eg, O, S, or N) and a carbon linker. In this procedure, an optionally protected aniline is reacted with an alkyl phosphonate 4-30 (Lv is a leaving group such as triflate, Br, Cl, mesyl, etc.) in the presence of a suitable base. The base required for this transformation depends on the nature of the heteroatom X. For example, when X is N or S, an excess of an inorganic base (such as potassium carbonate) is appropriate in the presence of an organic solvent such as dimethylformamide. The reaction proceeds from ambient temperature to about 80 ° C. to give the substituted product 4-31. When X is O, an equimolar amount of a strong base (such as lithium hexamethyldisilylazide) is used in the presence of a solvent such as tetrahydrofuran. Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Deprotection of the amine group described in Wuts, Wiley, Third Edition (1999), chapter 7 gives amine 4-32.

  (Scheme 4.12)

For example, Protective Groups in Organic Synthesis, by T.M. W. Greene and P.M. G. M.M. Monoprotected diamine 4-33 (Aldrich) as described in Wuts, Wiley, Third Edition (1999), 531ff, etc. in dimethylformamide containing excess potassium carbonate at about 60 ° C. Treatment with a molar amount of triflate 4-34 (the preparation of which is described in Tetrahedron Lett. 1986, 27, 1497) gives the phosphonate product 4-35. Subsequent deprotection by reduction using a palladium on carbon catalyst in the presence of hydrogen provides the amine 4-36. Using the above procedure, but using a different aniline 4-29 and / or a different alkyl phosphonate 4-30 instead of aniline 4-33, the corresponding product 4-32 is obtained.

  (Scheme 4.13)

Alternatively, CBZ carbamate protected aminophenol 4-37 as described above is treated with 1 equivalent of alkyl phosphonate 4-34 as described above to give phosphonate 4-38. Removal of the CBZ group by catalytic reduction using a palladium on carbon catalyst in the presence of hydrogen then provides amine 4-39.

  (Scheme 4.14)

Schemes 4.14-4.15 illustrate the preparation of 4-9 with phosphonate attached through an unsaturated or saturated carbon linker. In this procedure, a halo-substituted aniline 4-40, optionally protected by a palladium catalyzed Heck reaction as described above (Schemes 4.7-4.8), is coupled with a dialkylalkenyl phosphonate 4-18 to form a coupling. 4-41 is obtained. Deprotection of aniline is described in Protective Groups in Organic Synthesis, by T .; W. Greene and P.M. G. M.M. Wuts, Wiley, Third Edition (1999), chapter 7. Preferably, the aniline is treated with a BOC reagent such as BOC chloride or anhydrous BOC in the presence of DMAP and a base (eg, triethylamine) to give the protected aniline.

  Optionally, coupling product 4-41 is reduced as described above (Schemes 4.7-4.8) to give saturated phosphonate 4-42. Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Removal of the protecting group as described in Wuts, Wiley, Third Edition (1999) chapter 7 provides anilines 4-43 and 4-44.

  (Scheme 4.15)

For example, J. et al. Med. Chem. BOC-protected 3-chloro-4-fluoroaniline 4-45 (Aldrich) in the presence of bis (triphenylphosphine) palladium (II) chloride as described in U.S. Pat. (The preparation is described in J. Med. Chem., 1996, 39, 949) to give the coupling product 4-47. BOC protection of aniline is performed by treatment of aniline with anhydrous BOC in the presence of DMAP. For example, J. et al. Org. Chem. The product 4-47 is reduced by reaction with diimide as described in 1965, 30, 3965 to give the saturated product 4-48. Treatment of 4-47 and 4-48 with TFA in THF or dioxane gives the products 4-49 and 4-50, respectively. Using the above procedure, but using different pyridine 4-40 and / or different phosphonate 4-18 instead of halopyridine compound 4-45, the corresponding products 4-43 and 4-44 are obtained.

  The procedures described for the introduction of phosphonate moieties with appropriate modifications known to those skilled in the art (Schemes 4.5-4.15) are applicable to different chemical substrates. Thus, the above method for introducing a phosphonate group into the pyridyl ring of 4-2 is also applicable to the introduction of a phosphonate moiety into aniline 4-9 and vice versa.

  Example 5: Preparation of exemplary compounds of the invention

Desired phosphonate substituted analogs for conversion to prodrugs are described in arabinofuranosylcytosine 5-1 (US Patent No. 3,116,282, col. 26 line 65 to col. 28 line 25. And the respective alkylating agents 5-2. Schemes 5.1-5.2 show the preparation of the phosphonate linkage to 5-1 via the 5 'hydroxyl group. Triol 5-1 is dissolved in a solvent such as DMF, THF, and treated with a phosphonate reagent having a leaving group (eg, bromine, mesyl, tosyl, or trifluoromethanesulfonyl) in the presence of a suitable organic or inorganic base. To do.

  For example, 5-1 dissolved in DMF is mixed with 8 equivalents of sodium hydride and J.I. Org. Chem. Treatment with 2 equivalents of (toluene-4-sulfonylmethyl) -phosphonic acid diethyl ester 5-5, prepared according to the procedure described in 1996, 61, 7697, gives phosphonate 5-6 in which the bond is a methylene group. Using the above procedure, but using a different phosphonate reagent 5-2 instead of 5-5, the corresponding product 5-3 with a different linking group is obtained.

The desired phosphonate substituted analog for conversion to a prodrug is the first of glycal 5-7 (obtained as described in J. Am. Chem. Soc. 1972, 94, 3213) and the first phenylselenyl chloride. Prepared by reaction and subsequent treatment with each phosphonate alcohol 5-8 in the presence of silver perchlorate (J. Org. Chem. 1991, 56, 2642-2647). Oxidation of the resulting chloride using hydrogen peroxide and subsequent dihydroxylation of the resulting double bond with MCPBA and water yielded an antidiol (Synth. Commun. 1989, 19, 1939), which Aminolysis of uracil (Bioorg. Med. Chem. Lett. 1997, 7, 2567) using triazole, 2-chlorophenyldichlorophosphoric acid, pyridine, and ammonia provides the desired product 5-3. Alternatively, antidiols can be utilized by oxidation with osmium tetroxide followed by selective protection and conversion using Mitsunobu conditions.

Schemes 5.3-5.4 show the introduction of different phosphonate linkages. For example, 5-7 dissolved in CH ₂ Cl ₂ is treated with silver perchlorate in the presence of 1 equivalent of phenylselenyl chloride and then diethyl (hydroxymethyl) phosphonate at −70 ° C. to give 5-12 Is obtained. Initial oxidation with hydrogen peroxide followed by MCPBA oxidation converts the phosphonate to the desired analog, and finally uracil to cytosine to give the desired product 5-13. Using the above procedure, but using different phosphonate reagents 5-8 instead of 5-11, the corresponding products 5-10 with different linking groups are obtained. In some cases, conversion to the desired prodrug may require an appropriate protecting group and diol for the amino group of cytosine. Other bases can be used to obtain similar analogs of the 5-3 and 5-10 classes.

  Example 6: Preparation of exemplary compounds of the invention

Representative compounds of the present invention can be prepared as illustrated above. The desired phosphonate substituted analog is prepared by reaction of intermediate 6-5 (obtained as described in US Patent 5,464,826) with each alkylating reagent 6-6. Illustrated above is the preparation of a phosphonate linkage to a 2'2'-difluoronucleoside that has been converted to a 5'-hydroxyl group. A suitably protected base as described in US Pat. No. 5,464,826 is dissolved in a solvent such as DMF, THF and the like in the presence of a suitable organic or inorganic base (eg bromine, mesyl). , Tosyl, or trifluoromethanesulfonyl).

For example, 6-1 dissolved in DMF (obtained as described in US Patent 5,464,826) is obtained with 2 equivalents of sodium hydride and J.P. Org. Chem. Treatment with 1 equivalent of (toluene-4-sulfonylmethyl) -phosphonic acid diethyl ester prepared according to the procedure of 1996, 61, 7697 affords the corresponding phosphonate 6-9 in which the linkage is a methylene group. Using the above procedure, but using a different phosphonate reagent 6-6 instead of 6-8, the corresponding product 6-2 with a different linking group is obtained.

Example 7: Preparation of exemplary compounds of the invention (Scheme 7.1)

Compound 7-3 (X = —CH ₂ CH ₂ —) is prepared as outlined in Scheme 7.1. Camptosar (US Patent No. 4,604,463) is activated with p-nitrophenyl chloroformate in DMF and triethylamine and then reacted with aminophosphonate to give compound 7-3.

  (Scheme 7.2)

Compound 7-4 is obtained by published procedures (J. Chem. Soc. Perkin Trans. 2, 1972, 2035). Activation of 7-4 with 10-OH and subsequent reaction with amine 7-21 (as its acid chloride) provides 7-5 (US Patent No. 4,604,463). Compound 7-6 is prepared by refluxing 7-5 and aminoethylphosphonate in DMF and DIPEA.

  (Scheme 7.3)

Key intermediates are described in Dallavele, S .; et al. 7-hydroxymethyl-10-hydroxycamptothecin 7-7 prepared according to (J. Med. Chem. 2000, 43, 3963-3969). The 7-aldehyde derivative 7-10 is prepared by refluxing 7-7 in glacial acetic acid. Further oxidation of 7-10 gives 7-11. Reaction of 7-10 with triphenylphosphoranylideneacetoaldenide and t-butoxycarbonylmethylenetriphenylphosphorane provides 7-12 and 7-13, respectively (J. Med. Chem. 2000, 43, 3963). ).

  (Scheme 7.4)

Compound 7-7 is reacted with 7-22 (US Patent No. 4,604,463) and then reacted with triflated phosphonate and NaH to give compound 7-8.

  (Scheme 7.5)

The synthesis of 7-19, 7-18, 7-17, and 7-16 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 produce 7-15a, 7-15b, 7-15c. , And 7-15d. Aminoethyl phosphonate compounds are prepared 7-19 by reductive amination of 7-15a in NaBH ₃ CN, and AcOH. Compound 7-15b is activated with BOP reagent and then reacted with aminoethylphosphonate to give compound 7-18. Reductive amination of 7-15c with aminoethylphosphonate followed by hydrogenation in the presence of 10% Pd / C provides the desired 7-17. Hydrogenation of 7-15d and subsequent treatment with aminoethylphosphonate in the presence of a coupling agent (eg, BOP reagent, DIC) provides the desired product 7-16.

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 8: Preparation of exemplary compounds of the invention (Scheme 8.1)

As illustrated in Schemes 8.1-8.5, highcamtin derivatives at C-10 and O-20 are readily prepared from Hicamtin (topotecan) (US Patent No. 5,004,758). . Hycamtin is reacted with a triflated phosphonate to give an 8-2 analog. Activation of Hycamtin with p-nitrophenyl chloroformate and subsequent reaction with an appropriate aminophosphonate nucleophile provides the desired analog 8-4 containing a carbamate linkage.

  (Scheme 8.2)

Conversion of the OH group to triflate with C-10, followed by CO insertion, and reaction with aminophosphonate provides analog 8-7. Conversion of the triflate to an aldehyde by CO insertion followed by reductive amination with aminophosphonate provides 8-6 analogs. Protection of OH with C-10 and activation of OH-20 and subsequent reaction with aminophosphonate provides the desired analog of 8-8.

Analog 8-12 is synthesized from Pd-catalyzed reduction of triflated 8-10 followed by activation of 0-20 with p-nitrophenyl chloroformate and reaction with aminophosphonate. NaH in a DMF, by methylation of Hycamtin by treatment Hycamtin with CH ₃ I, 10-OCH ₃ Hycamtin is obtained. Analog 8-14 is obtained from OCH ₃ Hicamtin derivative in the same manner as 8-12.

  (Scheme 8.5)

Analog 8-17 is prepared by reaction of 10-hydroxycamptothecin with paraformaldehyde, methylamine, and acetic acid followed by amination with aldehyde phosphonate.

  (Scheme 8.6)

As shown in Scheme 8.6, the Hycamtin in presence of Cs ₂ CO ₃ in acetonitrile is reacted with diethyl phosphonate compound 8-18 is obtained. By reaction with OH-10 activation and amino phosphonate by reaction with chloroformate p- nitrophenyl of _CH 2 Cl ₂ in the presence of DIPEA, carbamates 8-20 is obtained.

  (Scheme 8.7)

As shown in Scheme 8.7, 10-OH triflation of Hicamtin (J. Am. Chem. Soc., 1984, 106, 7500) and subsequent CO insertion provides an aldehyde intermediate (J. Am. Org. Chem. 1999, 64, 178). Reductive amination of the aldehyde with aminophosphonate followed by acid treatment provides amine 8-21. Carboxylic acid is obtained by triflation of Hicamtin and CO insertion (J. Org. Chem. 1994, 59, 6683). The resulting carboxylic acid is activated with BOP reagent and then reacted with aminoethylphosphonate in the presence of DIPEA to give compound 8-22. Protection of 10-OH with TMS-Cl, activation of 20-0H with p-nitrophenyl chloroformate, and subsequent reaction with aminophosphonate provides 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. Removal of 8-10 hydroxyl groups in DMF using dppp, Pd (OAc) ₂ , and Et ₃ SiH yields 8-11. Compound 8-24 is prepared from 8-11 by activation with p-nitrophenyl chloroformate followed by coupling with an aminophosphonate and acid finishing.

  (Scheme 8.9)

The Hycamtin was treated with NaH in DMF, is reacted with CH ₃ I 10- methoxy derivative is obtained (Scheme 8.9). This 10-methoxy intermediate is activated with p-nitrophenyl chloroformate and then reacted with an aminophosphonate, acid finishing to give the desired phosphonate 8-25.

  (Scheme 8.10)

Scheme 8.10 describes the synthesis of compound 8-26 (an example of analog 8-17) and 9-methylaminomethyl-10-hydroxycamptothecin 8-16 (in place of dimethylamine) with a phosphonate having an aldehyde function. Reductive amination of methylamine in the preparation as Hicamtin as described in US Patent No. 5,004,758 gives the desired product 8-26.

  The phosphonate moiety can be further manipulated before final deprotection. These conversion types are described extensively by the phosphonate interconversion section herein.

Example 9: Preparation of exemplary compounds of the invention (Scheme 9.1)

Exemplary compounds of the present invention are illustrated above.

  (Scheme 9.2)

Synthetic examples of analogs 9-2 to 9-8 are illustrated in Schemes 9.2, 9.3, and 9.4. Reaction of ketone 9-9 (Chem. Lett. 1980, 51) and 1,2,4-triazole with n-BuLi in THF at −78 ° C. provides alcohol 9-10. Compound 9-10 is reacted with triflated phosphonate and NaH to give 9-12 (example of 9-7 (X = —CH ₂ —)). Compound 9-10 is activated with p-nitrophenyl chloroformate and then reacted with aminoethylphosphonate in the presence of diisopropylethylamine (DIPEA) to give the desired product 9-11 (example of analog 9-8 (X = -CH ₂ CH ₂ -)) is obtained.

  (Scheme 9.3)

For example, stirring a 1,2,4-tetrazole ester derivative with α-bromo-4-torunilyl in CH ₂ Cl ₂ provides 9-13 (US Patent). No. 4,978,672). Compound 9-13 is saponified with LiOH to give acid 9-14. U. S. Patent No. The acid is reacted with 4-fluorobenzonitrile according to the procedure described in 4,978,672 to give the key intermediate 9-15. Reaction of 9-15, DIC, HOAt, and aminoethylphosphonate provides 9-16 (analog 9-2 example (X = —CH ₂ CH ₂ —)). Reduction of 9-15 with borane in THF followed by reaction with triflated phosphonate and NaH yields the desired product 9-18 (analog 9-4 example (X = —CH ₂ CH ₂ —) ) Is obtained.

  (Scheme 9.4)

Oxidation of 9-17 with MnO ₂ gives the aldehyde derivative 9-19. Treatment of 9-19 with aminoethylphosphonate provides 9-22 (analog 9-5 example (X = —CH ₂ CH ₂ —)). Aldehyde 9-19 is reacted with hydroxyamine followed by reaction with triflated phosphonate to give 9-21 (analog 9-6 example (X = —CH ₂ CH ₂ —)). Reductive amination of 9-19 with aminoethylphosphonate, NaBH ₃ CN, and AcOH gives compound 9-20.

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 10: Preparation of exemplary compounds of the invention (Scheme 10.1)

Exemplary compounds of the present invention are illustrated above. Synthesis of novel compounds including phosphonates containing 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)

Like previously published procedures (J. Med. Chem. 1991, 34, 725), 10-12 (J. Heterocyclic Chem. 1975, 2, 577) and 10-13 (Bioorg. Med. Chem. Lett. ., 2001, 11, 1257) to prepare compound 10-14. Compound 10-14 was protected with a benzyl group by reaction with benzyl bromide and Cs ₂ CO ₃ followed by treatment with thionyl chloride followed by cyclization with KOt-Bu (J. Med. Chem. 1991, 34, 725). ), Compound 10-15 is obtained. Removal of the benzyl group by hydrogenation provides 10-16. Compound 10-16 is stirred with triflated phosphonate, Cs ₂ CO _{3 in} CH ₃ CN to give the desired product 10-17 (analog 10-8 example (X = —CH ₂ —)). Compound 10-16 was activated with p-nitrophenyl chloroformate in the presence of TEA and then treated with aminoethylphosphonate to give 10-18 (analog 10-7 example (X = —CH ₂ CH ₂ —)) Is obtained.

  (Scheme 10.3)

Compound 10-20 is prepared from 10-12 and 10-19 in the same manner as compound 10-14. Compound 10-21 is synthesized according to the procedure for 10-15 above and then hydrogenated in the presence of 10% Pd / C to give key intermediate 10-22. Reductive amination of 10-22 with aldehyde phosphonate, NaBH ₃ CN, and AcOH provides the desired product 10-23 (example of analog 10-9 (X = —CH ₂ CH ₂ —)). Compound 10-22 is reacted with phosphate formate phosphonate in the presence of TEA to give product 10-25 (analog 10-11 example (X = —CH ₂ CH ₂ —)). Reaction of 10-22 with carboxylic acid phosphonate and DIC gives the analog 10-10 example (X = —CH ₂ —) (10-24 compound). Formylation of fadrozole with n-BuLi, DMF gives intermediate aldehyde 10-26 (J. Med. Chem. 2000, 43, 2165). Oxidation of 10-26 yields the acid followed by reaction with aminoethylphosphonate, DIC, and HOAt to produce the desired product 10-31 (analog 10-5 example (X = —CH ₂ CH ₂ —)) Is obtained. Reductive amination of 10-26 with aldehyde phosphonate, NaBH ₃ CN, and AcOH provides the desired product 10-27 (example of analog 10-2 (X = —CH ₂ CH ₂ —)). By treatment 10-26 with aminoethyl phosphonate, 10-30 (example of analog _{10-6 (X = -CH 2 CH 2} -)) is obtained.

  (Scheme 10.4)

Reduction of 10-26 with NaBH ₄ gives the alcohol derivative, followed by reaction with triflated phosphonate and NaH to give product 10-29 (analog 10-4 example (X = —CH ₂ —)). It is done. The oxime is obtained by condensation of compound 10-26 with hydroxyamine in the presence of TEA. Alkylation of the oxime with triflated phosphonate and NaH affords the desired compound 10-28 (example of analog 10-3 (X = —CH ₂ —)).

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 11: Preparation of exemplary compounds of the invention (Scheme 11.1)

Exemplary compounds of the present invention are illustrated above.

  (Scheme 11.2)

Temozolomide, mitozolomide, and its derivatives were synthesized by several different synthetic routes (Scheme 11.2). 5-Aminoimidazole-4-carbozamide is reacted with alkyl isocyanate to give a 1- (N-alkylcarbamoyl) derivative. This derivative is treated with sodium nitrite to give 11-10 (J. Org. Chem. 1997, 62, 7288). Alternatively, 5-aminoimidazole-4-carbozamide is treated with sodium nitrite to obtain a diazonium salt, which is then reacted with an alkyl isocyanate to give amide 11-10 (US Patent No. 5,260). , 291). Conditions for hydrolyzing the amide 11-10 to the acid 11-13 can be selected (J. Med. Chem. 1990, 33, 1393). The acid 11-13 is converted to an aldehyde followed by reductive amination with aminoethylphosphonate to give analog 11-31, reaction with aminophosphonate gives analog 11-41, hydroxylamine, triflate phosphonate and To give 11-51. Compound 11-13 is reacted with an aminophosphonate and a coupling agent to give analog 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 was prepared stepwise from the reaction of 5-aminoimidazole-4-carbozamide with methyl isocyanate in acetonitrile, followed by nitrosation and cyclization with sodium nitrite in 50% acetic acid. -10 is obtained (J. Org. Chem. 1997, 63, 7288). Reaction of 11-10 and sodium nitrite in concentrated sulfuric acid converts temozolomide to acid 11-14. Treatment of acid 11-14 with thionyl chloride and a catalytic amount of DMF provides the acid chloride (J. Med. Chem. 1990, 33, 1393). Reaction of the acid chloride with aminoethylphosphonate gives 11-15. Reaction of the acid chloride with hydroxymethylamine followed by reduction with DIBAL in THF provides the aldehyde 11-16. The aldehyde is further reacted with aminoethylphosphonate and reductively aminated with aminoethylphosphonate, NaBH ₃ CN, and AcOH to give 11-18 and 11-19, respectively. Aldehyde 11-16 can be reacted with a hydrohydroamine amine in the presence of TEA and then reacted with triflated phosphonate and NaH to give 11-17.

  (Scheme 11.4)

Compounds 11-21 and 11-23, which are examples of analogs 11-6 and 11-7, are synthesized as illustrated in Scheme 11.4 above. Compound 11-10 is lithiated with n-BuLi in THF at −78 ° C. and then reacted with DMF to give aldehyde derivative 11-20. Reductive amination of aldehyde 11-20 with aminoethyl phosphonate, NaBH ₃ CN, AcOH yields the desired product 11-21 (analog 11-6 example (X = —CH ₂ CH ₂ —) ) Is obtained. Temozolomide 11-10 is lithiated with n-BuLi in THF and then reacted with CO ₂ to give acid derivative 11-22. The acid 11-22 is reacted with an aminoethyl phosphonate in the presence of a coupling agent (eg DIC, HOAt) to give the desired product 11-23 (an example of analog 11-7 (X = -CH). ₂ CH ₂ -)) is obtained. Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 12: Preparation of exemplary compounds of the invention (Scheme 12.1)

Exemplary compounds of the present invention are illustrated above.

  (Scheme 12.2)

Each analog _{12-2 (X = -CH 2 -)} , 12-3 (X = -CH 2 CH 2 -), 12-4 (X = -CH 2 CH 2 -), 12-5 (X = -CH ₂ -), and _{12-6 (X = -CH 2 CH 2} -) is an example of a compound containing a phosphonate moiety 12-10,12-14,12-16,12-15, and synthetic 12-13 Is illustrated in Scheme 12-2 above. Etoposide is obtained as described in the above procedure (US Patent No. 3,408,441). Etoposide in acetonitrile is reacted with triflate phosphonate with _Cs 2 CO _3, phosphonate 12-10 is obtained. Etoposide is activated with p-nitrophenyl chloroformate and then reacted with aminoethylphosphonate in the presence of TEA to give 12-13. Triflation of 12-9 with PhN (Tf) ₂ followed by CO insertion in the presence of Pd (OAc) ₂ , pdpp, TEA with DMF-H ₂ O gave the carboxylic acid derivative 12-12. It is done. Compound 12-12 is reacted with aminoethylphosphonate, DIC, and HOAt to give 12-16. Triflation of etoposide followed by CO insertion in the presence of Pd (OAc) ₂ , pdpp, TEA, and triethylsilane in DMF provides aldehyde intermediate 12-11. Aldehyde 12-11 is reacted with hydroxylamine hydrochloride and diisopropylethylamine (DIPEA) followed by reaction with triflated phosphonate and NaH to give phosphonate 12-15. Reductive amination of 12-11 with aminoethylphosphonate, NaBH ₃ CN, and AcOH provides the desired compound 12-14.

  (Scheme 12.3)

As shown in Scheme 12.3, glycosylation of 12-17 with appropriately prepared β-d-glucopyranose, BF ₃ -Et ₂ O in dichloroethane at −20 ° C. (Bioorg. Med. Chem. Lett 1994, 4, 2567) gives compound 12-18 (J. Med. Chem. 1989, 32, 1418). Deprotection of the 3′-sugar hydroxyl group using zinc powder in 2: 1 THF-AcOH followed by hydrogenation in the presence of 10% Pd / C of the benzyl group of the 2′-sugar amino group and phosphonate. Deprotection provides the free amine 12-19. Reductive amination of amine derivative 12-19 with aminoethylphosphonate, NaBH ₃ CN, and AcOH provides phosphonate 12-20 (analog 12-8 example (X = —CH ₂ CH ₂ —)).

  (Scheme 12.4)

As in Scheme 12.4, Bioor. Med. Chem. Lett. 2001, 11, 2667 and J.H. Med. Chem. Compound 12-21 is prepared by the procedure described in 1999, 42, 4640. 12-21 of -20 ° C. in _{dichloroethane,} the glycosylation of 12-17 with BF 3 -Et ₂ O, compound 12-22 is obtained (J.Med.Chem.1989,32,1418). Deprotection of 2'- and 3'-sugar hydroxyl groups using zinc powder in 2: 1 THF-AcOH followed by CBZ group of the terminal amino group of phosphonate by hydrogenation in the presence of 10% Pd / C And deprotection of the benzyl group provides the free amine 12-23. Reductive amination of amine 12-23 with aminoethyl phosphonate, NaBH ₃ CN, and AcOH gave the desired compound 12-24 (example of analog 12-7 (X = —CH ₂ CH ₂ —, n = 1)) is obtained.

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 13: Preparation of exemplary compounds of the invention (Scheme 13.1)

Exemplary compounds of the present invention are illustrated above. Analogs 13-15, 13-16, and 13-9 are prepared as outlined in Scheme 13.2.

Compound 13-13 is a precursor of analogs 13-15, 13-16, and 13-9. An example synthesis is illustrated in Scheme 13.3. U. S. Patent No. Re. Compound 13-13 is synthesized by alkylation of triazole with benzyl bromide 13-12 followed by hydrogenation of the NO ₂ group in the presence of 10% Pd / C according to the procedure described in 36,617. Reductive amination of 13-13 with aldehyde phosphonate, NaBH ₃ CN, and AcOH provides 13-40 (13-9 example (X = —CH ₂ —)). 13-13, the carboxylic acid phosphonate (Carboxylic phosphonate), DIC, a solution of HOAt was stirred at room temperature (examples of 13-8 and _{13-16 (X = -CH 2 -)} ) product 13-42 is obtained It is done. Activation of hydroxymethylphosphonate with phosgene and subsequent reaction with amine 13-13 in the presence of diisopropylethylamine in CH ₂ Cl ₂ gave 13-41 (examples of 13-7 and 13-15 (X = -CH2-)).

  (Scheme 13.4)

Analogs 13-2 and 13-4 are prepared as outlined in Scheme 13.4. Compound 13-18 is prepared as described in the procedure (US Patent No. Re. 36, 617). Ester 13-18 is saponified to give acid 13-19, the key precursor of analogs 13-2 and 13-4.

  (Scheme 13.5)

Compound 13-18 is first saponified with LiOH to give 13-19 as shown in Scheme 13.5. Compound 13-19 is reacted with aminoethylphosphonate in the presence of coupling reagent DIC, HOAt to give 13-21 (13-2 example (X = —CH ₂ —). Acid 13-19 is Reduction to alcohol with BH ₃ -THF followed by reaction with triflated phosphonate, NaH in THF at room temperature gives 13-20 (13-4 example (X = —CH ₂ —)).

  (Scheme 13.6)

Reduction of ester 13-18 provides compound 13-22. Aldehyde derivative 13-22 is an important intermediate of 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 (X = —CH ₂ CH ₂ —)). Is obtained. Aldehyde 13-22 is reacted with hydroxylamine, by subsequent reaction with triflate phosphonate, 13-50 (example of analog 13-6 and _{13-24 (X = -CH 2 CH 2} -)) is obtained. Amination of 13-22 with aminoethylphosphonate, NaBH ₃ CN, AcOH provides compound 13-23.

  (Scheme 13.8)

The bromo derivative 13-27 is prepared by the described procedure for anastrozole (US Patent No. Re. 36,617). Compounds 13-27 in the presence of a presence of a Pd catalyst is reacted with a Grignard reagent ^R 2 MgBr or ^R ₂ CH = CH 2 vinyl derivative obtained, aldehyde 13-28 is obtained by subsequent ozonolysis. The aldehyde 13-28 is converted to analogs 13-36 and 13-10 using the procedure described in Schemes 13.6 and 13.7.

  (Scheme 13.9)

As shown in Scheme 13.9, compound 13-27 was coupled with CH ₂ ═CH _{2 in} the presence of Pd (OAc) ₂ , n-Bu ₃ P, K ₂ CO ₃ in DMF at 100 ° C. ( Tetrahedron Lett. 2002, 43, 3401), followed by ozonolysis to give aldehyde 13-28. Reductive amination of 13-28 with aminoethylphosphonate, NaBH ₃ CN, AcOH yields the desired product 13-32 (examples of analogs 13-10 and 13-36 (X = —CH ₂ CH ₂ —)) Is obtained. Reduction of the aldehyde using NaBH ₄ gives the alcohol derivative. Reduction of the alcohol derivative with NaH and triflated phosphonate in THF gives compound 13-31 (examples of analogs 13-11 and 13-10 (X = —CH ₂ —).

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 14: Preparation of exemplary compounds of the invention (Scheme 14.1)

Exemplary compounds of the present invention are illustrated above.

  (Scheme 14.2)

The synthesis of novel compounds including phosphonates is illustrated in Scheme 14.2. Diethyl 3-nitrocyclobutane-1,1-dicarboxylate (J. Org. Chem. 1989, 54, 2869) is readily converted to the 3-amino derivative in two steps. Compound 14-12 is obtained from the reaction of 3-aminocyclobutane-1,1-dicarboxylic acid sodium salt with PtCl ₂ (NH ₃ ) ₂ (US Patent No. 4,625,927). Compound 14-12 is readily 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 outlined in Scheme 14.3, 3-amino-1,1-dicarboxylic acids from 3-nitro derivatives in two steps (first saponification with NaOH followed by hydrogenation in the presence of 10% Pd / C). An acid is obtained. This dicarboxylic acid is first converted to its disodium salt by a previously reported procedure (US Patent No. 4,657,729) and then reacted with PtCl ₂ (NH ₃ ) ₂ to give a carboplatin analog. 14-12 are obtained. Reaction of 14-12 with phosphonate carboxylic acid, HOAt, and DIC gives the 14-13 example (14-2 (X = —CH ₂ —)). Reductive amination of 14-12 with aldehyde phosphonate, NaBH ₃ CN, and AcOH provides compound 14-14 (14-3 example (X = —CH ₂ CH ₂ —)). Hydroxymethylphosphonate is reacted with triphosgene to form a chloroformate derivative and compound 14-12 is reacted in the presence of TEA to give the desired product 14-15 (example of 14-5 (X = —CH ₂ — )) Is obtained.

  (Scheme 14.4)

Diethyl 3-oxocyclobutane-1,1-dicarboxylate (J. Med. Chem. 1990, 33, 2905) was saponified with sodium hydroxide and then reacted with hydroxylamine hydrochloride in the presence of TEA to give an oxime intermediate. The body 14-17 is obtained. Treatment of dicarboxylic acid oxime with sodium hydroxide (sodium salt is formed) according to previously reported procedure (US Patent No. 4,657,729) followed by PtCl ₂ (NH ₃ ). _To give carboplatin derivative 14-18. Compound 14-18 is readily converted to analog 14-33. The 14-14 example (phosphonate 14-19) is prepared by treatment of 14-12 with NaH and triflated phosphonate (Scheme 14.4).

  (Scheme 14.5)

In Scheme 14.5, diethyl 3-hydroxycyclobutane-1,1-dicarboxylate (J. Med. Chem. 1990) was prepared according to a previously reported procedure (US Patent No. 4,657,729). , 33, 2905) with sodium hydroxide and the disodium salt of dicarboxylic acid is reacted with PtCl ₂ (NH ₃ ) ₂ to give 3-hydroxycarboplatin analog 14-22. This analog is readily converted to 14-6 by reaction with a triflated phosphonate. Hydroxyl group activation and subsequent reaction with aminophosphonate converts hydroxyl 14-22 to analog 14-7. 3-hydroxycyclobutane-1,1-dicarboxylic acid 14-21 can be oxidized to its oxo derivative and further converted to 14-23 and 14-24. Compound 14-23 was reacted with PtCl ₂ (NH ₃ ) ₂ according to previously reported procedures (US Patent No. 4,657,729) followed by hydrogenation and reductive amination. 14-9 is obtained. In three steps (hydrogenation, carboplatin formation, and reaction with aminophosphonate), compounds 14-24 are converted to 14-8.

  (Scheme 14.6)

Diethyl 3-hydroxycyclobutane-1,1-dicarboxylate (J. Med. Chem. 1990, 33, 2905) is saponified with sodium hydroxide as shown in Scheme 14.6. This dicarboxylic acid disodium salt is reacted with PtCl ₂ (NH ₃ ) ₂ according to a previously reported procedure (US Patent No. 4,657,729) to give 3-hydroxycarboplatin analog 14-22. can get. By reaction with NaH and triflate phosphonate, (example _{14-6 (X = -CH 2 -)} ) the analog 14-25 readily converted to. Activation of the hydroxyl group with p-nitrophenyl chloroformate gives 14-26. The activated acid derivative 14-26 is reacted with aminoethylphosphonate in the presence of TEA to give the desired product 14-27 (example 14-7 (X = —CH ₂ CH ₂ —)). Reaction of 3-oxocyclobutane-1,1-dicarboxylic acid 14-35 with Ph ₃ P═CHCHO or PH ₃ P═CHCOOBn in CH ₂ Cl ₂ gives 14-33 and 14-24, respectively. The disodium salt of compound 14-33 is reacted with PtCl ₂ (NH ₃ ) ₂ to form a carboplastin derivative followed by reduction of the double bond by hydrogenation in the presence of 10% Pd / C; Reductive amination with aminoethylphosphonate, NaBH ₃ CN, and AcOH gives the desired 14-28 (14-9 example (X = —CH ₂ CH ₂ —)). The disodium salt of compound 14-33 is reacted with PtCl ₂ (NH ₃ ) ₂ followed by reductive amination with aminoethylphosphonate, NaBH ₃ CN, and AcOH to give 14-29 (unsaturation of 14-28). Analog). Hydrogenation in the presence of 10% Pd / C followed by reaction with PtCl ₂ (NH ₃ ) ₂ and reaction with aminoethylphosphonate, DIC, AcOH to give compound 14-30 (14-8 (X = —CH ₂ CH ₂ —)) is obtained.

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 15: Preparation of exemplary compounds of the invention (Scheme 15.1)

(Scheme 15.2)
The phosphonate analog 15-2 is readily prepared from 1-alkanoyloxymethyl steroid 15-3 (US Patent No. 4,591,585) as described in Scheme 15.2. A methylene group can be introduced at the 6-position according to the method described in the literature (Synthesis 1982, 34). Hydrolysis of 15-4 gives 1-hydroxymethyl steroid 15-5. Alkylation of 15-5 with phosphonate reagent gives the desired compound 15-2.
(Scheme 15.3)

Scheme 15.3 shows an example of the preparation of exemestane phosphonate analog. Treatment of 1-acetyloxymethyl steroid 15-6 with formaldehyde acetal, phosphorus oxychloride, and sodium acetate in chloroform provides 6-methylene compound 15-7. Hydrolysis of 15-7 with sodium hydroxide gives 1-hydroxymethyl steroid 15-5. Alkylation of 15-5 with phosphonate triflate gives the desired product 15-8.

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

  Example 16: Preparation of exemplary compounds of the invention

The phosphonate analog 16-2 is readily prepared from 1-acetyloxymethyl steroid 16-3 (US Patent No. 4,591,585) as illustrated in Scheme 16.2. Hydrolysis of 16-3 gives 1-hydroxymethyl steroid 16-4. Alkylation of 16-4 with a phosphonate reagent provides the desired compound 16-2.

  (Scheme 16.3)

Scheme 16.3 shows an example of the preparation of the phosphonate analog of atamestan. 1-Acetyloxymethyl steroid 16-3 is hydrolyzed with sodium hydroxide to give 1-hydroxymethyl steroid 16-4. Alkylation of 16-4 with phosphonate triflate gives the desired product 16-5.

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 17: Preparation of exemplary compounds of the invention (Scheme 17.1)

Exemplary compounds of the present invention are illustrated above.

  (Scheme 17.2)

The phosphonate analog of type 17-2 is readily prepared from epirubicin (17-1) by reductive amination of the amine with phosphonate aldehyde, as illustrated in Scheme 17.2.

  (Scheme 17.3)

For example (Scheme 17.3), reductive alkylation of epirubicin 17-1 with aldehyde 17-15 (Synth. Commun. 1992, 22, 2219) provides the desired compound 17-5.

  (Scheme 17.4)

As illustrated in Scheme 17.4, the protected epirubicin 17-6 (available by the method reported in J. Org. Chem. 1997, 42, 3653) can be converted to type 17- by alkylation with a suitable phosphonate reagent. Three phosphonate analogs are readily prepared.

  (Scheme 17.5)

For example (Scheme 17.5), alkylation of triprotected epirubicin 17-7 with phosphonate triflate, followed by basic (0.1N sodium hydroxide) and acidic (80% acetic acid) deprotection, compound 17-8 Is obtained.

  (Scheme 17.6)

Substitution of the leaving group X with an appropriate nucleophile as illustrated in Scheme 17.6, by the method reported in epirubicin intermediate 17-9 (J. Med. Chem. 1985, 28, 1223). A phosphonate analog of type 17-4 is readily prepared from (available).

  (Scheme 17.7)

For example (Scheme 17.7), reaction of bromide 17-11 with phosphonate amine followed by deprotection yields the desired product 17-12.

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 18: Preparation of exemplary compounds of the invention (Scheme 18.1)

Exemplary compounds of the present invention are illustrated above.

  (Scheme 18.2)

The phosphonate analog of type 18-2 is readily prepared from adriamycin 18-1 by reductive alkylation of the amine with phosphonate aldehyde, as illustrated in Scheme 18.2.

  (Scheme 18.3)

For example (Scheme 18.3), reductive alkylation of adriamycin 18-1 with aldehyde 18-5 (Synth. Commun. 1992, 22, 2219) provides the desired compound 18-5.

  (Scheme 18.4)

As illustrated in Scheme 18.4, phosphonate analogs of type 18-3 are readily prepared from protected adriamycin 18-6 (J. Org. Chem. 1997, 42, 3653) by alkylation with a suitable phosphonate reagent. To do.

  (Scheme 18.5)

For example (Scheme 18.5), alkylation of the triprotected adriamycin 18-7 with phosphonate triflate, followed by basic (0.1N sodium hydroxide) and acidic (80% acetic acid) deprotection, compound 18-8 Is obtained.

  (Scheme 18.6)

Substitution of the leaving group X with an appropriate nucleophile from adriamycin intermediate 18-9 (J. Med. Chem. 1985, 28, 1223) as shown in Scheme 18.6 to form 18-4 The phosphonate analog is readily prepared.

  (Scheme 18.7)

For example (Scheme 18.7), reaction of bromide 18-10 with phosphonate amine and subsequent deprotection yields the desired product 18-11.

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 19: Preparation of exemplary compounds of the invention (Scheme 19.1)

Exemplary compounds of the present invention are illustrated above. Forms 19-2, 19-3, and 19-4 are readily prepared from taxotere 19-1.

  (Scheme 19.2)

Direct alkylation of 19-1 with a phosphonate reagent gives the analog of type 19-2 as the main product (Tetrahedron 1993, 49, 2805). Selective protection of taxotere at C-2 ′ (J. Org. Chem. 1995, 60, 761) yielded 19-6, followed by alkylation with phosphonate reagent followed by deprotection to form 19-3 and 19 -4 analog is obtained.

  (Scheme 19.3)

For example (Scheme 19.3), treatment of taxotere 19-1 with tert-butyldimethylsilyl chloride and triethylamine in DMF provides mono-TBS protected taxotere 19-7. Alkylation of 19-7 with phosphonate triflate and subsequent deprotection with tetrabutylammonium fluoride affords the desired products 19-9 and 19-8. Direct alkylation of taxotere 19-1 with phosphonate triflate can provide type 19-2 analogs.

  (Scheme 19.4)

As illustrated in Scheme 19.4, according to the method reported in the literature (Bioorg. Med. Chem. Lett. 1994, 4, 479; Synlett 1992, 761), β-lactam 19-10 and baccatin III ( 19-11) can be obtained from Taxotere analog 19-12 available from type 19-5.

  (Scheme 19.5)

For example (Scheme 19.5), β-lactam 19-14 is prepared by literature procedures (Synlett 1992, 761) using 4-nitrobenzaldehyde (instead of benzaldehyde) as starting material. Reaction of 19-14 with baccatin III in the presence of 4-dimethylaminopyridine provides compound 19-16. Reduction of 19-16 with zinc in acetic acid provides the amino compound 19-18. Alkylation of 19-18 with phosphonate triflate reagent provides the desired compound 19-17.

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 20: Preparation of exemplary compounds of the invention (Scheme 20.1)

Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

  As shown in Scheme 20.2, phosphonate analogs of types 20-2, 20-3, and 20-4 are readily prepared from taxol 20-1. Direct alkylation of 20-1 with a phosphonate reagent gives the analog of type 20-2 as the main product (Tetrahedron, (1993), 49, 2805). Selective protection of taxol at the C-2 ′ position (J. Org. Chem. (1995), 60, 761) gave 7 followed by alkylation with phosphonate reagent followed by deprotection to form 20- Three analogs are obtained. Complete protection of taxol at the C-2 ′ and C-7 positions yields 20-8, after which the C-10 hydroxyl group of 20-8 is exposed and alkylated with a phosphonate reagent, followed by deprotection to form 20-4 analogs are obtained. For example (Scheme 20.3), treatment of taxol 20-1 with tert-butyldimethylsilyl chloride and triethylamine in DMF provides bis-TBS protected taxol 8a. Treatment of hydrazine 8a in ethanol gives compound 2-11 (J. Org. Chem. (1995), 60, 761). Alkylation of 20-11 with phosphonate triflate followed by deprotection with tetrabutylammonium gives the desired product 20-10.

  (Scheme 20.2)

(Scheme 20.3)

As illustrated in Scheme 20.4, according to the method reported in the literature (Bioorg. Med. Chem. Lett. 1994, 4, 479; Synlett 1992, 761), β-lactam 20-12 and baccatin III ( 20-13, 20-16) from the available taxotere analog 20-14, the analog of type 20-5 can be obtained. For example (Scheme 20.5), β-lactam 20-15 is prepared by literature procedures (Synlett 1992, 761) using 4-nitrobenzoyl chloride (instead of benzoyl chloride) as the starting material. Reaction of 20-15 with baccatin III in the presence of 4-dimethylaminopyridine provides compound 20-17. Reduction of 20-17 with zinc in acetic acid provides the amino compound 20-19. Alkylation of 20-19 with a phosphonate triflate reagent gives the desired compound 20-18.

As shown in Scheme 20.6 and Scheme 20.7, analogs of type 20-6 can be prepared in the same manner as type 20-5.
(Scheme 20.6)

Example 21: Preparation of exemplary compounds of the invention

Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the following section.

  As illustrated in Scheme 21.2, the synthesis strategy of type 21-2 phosphonate analogs initially introduces the phosphonate moiety into catalanthin 21-5 to give 21-7, which is then the same method as the synthesis of vinorelbine (Bioorg. Med. Chem. Lett. (2002), 12, 505; Tetrahedron (1980), 36, 3053) is used to bind to vindrin 21-10 and convert to the final compound 21-2.

  (Scheme 21.2)

For example (Scheme 21.3), catalanthin 21-5 is hydrolyzed with sodium hydroxide to give 21-6. Coupling of 21-6 with phosphonate amine gives 21-9. Conversion of 21-9 and vindrin 21-10 to compound 21-11 is accomplished by sequential treatment of 3-chloroperoxybenzoic acid (mCPBA), trifluoroacetic anhydride (TFAA), and sodium borohydride. Treatment of 21-11 with N-bromosuccinimide (NBS) followed by treatment with silver tetrafluoroborate provides the desired compound 21-12.

  (Scheme 21.3)

A synthetic strategy similar to type 21-3 phosphonate analogs is used, as illustrated in Scheme 21.4. The phosphonate moiety is first introduced into vindrin 21-10 to give 21-14, which is then coupled to catalanthin 21-5 and converted to the final compound 21-3 using the same method as the synthesis of vinorelbine.

  (Scheme 21.4)

For example (Scheme 21.5), hydrolysis of vindrin 21-10 with sodium hydroxide and subsequent reprotection of the hydroxyl group provides 21-20. Coupling of 21-20 with phosphonate amine gives 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)

As illustrated in Scheme 21.6, a phosphonate analog of type 21-4 is readily prepared from vinorelbine 21-1. 21-1 hydrolysis yields 21-18, which is then alkylated with a phosphonate reagent to give type 21-4 analogs.

  For example (Scheme 21.7), treatment of 21-1 with sodium methoxide in anhydrous methanol gives compound 21-18. Alkylation of 21-18 with phosphonate triflate in the presence of sodium hydride provides the desired compound 21-19.

Example 22: Preparation of exemplary compounds of the invention (Scheme 22.1)

Using the examples shown in Schemes 22.4 to 22.6, these compounds and the like can be made according to the general route outlined in Schemes 22.2 to 22.3.

  (Scheme 22.2: Modification of sugar substituent)

(Scheme 22.3: Binding to epipodophyllotoxin)

(Scheme 22.4: Modification of 4,6 glucose acetal moiety)

Chem. Lett. (1987), 799-802. Glucose-derived starting materials are synthesized from glucose and benzylglyoxylate (J. Org. Chem., (2002), 67, 5408-5411). The glycosyl reaction is carried out using 4 ′ chloroacetyl protected epipodophyllotoxin (described in the above cited reference) under the catalyst of boron trifluoride (described in the above cited reference). The product of this reaction is dissolved in an organic solvent such as ethyl acetate and hydrogenated in the presence of Pd / C under a hydrogen atmosphere. The crude reaction mixture is filtered through Celite and the solvent is removed in vacuo. The crude reaction product is dissolved in an organic solvent such as DMF or chloroform and then treated with a tertiary amine such as diisopropylethylamine (DIEA) and isobutyl chloroformate at about −10 ° C. After completion of activation, 2-aminoethylphosphonic acid diethyl ester is added. After all starting material is consumed, the reaction mixture is washed with 0.1 M aqueous HCl and dicarbonate solution. After dry removal of the solvent, a crude coupling product is obtained. Further purification by chromatography. The material is dissolved in an organic solvent such as methanol and treated with zinc acetate at reflux temperature. After completion of the reaction, the mixture is cooled to room temperature and the solvent is removed under reduced pressure. The crude reaction product is dissolved in an organic solvent such as chloroform and the solution is washed with 0.1 M aqueous HCl and aqueous bicarbonate. After dry removal of the solvent, the crude final product is obtained. Further purification by chromatography.

  (Scheme 22.5: Modification of glucose core)

J. et al. Org. Chem., (1996), 61, 3849-3862, starting material (synthesized with Chem. Lett., (1987), 799-804) was prepared in diethyl phosphonate in an organic solvent such as DCM or THF. Treat with ethyl carbaldehyde and sodium triacetoxyborohydride. The reaction is quenched with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Further purification by chromatography.

  (Scheme 22.6: Binding to epipodophyllotoxin core)

J. et al. Org. Starting material (obtained as described in J. Med. Chem., (1991), 34, 3346-3350) as described in Chem, (1996), 61, 3849-3862, such as DCM or THF With diethyl phosphonatoethylcarbaldehyde and sodium triacetoxyborohydride in an organic solvent. The reaction is quenched with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Further purification by chromatography.

  Bioorg. Med. Chem. Lett. , (1994), 21, 2567-1572, all the final products are trichloride in organic solvents such as MeCN in the presence of tertiary organic amines such as DIEA of these compounds. Conversion to the corresponding 4 ′ phosphate analog by treatment with phosphoryl followed by treatment with aqueous sodium bicarbonate. Further purification by chromatography.

Example 23: Preparation of exemplary compounds of the invention
Using the examples shown in Schemes 23.7 to 23.12, these compounds and the like can be made according to the general route outlined in Schemes 23.1 to 23.6.

  (Scheme 23.1: Modification at C4)

(Scheme 23.2: Binding 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)

J. et al. Med. Chem. , (1991), 34, 1001-1018, 2-diethylphosphonatoacetic acid dissolved in an organic solvent such as benzene, tetrahydrofuran (THF), or chloroform, and a tertiary amine base such as diisopropylethylamine (DIEA) and Mix with diphenylphosphoradidate (1.2 eq) and stir at room temperature. After formation of the acyl azide, 4-deacetylvinblastine (prepared from vinblastine according to J. Med. Chem., (2002), 45, 4706-4715) is added and the reaction mixture is heated to about 80 ° C. for about 4 hours ( Biochemistry (2002), 41, 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous hydrochloric acid (HCl) (1N) and aqueous bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography.

  The product of this step is dissolved in an organic solvent such as acetonitrile and the solution is cooled to -20 ° C. Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. 37,145, Academic Press San Diego, (1990), an inorganic strong acid such as perchloric acid (2 equivalents) is added, followed by ferrous perchlorate and hydrogen peroxide (excess). After the reaction, an aqueous ammonium hydroxide solution is added, and the reaction mixture is extracted with an organic solvent such as dichloromethane (DCM). Removal of the solvent under reduced pressure gives the crude product. Further purification by chromatography.

  (Scheme 23.8: Binding to C23)

J. et al. Med. The starting material (synthesis from vinblastine published in J. Med. Chem., (1978), 21, 88-96) is brought to room temperature according to the procedure described in Chem, (1979), 22, 391-400. Treatment with 2-aminoethylphosphonic acid diethyl ester in an organic solvent such as DCM or THF. After completion of the reaction, the solution is washed with water, aqueous bicarbonate solution, and water and dried. The crude product is obtained by depressurizing the solvent. Further purification by chromatography.

  The product of this step is dissolved in an organic solvent such as DCM or THF. J. et al. Med. Chem. , (1979), 22, 391-400, pyridine is added followed by acetic anhydride and the reaction is stirred at room temperature. After completion of the reaction, methanol is added and the solvent is removed under reduced pressure. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The crude product is obtained by removing the solvent under reduced pressure. Further purification by chromatography.

  The product of this step is dissolved in an organic solvent such as acetonitrile and the solution is cooled to -20 ° C. Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. 37,145, Academic Press San Diego, (1990), an inorganic strong acid such as perchloric acid (2 equivalents) is added, followed by ferrous perchlorate and excess hydrogen peroxide. After the reaction, aqueous ammonium hydroxide solution is added and the reaction mixture is extracted with an organic solvent such as DCM. Removal of the solvent under reduced pressure gives the crude product. Further purification by chromatography.

  (Scheme 23.9: Binding to N1)

J. et al. Med. Chem. , (1991), 34, 1001-1018, 2-diethylphosphonatoacetic acid is dissolved in an organic solvent such as benzene, THF or chloroform and a tertiary amine base such as diisopropylethylamine (DIEA). And diphenylphosphoradidate (1.2 eq) and stirred at room temperature. After formation of the acyl azide, N-1- (β-hydroxyethylthiomethyl) vinblastine (Pearce, “Medicalal Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. Thus, CrO ₃ mediated oxidation in the presence of methanol followed by replacement of methoxy with β-hydroxylthioethanol was added and the reaction mixture was heated to about 80 ° C. for about 4 hours (Biochemistry (2002)). ), 41, 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous hydrochloric acid (HCl) (1N) and aqueous bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography.

  (Scheme 23.10: Binding to C4 ')

Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. 37,145, Academic Press San Diego, (1990) (described for acetonitrile), vinblastine and diethyl (cyanomethyl) phosphonate (commercially available) are dissolved in concentrated sulfuric acid at about 0 ° C. Upon consumption of the starting material, the reaction mixture is carefully diluted with water and further neutralized. The crude reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous sodium bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography.

  The product of this step is dissolved in an organic solvent such as acetonitrile and cooled to -20 ° C. Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. 37,145, Academic Press San Diego, (1990), an inorganic strong acid such as perchloric acid (2 equivalents) is added, followed by ferrous perchlorate and excess hydrogen peroxide. After the reaction, aqueous ammonium hydroxide solution is added and the reaction mixture is extracted with an organic solvent such as DCM. Removal of the solvent under reduced pressure gives the crude product. Further purification by chromatography.

  (Scheme 23.11: Binding to 12 ')

C12′-iodo-vinblastine (Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. 37, 145, Academic Press San Di peri-acid (1) Propyl) ammonium periodate and prepared by iodination of vinblastine with a catalytic amount of ruthenium dioxide) to a mixture of copper (I) iodide, potassium phosphate, and 2-aminoethylphosphonic acid diethyl ester (commercially available) To do. Buchwald in Org. Lett. , (2002), 4,581-584, the reaction mixture is heated to about 80 ° C. under an inert gas atmosphere. After the reaction is complete, the material is cooled to room temperature and the solvent is removed in vacuo. The crude reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous sodium bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography. The product of this step is dissolved in an organic solvent such as DCM or THF. J. et al. Med. Chem. , (1979), 22, 391-400, pyridine is added followed by acetic anhydride and the reaction is stirred at room temperature. After completion of the reaction, methanol is added and the solvent is removed under reduced pressure. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The crude product is obtained by removing the solvent under reduced pressure. Further purification by chromatography.

  The product of this step is dissolved in an organic solvent such as acetonitrile and the solution is cooled to -20 ° C. Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. 37,145, Academic Press San Diego, (1990), an inorganic strong acid such as perchloric acid (3 equivalents) is added, followed by ferrous perchlorate and excess hydrogen peroxide. After the reaction, aqueous ammonium hydroxide solution is added and the reaction mixture is extracted with an organic solvent such as DCM. Removal of the solvent under reduced pressure gives the crude product. Further purification by chromatography.

  (Scheme 23.12: Binding to 22 ')

Starting material (Pearce, Medicinal Chemistry of Bisindole Alkaloids from Catalanthus), in The Alkaloids, Vol. (Prepared by complete hydrolysis) is dissolved in an organic solvent such as dimethylformamide (DMF) at room temperature. Methyl iodide (1 equivalent) is added followed by potassium carbonate. Continue stirring at room temperature. After the reaction, the reaction product is filtered and the solvent is removed under reduced pressure. 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 <0> C. A tertiary amine base such as DIEA is added, followed by a coupling reagent such as isobutyl chloroformate. Continue stirring at −10 ° C. until activation is complete. Add aminoethylphosphonic acid diethyl ester and continue stirring at 0 ° C. with slow warming. After the reaction, the solution is warmed to room temperature and the solvent is removed under reduced pressure. Further purification by chromatography. The product of this step is dissolved in an organic solvent such as DCM or THF. J. et al. Med. Chem. , (1979), 22, 391-400, pyridine is added followed by acetic anhydride and the reaction is stirred at room temperature. After completion of the reaction, methanol is added and the solvent is removed under reduced pressure. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The crude product is obtained by removing the solvent under reduced pressure. Further purification by chromatography.

  The product of this step is dissolved in an organic solvent such as acetonitrile and the solution is cooled to -20 ° C. Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. 37,145, Academic Press San Diego, (1990), an inorganic strong acid such as perchloric acid (2 equivalents) is added, followed by ferrous perchlorate and excess hydrogen peroxide. After the reaction, aqueous ammonium hydroxide solution is added and the reaction mixture is extracted with an organic solvent such as DCM. Removal of the solvent under reduced pressure gives the crude product. Further purification by chromatography.

Example 24 Preparation of Exemplary Compounds of the Invention Using the examples shown in Schemes 24.2 and 24.4, the compounds of the invention are prepared according to the general route outlined in Schemes 24.1 and 24.3. Can be prepared.

  (Scheme 24.1)

(Scheme 24.2)

Prepared according to the procedure of 2-chloro-2′-deoxyadenosine 24-1 (Ikehara, M. et al., J. Am. Chem. Soc., (1963), 85, 2344 (Ikehara, M. et al. J. Am. Chem. Soc., (1965), 87, 3,606)) can also be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyl triflate (prepared according to Tetrahedron Lett., (1986), 27, 1477)) is added to give the desired phosphonate diester 24-2, 24-3.

  (Scheme 24.3)

The preparation of compounds 24-7, 24-13 is described in Scheme 24.3. Ikehara, M .; et al. , J .; Am. Chem. Soc. (1963), 85, 2344 (see also Ikehara, M. et al., J. Am. Chem. Soc., (1965), 87, 3,606), compound 24-1. (2-Chloro-2′-deoxyadenosine) can be prepared. Oxidation of 5′-OH and subsequent elimination yields glycal 24-4 (see the procedure of Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). ) Protection of chloroadenosine at the 6-position and subsequent selenoetherification affords protected phosphonates 24-5, 24-10 (Kim, C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative elimination of phenyl selenide (described in Kim, C. et al., J. Org. Chem., (1991), 56, 2642) and subsequent stereoselective dihydroxylation yields a diol, followed by Can be converted to a 3 'monoprotected sugar. Acylation of the 2 ′ alcohol with phenylchlorothionoformate provides a precursor for Robins deoxygenation. Subsequent deoxygenation gives compounds 24-6, 24-12 (Metteucci, MD et al., Tetrahedron Lett., (1987), 28, 22, 2469 (Robins, MJ et al. , J. Org. Chem., (1995), 60, 7902)). Finally, the protecting group is removed.

  (Scheme 24.4)

Specifically, 2-chloro-2′-deoxyadenosine (compound 24-1) is oxidized with PtO ₂ to give carboxylic acid 24-8. Decarboxylation is performed using dimethylformamide dineopentyl acetal in DMF at high temperature (Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). ). Once the furanoid glycal 24-4 is obtained, Greene, T .; First, the 6-position of 2-chloroadenosine is protected using PivCl conditions as described in, Protective groups in organic synthesis, Wiley-Interscience, 1999. Treatment of protected glycals with silver perchlorate in the presence of diethyl (hydroxymethyl) phosphonate (Philion, D. et al., Tetrahedron Lett., 1986, 27, 1477) leads to phosphonates 24-5, 24-10. (Kim, C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative elimination of selenide followed by dihydroxylation using osmium tetroxide provides a diol that can be monoprotected at the 3 'position using a THP group. Further acylation of the 2 ′ alcohol with phenylchlorothionoformate provides the precursor and Robins deoxygenation using tributyltin hydride to give compounds 24-6, 24-12 (Metteucci, M See also D. et al., Tetrahedron Lett., (1987), 28, 22, 2469 (Robins, MJ et al., J. Org. Chem., (1995), 60, 7902). ). Deprotection of the pivaloyl group by treatment with sodium methoxide (Greene, T., Protective groups in organic synthesis, Wiley-Interscience, (1999)) followed by final deprotection of the THP group in acetic acid.

Example 25: Preparation of Exemplary Compounds of the Invention These compounds are followed according to the general route outlined in Schemes 25.1 to 25.5, using the specific examples shown in Schemes 25.2 to 25.5. Etc. can be produced. Final compounds that are diastereoisomers or enantiomers can be purified by chromatographic means.

  (Scheme 25.1: General access to all compound classes)

(Scheme 25.2 :)

Starting carboxylic acid using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as diisopropylethylamine (DIEA) in an organic 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). Upon completion of activation, 2-aminoethylphosphonic acid diethyl ester (commercially available) is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 25.3 :)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as diisopropylethylamine (DIEA) in an organic solvent such as DMF or NMP at room temperature (J. Med). Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Upon completion of activation, the base of (2-amino-ethylsulfanylmethyl) -phosphonic acid diethyl ester (2-aminoethanethiol and diethylphosphonomethyltriflate prepared by Tetrahedron Lett., (1986), 27, 1477) Prepared by catalytic coupling). After consumption of the activated species is observed, the solvent is removed under reduced pressure and the intermediate is isolated by chromatography. Alternatively, the intermediate can be isolated 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 a hydrogen peroxide solution (excess). After removal of the solution, the product is isolated by chromatography. Alternatively, the intermediate can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 25.4 :)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as DIEA in an organic solvent such as DMF or NMP at room temperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Upon completion of activation, (L) -2-amino-6- (diethylphosphonato) -hexanoic acid is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 25.5 :)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as DIEA in an organic solvent such as DMF or NMP at room temperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Upon completion of activation, 4-amino-4- (diethylphosphonato) butyric acid tertbutyl ester (J. Am. Chem. Soc., (1995), 117, 10879-10888) is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the intermediate is isolated by chromatography. Alternatively, the intermediate can be isolated 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 solution, the product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Example 26: Preparation of Exemplary Compounds of the Invention Using the specific examples shown in Schemes 2-4, these compounds are made according to the general route outlined in Schemes 26.1-26.5. be able to. Final compounds that are diastereoisomers or enantiomers can be purified by chromatographic means.

  (Scheme 26.1: General access to all compound classes)

If direct coupling to aminopterin is hindered by the presence of free secondary amines in the starting material (R = H), this component can be tert according to standard procedures (Green Wuts: Protective groups in organic chemistry). -Transient protection with either a butoxycarbonyl group (R = Boc) or benzyloxycarbonyl (R = Cbz or Z).

  (Scheme 26.2 :)

Starting carboxylic acid using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as diisopropylethylamine (DIEA) in an organic 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). Upon completion of activation, 2-aminoethylphosphonic acid diethyl ester (commercially available) is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the product is isolated by chromatography. Alternatively, the product can be isolated 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 a hydrogen atmosphere until the starting material is consumed. Pd / C is removed by filtration and the solvent is evaporated under reduced pressure. The product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 26.3 :)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as diisopropylethylamine (DIEA) in an organic solvent such as DMF or NMP at room temperature (J. Med Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Upon completion of activation, the base of (2-amino-ethylsulfanylmethyl) -phosphonic acid diethyl ester (2-aminoethanethiol and diethylphosphonomethyltriflate prepared by Tetrahedron Lett., (1986), 27, 1477) Prepared by catalytic coupling). After consumption of the activated species is observed, the solvent is removed under reduced pressure and the intermediate is isolated by chromatography. Alternatively, the intermediate can be isolated 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 a hydrogen peroxide solution (excess). After removal of the solution, the product is isolated by chromatography. Alternatively, the intermediate can be isolated 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 a hydrogen atmosphere until the starting material is consumed. Pd / C is removed by filtration and the solvent is evaporated under reduced pressure. The product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 26.4 :)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as DIEA in an organic solvent such as DMF or NMP at room temperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Upon completion of activation, (L) -2-amino-6- (diethylphosphonato) -hexanoic acid is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the product is isolated by chromatography. Alternatively, the product can be isolated 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 a hydrogen atmosphere until the starting material is consumed. Pd / C is removed by filtration and the solvent is evaporated under reduced pressure. The product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 26.5 :)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as DIEA in an organic solvent such as DMF or NMP at room temperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Upon completion of activation, 4-amino-4- (diethylphosphonato) butyric acid tertbutyl ester (J. Am. Chem. Soc., (1995), 117, 10879-10888) is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the intermediate is isolated by chromatography. Alternatively, the intermediate can be isolated 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 solution, the product is isolated by chromatography. Alternatively, the product can be isolated 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 a hydrogen atmosphere until the starting material is consumed. Pd / C is removed and the solvent is evaporated under reduced pressure. The product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Example 27: Preparation of Exemplary Compounds of the Present Invention These examples are followed according to the general route outlined in Schemes 27.1 to 27.3, using the examples shown in Scheme 27.2 and Schemes 27.4 to 27.6. And the like can be prepared.

  (Scheme 27.1)

The bisanisole derivative of flavopiridol (see Bioorg. Med. Chem. Lett., (2000), 10, 1037) is used as an ideal starting point for attachment of the phosphonate moiety to the piperidine nitrogen. . After protection of the alcohol, the tertiary amine is demethylated and derivatized using optimal reagents. Removal of the methyl ether and protection of the group on the alcohol provides the desired analog.

  An example of an alvocidiv analog having a phosphonate moiety attached to the piperidine nitrogen in this manner is illustrated in Scheme 27.2.

  (Scheme 27.2)

Protect alcohol as acetate under standard conditions (see Greene, T., Protective groups in organic synthesis, Wiley-Interscience, (1999)). N-methylpiperidine is demethylated by reaction with α-chloroethyl chloroformate in the presence of a base such as N, N-diisopropylethylamine (DIEA) followed by brief heating in acidic methanol. The free secondary amine is condensed with (2-oxo-ethyl) -phosphonic acid diethyl ester under reducing conditions, such as those performed by use of sodium cyanoborohydride in a solvent such as methanol or dimethylformamide (Tet. Lett. (1990), 31, 5595). The alcohol is deacetylated by treatment with sodium ethoxide in ethanol. Finally, it is bis-demethylated by heating with pyridinium hydrochloride (see Bioorg. Med. Chem. Lett., (2000), 10, 1037).

  (Scheme 27.3)

2-Hydroxyacetophenone (see Bioorg. Med. Chem. Lett., (2000), 10, 1037) is treated with the appropriate phosphonate-carrying benzoyl chloride derivative. Cyclization forms a flavone ring system and removes the methyl group.

  Such a synthesis is illustrated in Scheme 27.4.

  (Scheme 27.4)

After condensation with [4- (2-chlorocarbonyl-phenoxy) -but-2-enyl] -phosphonic acid diethyl ester (synthesized as follows), it is treated successively with sodium hydride, hydrochloric acid and sodium carbonate. Thus, 5.7-dimethoxyflavone is obtained. Demethylation yields the 5,7-dihydroxyflavone final product as in Scheme 27.2 (see Bioorg. Med. Chem. Lett., (2000), 10, 1037).

  (Scheme 27.5. Synthesis of [4- (2-Chlorocarbonyl-phenoxy) -but-2-enyl] -phosphonic acid diethyl ester)

Treat salicylic acid methyl ester with a base such as sodium hydride in an organic solvent such as dimethylformamide or tetrahydrofuran. At the time of defoaming, an excess amount of E-1,4-dibromobutene is added. After quenching with aqueous ammonium chloride and extracting the product with an organic solvent such as ethyl acetate, the monoalkylated product is isolated by chromatography. The resulting monobromide is heated with triethyl phosphite in a solvent such as toluene (or other Arbuzov reaction conditions: see Engel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988), The diethyl ester of the desired phosphonic acid is obtained. The methyl ester is saponified with the acid chloride purified by treatment with oxalyl chloride in a solvent such as dichloromethane in the presence of lithium hydroxide and a catalytic amount of dimethylformamide.

  The synthesis of another suitable acid chloride is illustrated below.

  (Scheme 27.6)

Treat the phenol with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diester.

  Similarly, 4-hydroxybenzoic acid methyl ester can be produced by a reagent suitable for the production of an analog having a phosphonate moiety attached to the 4-position of the phenyl ring at the 2-position of the flavone.

Example 28: Preparation of exemplary compounds of the invention Reduction of dose and / or improved efficacy by use of prodrugs of vinblastine analogs that yield drugs with increased intracellular half-life by cleavage inside target cells. Is achieved. Such compounds are described below.

  (Scheme 28.1)

Using the examples shown in Schemes 28.8 to 28.13, these compounds and the like can be made according to the general route outlined in Schemes 28.2 to 28.7.

  (Scheme 28.2: Modification with 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)

J. et al. Med. Chem. , (1991), 34, 1001-1018, 2-diethylphosphonatoacetic acid is dissolved in an organic solvent such as benzene, tetrahydrofuran (THF) or chloroform, and a tertiary amine base such as diisopropylethylamine (DIEA). And diphenylphosphoradidate (1.2 eq) 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 mixture is heated to about 80 ° C. for about 4 hours. (Biochemistry, (2002), 41, 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous hydrochloric acid (HCl) (1N) and aqueous bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography.

  (Scheme 28.9: Binding to C23)

J. et al. Med. The starting material (synthesis from vinblastine published in J. Med. Chem., (1978), 21, 88-96) is brought to room temperature according to the procedure described in Chem, (1979), 22, 391-400. Treatment with 2-aminoethylphosphonic acid diethyl ester in an organic solvent such as dichloromethane (DCM) or THF. After completion of the reaction, the solution is washed with water, aqueous bicarbonate solution, and water and dried. The crude product is obtained by depressurizing the solvent. Further purification by chromatography.

  The product of this step is dissolved in an organic solvent such as DCM or THF. J. et al. Med. Chem. , (1979), 22, 391-400, pyridine is added followed by acetic anhydride and the reaction is stirred at room temperature. After completion of the reaction, methanol is added and the solvent is removed under reduced pressure. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The crude product is obtained by removing the solvent under reduced pressure. Further purification by chromatography.

  (Scheme 28.10: Binding to N1)

J. et al. Med. Chem. , (1991), 34, 1001-1018, 2-diethylphosphonatoacetic acid is dissolved in an organic solvent such as benzene, THF or chloroform and a tertiary amine base such as diisopropylethylamine (DIEA). And diphenylphosphoradidate (1.2 eq) and stirred at room temperature. After formation of the acyl azide, N-1- (β-hydroxyethylthiomethyl) vinblastine (Pearce, “Medicalal Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. Thus, CrO ₃ mediated oxidation in the presence of methanol followed by replacement of methoxy with β-hydroxylthioethanol was added and the reaction mixture was heated to about 80 ° C. for about 4 hours (Biochemistry (2002)). ), 41, 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous hydrochloric acid (HCl) (1N) and aqueous bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography.

  (Scheme 28.11: Binding to C4 ')

Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. 37,145, Academic Press San Diego, (1990), vinblastine and diethyl cyanomethylphosphonate (commercially available) are dissolved in concentrated sulfuric acid at about 0 ° C. Upon consumption of the starting material, the reaction mixture is carefully diluted with water and further neutralized. The crude reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous sodium bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography.

  (Scheme 28.12: Binding to 12 ')

C12′-iodo-vinblastine (Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. 37, 145, Academic Press San Di peri-acid (1) Propyl) ammonium periodate and prepared by iodination of vinblastine with a catalytic amount of ruthenium dioxide) to a mixture of copper (I) iodide, potassium phosphate, and 2-aminoethylphosphonic acid diethyl ester (commercially available) To do. Buchwald in Org. Lett. , (2002), 4,581-584, the reaction mixture is heated to about 80 ° C. under an inert gas atmosphere. After the reaction is complete, the material is cooled to room temperature and the solvent is removed under reduced pressure. The crude reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous sodium bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography. The product of this step is dissolved in an organic solvent such as DCM or THF. J. et al. Med. Chem. , (1979), 22, 391-400, pyridine is added followed by acetic anhydride and the reaction is stirred at room temperature. After completion of the reaction, methanol is added and the solvent is removed under reduced pressure. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The crude product is obtained by removing the solvent under reduced pressure. Further purification by chromatography.

  (Scheme 28.13: Binding to 22 ')

Starting material (Pearce, Medicinal Chemistry of Bisindole Alkaloids from Catalanthus), in The Alkaloids, Vol. (Prepared by complete hydrolysis) is dissolved in an organic solvent such as dimethylformamide (DMF) at room temperature. Methyl iodide (1 equivalent) is added followed by potassium carbonate. Continue stirring at room temperature. After the reaction, the reaction product is filtered and the solvent is removed under reduced pressure. 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 <0> C. A tertiary amine base such as DIEA is added, followed by a coupling reagent such as isobutyl chloroformate. Continue stirring at −10 ° C. until activation is complete. Add aminoethylphosphonic acid diethyl ester and continue stirring at 0 ° C. with slow warming. After the reaction, the solution is warmed to room temperature and the solvent is removed under reduced pressure. Further purification by chromatography. The product of this step is dissolved in an organic solvent such as DCM or THF. J. et al. Med. Chem. , (1979), 22, 391-400, pyridine is added followed by acetic anhydride and the reaction is stirred at room temperature. After completion of the reaction, methanol is added and the solvent is removed under reduced pressure. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The crude product is obtained by removing the solvent under reduced pressure. Further purification by chromatography.

Example 29: Preparation of Exemplary Compounds of the Invention Use of tipifanib analog prodrugs resulting in drugs with increased intracellular half-life by cleavage inside target cells, resulting in dose reduction and / or efficacy Improvement is achieved. Such compounds are described below.

  (Scheme 29.1)

Using the specific examples shown in Schemes 29.3, 29.5, 29.7, 29.9, and 29.11, Schemes 29.2, 29.4, 29.6, 29.8, 29. These compounds and the like can be made according to the general route outlined in 10.

  (Scheme 29.2)

(Scheme 29.3)

Treat quinolone (see US Patent No. 5,968,952) with a base such as potassium carbonate in a solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF). An excess of E-1,4-dibromobutene is added. After quenching with aqueous ammonium chloride and extracting the product with an organic solvent such as ethyl acetate, the monoalkylated product is isolated by chromatography. The resulting monobromide is heated with triethyl phosphite in a solvent such as toluene (or other Arbuzov reaction conditions: see Engel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988), The diethyl ester of the desired phosphonic acid is obtained. Thereafter, Bioorg. Med. Chem. Lett. , (2003), 13, 1543, to convert tertiary alcohols to amines via chlorides. The desired enantiomer is isolated by chromatography or classical separation using chiral acids such as camphorsulfonic acid.

  N-methylquinolone (made by treatment of the starting material of Scheme 29.3 with methyl iodide and potassium carbonate in a solvent such as DMF (see US Pat. No. 5,968,952)) Were prepared from the indicated lithiated imidazole (1- (3-tetrahydropyranyloxy) propyl) imidazole (Bioorg. Med. Chem. Lett by sequential treatment with n-butyllithium, chlorotriethylsilane, and n-butyllithium). , (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 tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diester. Thereafter, Bioorg. Med. Chem. Lett. , (2003), 13, 1543, to convert tertiary alcohols to amines via chlorides. The desired enantiomer is isolated by chromatography or classical separation using chiral acids such as camphorsulfonic acid.

The primary amine is condensed with (2-oxo-ethyl) -phosphonic acid diethyl ester under reducing conditions, such as those performed by using sodium cyanoborohydride in a solvent such as methanol or dimethylformamide (Tet. Lett (1990) 31, 5595).

  (Scheme 29.8)

Quinolone (see Bioorg. Med. Chem. Lett., (2003), 13, 1543) was N-methylated under standard conditions such as by treatment with iodomethane and potassium carbonate in DMF to give the three odors. Treatment with boron bromide liberates phenol. This is alkylated as in the above scheme 29.3, and the subsequent steps are the same.

Treat 5-chloro-1-pentyne with triethyl phosphite in a solvent such as toluene (or see other Arbuzov reaction conditions: Engel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988). ), The diethyl ester of the desired phosphonic acid is obtained. This acetylene was obtained under conditions such as those found by Sonagashira (Sonagashira, K .; Tohda, Y .; Hagihara, N. Tetrahedron Lett., (1975), 4467), the bromo-containing analog of tipifanib shown ( Bioorg.Med.Chem.Lett., (2003), 13, 1543, but coupled with 2-bromo-4-chloro-4'-nitrobenzophenone).

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 30: Preparation of Exemplary Compounds of the Invention Using the examples shown in Schemes 30.4-30.6, the compounds of the invention are prepared as generally described in Schemes 30.1-30.3. can do.

  (Scheme 30.1: Substitution of one amino substituent)

(Scheme 30.2: Coupling with one secondary alkylamine)

(Scheme 30.3: Chain extension)

(Scheme 30.4: Substitution of one amino substituent)

J. et al. Org. Chem., (1996), 61, 3849-3862, starting material (synthesized as described in J. Med. Chem., (1999), 42, 3494-3501) with tetrahydrofuran (THF) or Treat with diethylphosphonatoethylcarbaldehyde (1 equivalent) and sodium triacetoxyborohydride in an organic solvent such as dichloromethane (DCM). The reaction is quenched with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. The crude product is obtained by drying off the solvent. Further purification by chromatography.

  J. et al. Med. Chem. (1999), 42, 3494-3501, the product of this step is dissolved in trifluoroacetic acid (TFA) and stirred at room temperature. After completion of the reaction, benzene is added and the solvent is removed under reduced pressure. The crude material is sufficiently pure for the next step.

  J. et al. Med. Chem. , (1999), 42, 3494-3501, the crude material is purified from N, N, N ′, N′tetramethylethylenediamine, water, and N- (β-hydroxyethyl) -N- (β-amino). Dissolve in a mixture of ethyl) amine and heat the mixture at reflux for several hours. After completion of the reaction, chloroform is added and the reaction mixture is washed with dilute aqueous hydrochloric acid and water and dried. Removal of the solvent gives a crude product. Further purification by chromatography.

  (Scheme 30.5: Coupling with one secondary alkylamine)

J. et al. Org. Chemoxantrone can be prepared with diethylphosphonatoethylcarbaldehyde (1 equivalent) and sodium triacetoxyborohydride in an organic solvent such as THF or DCM as described in Chem, (1996), 61, 3849-3862. Process. The reaction is quenched with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. The crude product is obtained by drying off the solvent. Further purification by chromatography.

  (Scheme 30.6: Chain extension)

J. et al. Org. Chem., (1996), 61, 3849-3862, starting materials (synthesized as described in J. Med. Chem., (1999), 42, 3494-3501) such as THF or DCM. Treat with chloroacetaldehyde (1 equivalent) and sodium triacetoxyborohydride in an organic solvent. The reaction is quenched with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. The crude product is obtained by drying off the solvent. Further purification by chromatography.

  The product of this step is dissolved in an organic solvent such as dimethylformamide or acetonitrile. 3-Aminopropylphosphonic acid diethyl ester was added followed by potassium carbonate and sodium iodide. The reaction mixture is heated to about 50-60 ° C. After the reaction is complete, the mixture is cooled to room temperature. Chloroform is added and the reaction mixture is washed with dilute aqueous hydrochloric acid and water. The crude product is obtained by drying off the solvent. Further purification by chromatography.

  J. et al. Med. Chem. (1999), 42, 3494-3501, the product of this step is dissolved in trifluoroacetic acid (TFA) and stirred at room temperature. After completion of the reaction, benzene is added and the solvent is removed under reduced pressure. The crude material is sufficiently pure for the next step.

  J. et al. Med. Chem. , (1999), 42, 3494-3501, the crude material is purified from N, N, N ′, N′tetramethylethylenediamine, water, and N- (β-hydroxyethyl) -N- (β-amino). Dissolve in a mixture of ethyl) amine and heat the mixture at reflux for several hours. After completion of the reaction, chloroform is added and the reaction mixture is washed with dilute aqueous hydrochloric acid and water and dried. Removal of the solvent gives a crude product. Further purification by chromatography.

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the phosphonate interconversion section herein.

Example 31 Preparation of Exemplary Compounds of the Invention Compounds of the invention are generally prepared as described in Schemes 31.1 to 31.6 using the examples shown in Schemes 31.7 to 31.12. can do.

(Scheme 31.7: Binding to C4)

J. et al. Med. Chem. , (1991), 34, 1001-1018, 2-diethylphosphonatoacetic acid is dissolved in an organic solvent such as benzene, tetrahydrofuran (THF) or chloroform, and a tertiary amine base such as diisopropylethylamine (DIEA). And diphenylphosphoradidate (1.2 eq) and stirred at room temperature. After the acyl azide is formed, vindesine is added and the reaction mixture is heated to about 80 ° C. for about 4 hours (Biochemistry, (2002), 41, 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous hydrochloric acid (HCl) (1N) and aqueous bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography.

  (Scheme 31.8: Binding to C23)

J. et al. Med. The starting material (synthesis from vinblastine published in J. Med. Chem., (1978), 21, 88-96) is brought to room temperature according to the procedure described in Chem, (1979), 22, 391-400. Treatment with 2-aminoethylphosphonic acid diethyl ester in an organic solvent such as dichloromethane (DCM) or THF. After completion of the reaction, the solution is washed with water, aqueous bicarbonate solution, and water and dried. The crude product is obtained by depressurizing the solvent. Further purification by chromatography.

  (Scheme 31.9: Binding to N1)

J. et al. Med. Chem. , (1991), 34, 1001-1018, 2-diethylphosphonatoacetic acid is dissolved in an organic solvent such as benzene, THF or chloroform and a tertiary amine base such as diisopropylethylamine (DIEA). And diphenylphosphoradidate (1.2 eq) and stirred at room temperature. After formation of the acyl azide, N-1- (β-hydroxyethylthiomethyl) vinblastine (Pearce, “Medicalal Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. Thus, CrO ₃ mediated oxidation in the presence of methanol followed by replacement of methoxy with β-hydroxylthioethanol was added and the reaction mixture was heated to about 80 ° C. for about 4 hours (Biochemistry (2002)). ), 41, 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous hydrochloric acid (HCl) (1N) and aqueous bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography.

  The product of this step is dissolved in an anhydrous organic solvent such as methanol and dry liquid ammonia is added. J. et al. Med. Chem. , (1978), 21, 88-96, the reaction mixture is heated to about 100 ° C. in a sealed reaction vessel. After completion of the reaction, the mixture is cooled to room temperature and the solvent is removed under reduced pressure. Further purification by chromatography.

  (Scheme 31.10: Binding to C4 ')

Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. According to the procedure described in 37,145, Academic Press San Diego, (1990) (described for acetonitrile), vindesine and diethyl (cyanomethyl) phosphonate (commercially available) are dissolved in concentrated sulfuric acid at about 0 ° C. Upon consumption of the starting material, the reaction mixture is carefully diluted with water and further neutralized. The crude reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous sodium bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography.

  (Scheme 31.11: Binding to 12 ')

C12′-iodo-vinblastine (Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. 37, 145, Academic Press San Di peri-acid (1) Propyl) ammonium periodate and prepared by iodination of vinblastine with a catalytic amount of ruthenium dioxide) to a mixture of copper (I) iodide, potassium phosphate, and 2-aminoethylphosphonic acid diethyl ester (commercially available) To do. Buchwald in Org. Lett. , (2002), 4,581-584, the reaction mixture is heated to about 80 ° C. under an inert gas atmosphere. After the reaction is complete, the material is cooled to room temperature and the solvent is removed in vacuo. The crude reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous sodium bicarbonate and dried. Removal of the solvent gives the crude product. Further purification by chromatography.

  The product of this step is dissolved in an anhydrous organic solvent such as methanol and dry liquid ammonia is added. J. et al. Med. Chem. , (1978), 21, 88-96, the reaction mixture is heated to about 100 ° C. in a sealed reaction vessel. After completion of the reaction, the mixture is cooled to room temperature and the solvent is removed under reduced pressure. Further purification by chromatography.

  (Scheme 31.12: Binding to 22 ')

Pearce, “Medical Chemistry of Bisindole Alkaloids from Catalanthus”, in The Alkaloids, Vol. 37,145, Academic Press, San Diego, (1990) (described for vinblastine), vindesine is suspended in aqueous sodium hydroxide (5N) and heated to reflux for several hours. After the reaction is complete, 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 removed under reduced pressure to obtain the crude acid. Further purification 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. A tertiary amine base such as DIEA is added, followed by a coupling agent such as isobutyl chloroformate. Continue stirring at −10 ° C. until activation is complete. Add aminoethylphosphonic acid diethyl ester and continue stirring at 0 ° C. with slow warming. After the reaction, the solution is warmed to room temperature and the solvent is removed under reduced pressure. Further purification by chromatography.

  Example 32: Preparation of exemplary compounds of the invention

Treat 5-chloro-1-pentyne with triethyl phosphite in a solvent such as toluene (or see other Arbuzov reaction conditions: Engel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988). ), The diethyl ester of the desired phosphonic acid is obtained. This acetylene is coupled with Lonafarnib under conditions such as those found by Sonagashira (Sonagashira, K .; Tohda, Y .; Hagihara, N. Tetrahedron Lett., (1975), 4467). .

J. et al. Med. Chem. , (1982), 25, 960-964 and J. Am. Med. Chem. , (1984), 27, 600-604 and the indicated piperazine (see J. Med. Chem., (1998), 41, 4890) is activated by diethyl phosphonoacetic acid. To give the desired amide linker compound. Treatment with a coupling reagent such as diethyl cyanophosphonate and a base such as diisopropylethylamine in a solvent such as dimethylformamide at room temperature provides the activated diethylphosphonoacetic acid.

  (Scheme 32.5)

(Scheme 32.6)

4-Allyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester for the formation of secondary amides such as dicyclohexylcarbodiimide (DCC) and hydroxybenztriazole (HOBT) in a solvent such as dimethylformamide Coupling with 2-aminoethylphosphonic acid diethyl ester (commercially available) using standard reagents. Olefin is oxidized with ozone to give the carboxylic acid, which is then coupled with the piperidine reagent shown (see J. Med. Chem., (1998), 41, 4890). Finally, trifluoroacetic acid and J.P. Med. Chem. , (1998), 41, 4890, deprotect the piperidine nitrogen under standard conditions using primary urea formed.

4-Carboxymethyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (commercially available) is monoprotected by treatment with acidic methanol. The remaining acid is converted into diethyl 2-aminoethylphosphonate using standard reagents for the formation of secondary amides such as dicyclohexylcarbodiimide (DCC) and hydroxybenztriazole (HOBT) in a solvent such as dimethylformamide. Coupling with ester (commercially available). The methyl ester is then saponified and coupled to the indicated piperazine (see J. Med. Chem., (1998), 41, 4890). Finally, trifluoroacetic acid and J.P. Med. Chem. , (1998), 41, 4890, deprotect the piperidine nitrogen under standard conditions using primary urea formed.

Example 33 Preparation of Exemplary Compounds of the Invention Using the examples shown in Schemes 33.5 to 33.8, these compounds and the like are prepared according to the general route outlined in Schemes 33.1 to 33.4. Can be produced.

As described in Synthesis, (1985), 274, amsacrine can be treated with excess iodotrimethylsilane in a solvent such as dimethylformamide (DMF), acetonitrile (MeCN), or dichloromethane (DCM). After quenching with aqueous sodium bicarbonate and extraction of the product with an organic solvent such as ethyl acetate, the free alcohol can be further purified by chromatography. This material is then treated with t-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. Treatment with sodium hydride (NaH) (about 1 equivalent) in an organic solvent such as THF or DMF then yielded the anion of the alkoxide, which was converted to diethylphosphonomethyltriflate (Tetrahedron Lett., (1986). ), 27, 1477. Upon consumption of the starting material, the reaction is quenched with water and the product is extracted with a significant solvent such as ethyl acetate. Final chromatographic purification can be included. The tert-butoxycarbonyl protecting group is removed with trifluoroacetic acid (TFA) in DCM according to standard procedures (Green and Wutts: Protective Groups in Organic chemistry).

  (Scheme 33.6)

J. et al. Med. Chem. , (2000), 43, 489, followed by deprotonation of amsacrine by treatment with NaH (about 1 equivalent) in an organic solvent such as tetrahydrofuran (THF) followed by diethylphosphono Treat with methyl triflate (prepared according to Tetrahedron Lett., (1986), 27, 1477). After consumption of the starting material, upon consumption of the starting material, the reaction is quenched with water and the product is extracted with a significant solvent such as ethyl acetate. Final chromatographic purification can be included.

  (Scheme 33.7)

The 2,5-dinitrophenol is converted to the sodium salt 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 reacted with an appropriate solvent such as butyl chloroformate in an organic solvent such as DMF at a low temperature of about −10 ° C. and in the presence of a tertiary amine base such as N, N-diisopropylethylamine (DIEA). Activate with a coupling agent. 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 under reduced pressure and the crude material is dissolved in an organic solvent such as ethyl acetate and washed with dilute hydrochloric acid. If necessary, purify the product by chromatography. The material is dissolved in an organic solvent such as THF and treated with sodium carbonate and methyl iodide or dimethyl sulfate. After completion of the reaction, the solid is removed by filtration, and the filtrate is concentrated under reduced pressure. If necessary, purify the product by chromatography. The material is then dissolved in a solvent such as ethyl acetate or DMF and hydrogenated with the aid of Pd / C under a hydrogen atmosphere. The crude reaction mixture is filtered through Celite and the solvent is removed in vacuo. If the posture is not sufficiently pure, it can be further purified by chromatography. The amine is then reacted with 9-chloroacridine in an organic solvent such as DMF in the presence of a tertiary amine base such as DIEA (J. Med. Chem. (1999), 42, 4741-4748). The solvent is removed under reduced pressure and the crude material is purified by chromatography. The product is then treated with methanesulfonyl chloride in the presence of a tertiary amine base such as DIEA in an organic solvent such as DCM or THF. After removal of the solvent, the final product is isolated by chromatography.

  (Scheme 33.8)

The starting material for Scheme 33.8 is J. Med. Chem. (1999), 42, 4741-4748, which can be used by reaction of 9-oxoacrididane-4-methyl-5-carboxylic acid chloride with 2-aminoethylphosphonic acid diethyl ester. The material is then treated with thionyl chloride as described in the above cited references to give the corresponding 9-chloroacridine derivative. The crude material is then dissolved in an organic solvent such as chloroform, DCM, or THF and treated with 2-ethoxy-4-nitroaniline. The crude product can be isolated by precipitation and further purified by chromatography. This material is dissolved in an organic solvent such as DMF and reduced in the presence of Pd / C under a hydrogen atmosphere. After filtration of the reaction mixture through Celite, the solvent is removed under reduced pressure. The product can be further purified by chromatography. The 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 removal of the solvent, the final product is isolated by chromatography.

Example 34 Preparation of Exemplary Compounds of the Invention Using the examples shown in Schemes 34.4 to 34.6, these compounds and others are prepared according to the general route outlined in Schemes 34.1 to 34.3. Can be produced.

  (Scheme 34.1)

CEP-701 can be treated with 2 equivalents of a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. When defoaming, benzyl bromide is added in excess to give the diprotected intermediate. After further treatment with a base such as magnesium tert-butoxide, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diester. Greene, T .; , Protective groups in organic synthesis, Wiley-Interscience, (1999), final deprotection by hydrogenation in the presence of a palladium carbon catalyst in a solvent such as methanol gives the desired product.

  (Scheme 34.5)

CEP-701 can be treated with 1 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, diethylphosphonomethyltriflate is added to give the desired phosphonate diester. Final deprotection by hydrogenation in the presence of palladium on carbon catalyst in a solvent such as methanol using the method described in Greene (supra) gives the desired product.

  (Scheme 34.6)

Treatment of 4-hydroxybenzaldehyde with a base such as sodium hydride and diethylphosphonomethyltriflate in a solvent such as dimethylformamide or tetrahydrofuran provides (4-formyl-phenoxymethyl) -phosphonic acid diethyl ester. The product is condensed with CEP-701 in the presence of a catalytic amount of p-toluenesulfonic acid in a solvent such as toluene and the water formed is removed azeotropically to give the desired acetal.

  The phosphonate moiety can be further manipulated before final deprotection.

Example 35: Preparation of Exemplary Compounds of the Invention Using the examples shown in Schemes 35.2 and 35.4, these compounds and the like are prepared according to the general route outlined in Schemes 35.1 and 35.3. Can be produced.

Winkley, M .; W. Robins, R .; K. , J .; Org. Chem. , (1970), 35, 2, 491 (see also Ben-Hatter J., Jiricny, J. J. Org. Chem., (1986), 51, 3211) and appropriately protected. 5-Aza-2′-deoxycytidine can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Protection of 5-aza-2'-deoxycytidine with a pivaloyl group can form pivaloyl compound 35-1 (Greene, T., Protective groups in organic synthesis, Wiley-Interscience, (1999)). Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the protected product. Removal of the pivaloyl group with sodium ethoxide provides the desired phosphonate diesters 35-2, 35-3.

  (Scheme 35.3)

The preparation of compound 35-9 is described in Scheme 35.3. Compound 35-15 was prepared according to Winley, M .; W. Robins, R .; K. , J .; Org. Chem. , (1970), 35, 2, 491 and Ben-Hatta J. et al. , Jiricny, J .; , J .; Org. Chem. (1986), 51, 3211. The pivaloyl protected 5-aza-2'deoxycytidine. Protection of the 5 ′ hydroxyl group followed by protection of the 2 ′ alcohol provides compound 35-4. Removal of the 5 ′ protecting group provides the free primary alcohol. Converting the primary alcohol to the ester 35-6 using Corey's one-step oxidation procedure (Corey, EJ et al., J. Org. Chem., (1984), 49, 4735). Can do. 35-7 was converted to acetate 35-8 by deesterification and subsequent oxidative decarbonylation using a modified Husdiecker reaction (Chu, CK et al., Tetrahedron Lett., (1991), 32, 3791). Convert to Protection from group involvement at the 4 ′ position controls the stereochemical nature of Vorbruggen glycosylation under Lewis acid conditions. Final deprotection provides the desired prodrug 35-9.

  (Scheme 35.4)

Specifically, 5-aza-2′deoxycytidine (Winkley, MW, Robins, RK, J. Org. Chem., (1970), 35, 2, 491 and Ben using pivaloyl chloride. -Compound 35-1 prepared by protection of Hattar J., Jiricny, JJ Org. Chem., (1986), 51, 3211) is protected with a tert-butyldiphenylsilyl (TBDPS) group Thus, a 5′-O-TBDPS analog is obtained. Further protection of the 3 ′ alcohol with the benzyl group provides compound 35-10 (Teng, K., Cook, DJ Org. Chem. (1994), 59, 278). Exposure of the fully protected compound 35-10 to HF-pyridine reagent selectively deprotects the 5 ′ hydroxyl group, which is then oxidized to the t-butyl ester using Corey-Samuelsson oxidation (Corey, EJ, Samuelsson, BJ Org. Chem., (1984), 49, 4735). Deesterification of the oxidized product using trifluoroacetic acid (TFA) provides compound 35-12. Oxidative decarbonylation using a modified Husdiecker reaction (Chu, CK et al., Tetrahedron Lett., (1991), 32, 3791) converts the free acid to acetate 35-13, which can be a mixture of anomers. Convert. Although anomers can be separated by column chromatography, it is not necessary to do so. The stereochemical consequences of Vorbrugen glycosylation are controlled by the stereochemical nature of the 4'-benzoyl group due to neighboring group participation, without the need to separate isomers. Vorbruggen glycosylation using hydroxymethylphosphonic acid diethyl ester proceeds to give the protected phosphonate. Final saponification removes pivaloate and completes the synthesis of compound 35-20 with a benzoate group (Greene, T., Protective groups in organic synthesis, Wiley-Interscience, (1999)).

Example 36: Preparation of Exemplary Compounds of the Invention Using the examples shown in Schemes 36.3-36.5, these compounds, etc. are prepared according to the general route outlined in Schemes 36.1-36.2. Can be produced.

  (Scheme 36.1: Modification of sugar substituents)

(Scheme 36.2: Binding to epipodophyllotoxin)

Chem. Lett. , (1987), 799-802, using glucose and starting material of 5-bromomethylthiophene-2-carbaldehyde (Organikum, 17 ^th edition, page 167) Synthesized from 5-methylthiophene-2-carboxaldehyde and N-bromosuccinimide). Glycosylation is carried out using 4'-chloroacetyl protected epipodophyllotoxin (described in the above cited reference) under the catalyst of boron trifluoride (described in the above cited reference). The product of this reaction is dissolved in an organic solvent such as methanol and treated with zinc acetate at reflux temperature. After completion of the reaction, the mixture is cooled to room temperature and the solvent is removed under reduced pressure. The crude reaction product is dissolved in an organic solvent such as chloroform and the solution is washed with 0.1 M aqueous HCl and aqueous sodium bicarbonate. After dry removal of the solvent, a crude product is obtained. Further purification by chromatography. The crude reaction product is dissolved in an organic solvent such as dimethylformamide (DMF) or chloroform and then treated with a base such as sodium carbonate at about 40 ° C. and reacted with aminoethyl diethylphosphonate. After all starting material is consumed, the reaction mixture is washed with 0.1 M aqueous HCl and dicarbonate solution. After drying off the solvent, a crude reaction product is obtained. Further purification by chromatography.

  (Scheme 36.4: Modification of glucose core)

J. et al. Org. Chem., (1996), 61, 3849-3862. Synthesis from glucosamine and thiophene-2-carbaldehyde (commercially available) with starting materials (Chem. Lett., (1987), 799-804). Treatment with diethylphosphonatoethylcarbaldehyde and sodium triacetoxyborohydride in an organic solvent such as dichloromethane (DCM) or tetrahydrofuran (THF). The reaction is quenched with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Further purification by chromatography.

  (Scheme 36.5: Binding to epipodophyllotoxin core)

J. et al. Org. Amine-containing starting materials (obtained as described in J. Med. Chem., (1991), 34, 3346-3350) as described in Chem. Treat with diethylphosphonatoethylcarbaldehyde and sodium triacetoxyborohydride in an organic solvent such as DCM. The reaction is quenched with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Further purification by chromatography.

  Bioorg. Med. Chem. Lett. , (1994), 21, 2567-2572, all the final products of these compounds in an organic solvent such as acetonitrile in the presence of a tertiary organic amine such as N, N-diisopropylethylamine. Conversion to the corresponding 4 ′ phosphate analog by treatment with phosphoryl trichloride in sodium followed by treatment with aqueous sodium bicarbonate. The final product is purified by chromatography.

Example 37 Preparation of Exemplary Compounds of the Invention These compounds and the like can be made according to the general route outlined in Schemes 37.1-37.5.

  (Scheme 37.1)

Staurosporine is acylated with an activated benzoic acid derivative such as benzyl chloride in a solvent such as chloroform in the presence of a base such as N, N-diisopropylethylamine (DIEA) (Bioorg. Med. Chem. Lett., (1994), 4, 399). Examples of benzyl chloride for use in the synthesis of suitable phosphonate-containing midostaurine analogs are illustrated in Schemes 37.2-37.3 below.

  (Scheme 37.2)

4-Hydroxybenzoic acid methyl ester is treated with magnesium tert-butoxide and diethylphosphonomethyl triflate (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 from benzoic acid by reaction with oxalyl chloride catalyzed with dimethylformamide in a solvent such as dichloromethane. The acid chloride is obtained.

  (Scheme 37.3)

The 3-hydroxybenzoic acid methyl ester is treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. When defoaming, E-1,4-dibromobutene is added in excess. After quenching with aqueous ammonium chloride and extracting the product with an organic solvent such as ethyl acetate, the monoalkylated product is isolated by chromatography. The bromide is heated with triethyl phosphite in a solvent such as toluene (or see other Arbuzov reaction conditions: Engel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988), 3- [ 4- (Diethoxy-phosphoryl) -but-2-enyloxy] -benzoic acid methyl ester is obtained. The remaining steps are similar to Scheme 37.2.

  (Scheme 37.4)

Alkylation of staurosporine secondary amines was performed under various standard conditions (see Bioorg. Med. Chem. Lett., (1994), 4,399). A synthesis example of a phosphonate-containing alkyl derivative is shown in Scheme 37.5.
Scheme 37.5

Alkylation of staurosporine with diethylphosphonomethyltriflate in the presence of a base such as DIEA.

Example 38 Preparation of Exemplary Compounds of the Invention Compounds of the invention are prepared as generally described in Schemes 38.1 and 38.4 and Schemes 38.2, 38.3, and 38.5. be able to.

  (Scheme 38.1)

The introduction of a phosphonate-bearing component at the quinazoline 7 position is most conveniently accomplished by alkylation of a suitably protected 4-piperazinylquinazoline prior to urea formation.

  (Scheme 38.2)

6,7-dimethoxy-3,4-dihydroquinazolin-4-one is reacted with boron tribromide to give a mixture of monodemethylated products. Although they can be separated by chromatography at this stage, the mixture of acetates resulting from the reaction with an acetylating reagent such as acetyl chloride in the presence of a base such as pyridine can be more conveniently separated. The desired isomer is reacted with thionyl chloride (see Bioorg. Med. Chem. Lett., (2001), 11, 1911) and the resulting 4-chloroquinazoline is converted to piperazine-1-carboxylic acid benzyl ester. Process with. Intermediate A is removed by removal of the acetyl protecting group under standard conditions such as treatment with ammonia in methanol (see Greene, T., Protective groups in organic synthesis, Wiley-Interscience, (1999)). can get.

  Upon treatment with a base such as magnesium tert-butoxide and diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477), a phosphonate-containing moiety is introduced at position 7 of the quinazoline. Thereafter, removal of the benzyl carbamate hydrogenate protecting group under a catalyst such as palladium on carbon in a solvent such as methanol (see Greene, supra) and 4-isopropoxyaniline (commercially available) and 4-nitro chloroformate. Condensation with phenyl gives the desired compound.

  (Scheme 38.3)

As described by Mitsunobu (Bull. Chem. Soc. Japan., (1971), 44, 3427), 4- (2-hydro Intermediate A can be alkylated on phenol by reaction with -ethyl) -piperazine-1-carboxylic acid tert-butyl ester. Reduction conditions such as those performed by use of sodium cyanoborohydride in a solvent such as methanol or dimethylformamide after deprotection with trifluoroacetic acid (see Tet. Lett. (1990), 31, 5595). Under condensation of the free secondary amine with (2-oxo-ethyl) -phosphonic acid diethyl ester. The remaining steps are similar to Scheme 38.2.

  (Scheme 38.4)

The route is similar to that shown in Schemes 38.1-38.3, but using selective demethylation at the 6-position of 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (Bioorg Med. Chem. Lett., (2001), 11, 1911). A specific example of such a synthesis is shown in Scheme 38.5.

  (Scheme 38.5)

After selective demethylation, the process is similar to that described in the previous examples up to the point of alkylating the phenol. However, in this example, alkylation with E-1,4-dibromobutene is performed and the monobromide product is reacted with triethyl phosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R , Synthesis of carbon-phosphorus bonds, CRC press, 1988), making the diethyl ester of the desired phosphonic acid. Thereafter, the process is again similar to the process described in the previous example.

Example 39: Preparation of exemplary compounds of the invention Using the examples shown in Schemes 39.2 and 39.4, compounds of the invention are prepared as generally described in Schemes 39.1 and 39.3. can do.

  (Scheme 39.1)

Patent application WO 2001-U. S. Patent No. Coupling of aniline with 2,3,4-trifluorobenzoic acid in the presence of excess base such as diisopropylamidolithium in a solvent such as tetrahydrofuran and at or below ambient temperature as described in 22948 . Subsequent introduction of the phosphonate moiety can be accomplished by a variety of means such as those exemplified in Scheme 39.2 below. Thereafter, the patent application WO 2000-U. S. Patent No. O- (2) in the presence of a coupling reagent such as benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphonate (PyBOP) in a solvent such as tetrahydrofuran or dichloromethane. Treatment of benzoic acid with tetrahydro-2H-pyran-2-yl) hydroxylamine and diisopropylethylamine followed by treatment with hydrochloric acid in ethanol gives the hydroxamic acid ester.

  (Scheme 39.2)

After coupling 2,3,4-trifluorobenzoic acid with 2-iodo-5-nitroanisole (commercially available), methyl ether is removed under standard conditions such as treatment with hydrobromic acid in acetic acid (See Greene, T., Protective groups in organic synthesis, Wiley-Interscience, (1999)). Benzoic acid is esterified by dissolution in acidic methanol. The phenol is then treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diester. Saponify benzoic acid (prepared for coupling to form hydroxamic acid ester—see Scheme 39.1) in a solvent such as tetrahydrofuran or ethanol.

  (Scheme 39.3)

As illustrated in Scheme 39.4 below, the iodo substituent in PD-184352 can be used in the introduction of a phosphonate-bearing moiety.

  (Scheme 39.4)

Treat 5-chloro-1-pentyne with triethyl phosphite in a solvent such as toluene (or other Arbuzov reaction conditions: see Engel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988). That is, the desired diethyl ester of phosphonic acid is obtained. This acetylene is coupled with 39.5 under conditions such as those found by Sonagashira (Sonogashira, K .; Tohda, Y .; Hagihara, N. Tetrahedron Lett., (1975), 4467).

Example 40: Preparation of Exemplary Compounds of the Invention The specific examples shown in Schemes 40.2-40.4 can be used to make compounds as generally shown in Schemes 40.1-40.5. it can. Final compounds that are diastereoisomers or enantiomers can be purified by chromatographic means.

  (Scheme 40.1: General access to all compound classes)

If direct coupling to aminopterin is hindered by the presence of free secondary amines in the starting material (R = H), this component can be tert according to standard procedures (Green Wuts: Protective groups in organic chemistry). -Transient protection with either a butoxycarbonyl group (R = Boc) or benzyloxycarbonyl (R = Cbz or Z).

  (Scheme 40.2: specific example for class A)

Starting carboxylic acid using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as diisopropylethylamine (DIEA) in an organic 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). Upon completion of activation, 2-aminoethylphosphonic acid diethyl ester (commercially available) is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the product is isolated by chromatography. Alternatively, the product can be isolated 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 a hydrogen atmosphere until the starting material is consumed. Pd / C is removed and the solvent is evaporated under reduced pressure. The product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 40.3: second specific example for class A)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate 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. Upon completion of activation, the base of (2-amino-ethylsulfanylmethyl) -phosphonic acid diethyl ester (2-aminoethanethiol and diethylphosphonomethyltriflate prepared by Tetrahedron Lett., (1986), 27, 1477) Prepared by catalytic coupling). After consumption of the activated species is observed, the solvent is removed under reduced pressure and the intermediate is isolated by chromatography. Alternatively, the intermediate can be isolated 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 a hydrogen peroxide solution (excess). After removal of the solution, the product is isolated by chromatography. Alternatively, the intermediate can be isolated 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 a hydrogen atmosphere until the starting material is consumed. Pd / C is removed and the solvent is evaporated under reduced pressure. The product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 40.4)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate 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). Upon completion of activation, (L) -2-amino-6- (diethylphosphonato) -hexanoic acid is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the product is isolated by chromatography. Alternatively, the product can be isolated 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 a hydrogen atmosphere until the starting material is consumed. Pd / C is removed and the solvent is evaporated under reduced pressure. The product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 40.5)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as DIEA in an organic solvent such as DMF or NMP at room temperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Upon completion of activation, 4-amino-4- (diethylphosphonato) butyric acid tertbutyl ester (J. Am. Chem. Soc., (1995), 117, 10879-10888) is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the intermediate is isolated by chromatography. Alternatively, the intermediate can be isolated 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 solution, the product is isolated by chromatography. Alternatively, the product can be isolated 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 a hydrogen atmosphere until the starting material is consumed. Pd / C is removed and the solvent is evaporated under reduced pressure. The product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Example 41 Preparation of Exemplary Compounds of the Invention Using the specific examples shown in Schemes 41.2-41.4, following the general route outlined in Schemes 41.1-41.5, Compounds can be made. Final compounds that are diastereoisomers or enantiomers can be purified by chromatographic means.

  (Scheme 41.1: General access to compounds of the invention)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate 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. Upon completion of activation, 2-aminoethylphosphonic acid diethyl ester (commercially available) is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 41.3 :)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate 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. Upon completion of activation, the base of (2-amino-ethylsulfanylmethyl) -phosphonic acid diethyl ester (2-aminoethanethiol and diethylphosphonomethyltriflate prepared by Tetrahedron Lett., (1986), 27, 1477) Prepared by catalytic coupling). After consumption of the activated species is observed, the solvent is removed under reduced pressure and the intermediate is isolated by chromatography. Alternatively, the intermediate can be isolated 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 a hydrogen peroxide solution (excess). After removal of the solution, the product is isolated by chromatography. Alternatively, the intermediate can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 41.4 :)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate 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). Upon completion of activation, (L) -2-amino-6- (diethylphosphonato) -hexanoic acid is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 41.5 :)

The starting carboxylic acid can be treated using a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as DIEA in an organic solvent such as DMF or NMP at room temperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Upon completion of activation, 4-amino-4- (diethylphosphonato) butyric acid tertbutyl ester (J. Am. Chem. Soc., (1995), 117, 10879-10888) is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the intermediate is isolated by chromatography. Alternatively, the intermediate can be isolated 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 solution, the product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Example 42 Preparation of Exemplary Compounds of the Invention The examples shown in Scheme 42.2 can be used to make compounds of the invention as generally shown in Scheme 42.1.

  (Scheme 42.1)

The preparation of certain prodrugs of tassedinalin is shown in Scheme 42.1. The synthesis is planned so that the prodrug moiety is attached late in the synthesis. Synthesis is completed by reduction of the nitro group. Numerous methods for such reduction have been reported in the literature, some examples being hydrogenation, Raney nickel, and tin chloride dihydrate (Suzuki, T. et al., J. Med. Chem. (1999), 42, 3001).

  (Scheme 42.2)

The preparation of certain prodrug-linked tassedinalins is shown in more detail in Scheme 42.2. U. S. Patent No. Compound 42-1 can be prepared according to 5,137,918. Compound 42-1 is treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyl triflate (prepared according to Tetrahedron Lett., (1986), 27, 1477)) is added to give the desired phosphonate diesters 42-2, 42-5. Reduction of the nitro group by hydrogenation or Raney nickel conditions provides the desired prodrug.

Example 43: Preparation of Exemplary Compounds of the Invention The examples shown in Scheme 43.2 can be used to make compounds of the invention as shown generally in Scheme 43.1.

Bioorg. Med. Chem. Lett. , (1999), 9, 1625, and 5-nitro-isobenzofuran-1,3-dione (commercially available) was converted to 5-amino-2- (2,6-dioxo-piperidine-3- Yl) -isoindole-1,3-dione. In the presence of a reducing agent such as sodium triacetoxyborohydride, this amine intermediate is subjected to reductive amination using diethylphosphonoacetaldehyde (obtained from ozonolysis of diethyl allyl sulfonate) to give the desired Amine linker analogs are obtained (J. Org. Chem., (1996), 61, 3849). Alternatively, J. Org. Med. Chem. , (1982), 25, 960 and J. Am. Med. Chem. The amine is acylated with activated diethylphosphonoacetic acid to give the desired amide linker compound, according to procedures such as those reported in, (1984), 27,600. Activated diethylphosphonoacetic acid can be obtained by treatment with a coupling reagent such as diethyl cyanophosphonate and a base such as diisopropylethylamine in a solvent such as diethylformamide at room temperature.

  2- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -pentandionic acid (commercially available) in a solvent such as acetonitrile, triethylamine, 1-hydroxybenzotriazole, 4-methoxybenzyl Treat with amine and 1,3-dicyclohexylcarbodiimide. J. et al. Med. Chem. , (2003), 46, 3793, and after completion of the reaction, the solvent is removed and the residue purified by chromatography to give the desired analog.

Example 44 Preparation of Exemplary Compounds of the Invention The examples shown in Scheme 44.2 can be used to make compounds of the invention as generally shown in Scheme 44.1.

  (Scheme 44.1)

The synthesis of TLK-286 prodrug is shown in Schemes 44.1 and 44.2. Using the two carboxylic acids present in the prodrug moiety, the mixture of coupling products is separated by HPLC to yield the desired product. Aminoethyl diethyl phosphonate is commercially available from Fluka as an oxalate salt and can be liberated using triethylamine in the reaction medium. Peptide coupling reactions are typically performed in dimethylformamide (DMF) with the addition of dichloromethane. A carbodiimide coupling reagent can be used in the presence of dimethylaminopyridine to facilitate the reaction. Hydroxybenzotriazole (HOBt) can be used to avoid racemization.

Example 45: Preparation of Exemplary Compounds of the Invention The examples shown in Scheme 45.3 can be used to make compounds of the invention as generally shown in Schemes 45.1-45.2.

  (Scheme 45.1: Modification of one aminoethyl substituent)

J. et al. Org. Chem., (1996), 61, 3849-3862, in an organic solvent such as tetrahydrofuran (THF) or dichloromethane (DCM), pixanthrone and (2-oxoethyl) phosphonic acid diethyl ester (1 equivalent) and Treat with sodium triacetoxyborohydride. The reaction is quenched with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. The product, other regioisomers, and bisalkylated material are separated by chromatography.

  (Scheme 45.4: Modification of the pyridine moiety)

Titrate Pixanthrone in organic solvents such as dimethylformamide (DMF), THF, or chloroform according to standard procedures in the literature (Greene, TW: Protective groups in organic chemistry, Wiley-Interscience, (1999)). -Treat with butoxycarbonyl anhydride, remove the solvent under reduced pressure, dissolve the crude material in an organic solvent such as chloroform and wash the solution with 0.1 N aqueous HCl and bicarbonate aqueous solution. Purify the product further by chromatography, if necessary, dissolve the product from Step 1 in an organic solvent such as DMF and add bromoacetic acid (1 equivalent), inert as nitrogen In a gas atmosphere, the solution is 5 Heat to a high temperature such as ~ 70 ° C. After the reaction is complete, remove the solvent under reduced pressure and further purify the product by chromatography, dissolve this material in an organic solvent such as chloroform or DMF, and add dicyclohexylcarbodiimide (DCC) or the like. React with 2-aminoethylphosphonic acid diethyl ester (commercially available) in the presence of a coupling reagent, an organic tertiary amine base such as diisopropylethylamine (DIEA), and a catalytic amount of N, N-dimethylaminopyridine (DMAP). After completion of the reaction, the reaction mixture is filtered and the solvent is removed under reduced pressure.The crude material is converted to DCM at room temperature according to standard (Greene, TW: Protective groups in organic chemistry, Wiley-Interscience (1999)). Dissolved, after completion of processing. Reaction with trifluoroacetic acid, the solvent was removed under reduced pressure and the crude final product is obtained, further purified by chromatography.

Example 46: Preparation of Exemplary Compounds of the Invention Using the examples shown in Schemes 46.2 and 46.4, making compounds of the invention as generally shown in Schemes 46.1 and 46.3 Can do.

In a solvent such as tetrahydrofuran or dimethylformamide; S. Patent No. Appropriately protected 2′-deoxycoform prepared according to 3,923,785 (also reported in Chan, E. et al., J. Org. Chem., (1982), 47, 3457). Sewing machine (2′-deoxycoformin) can be treated with a base such as sodium hydride. Truong, T.A. V. et al. J. et al. Org. Chem. (1993), 58, 6090 (8R) -6- (t-butoxycarbonyl) -8-[(t-butyldiethylsilyl) oxy] -3,6,7,8-tetrahedroimidazo [4 , 5-d]-[1,3] diazapine, using Chan, E., et al. et al. , J .; Org. Chem. , (1982), 47, 3457, the fully protected compounds 46-1, 46-3 can be formed via the Vorbrugen glycosylation reaction. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diesters 46-1, 46-3.

  (Scheme 46.3)

The preparation of compound 46-9 is described in Scheme 46.3. Truong, T.A. V. et al. J. et al. Org. Chem. , (1993), 58, 6090 and Chan, E .; et al. , J .; Org. Chem. , (1982), 47, 3457, compound 46-1 ((8- (tert-butyl-dimethyl-silanyloxy) -3- (4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2- Yl) -7,8-dihydro-3H-imidazole [4,5-d] [1,3] diazepine-6-carboxylic acid tert-butyl ester)). Oxidation of 5'-OH and subsequent elimination of the carboxylic acid yields glycal 46-5 (Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). See instructions). Selenoetherification provides the protected phosphonate 46-6 (Kim, C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative elimination of phenyl selenide (described in Kim, C. et al., J. Org. Chem., (1991), 56, 2642) followed by stereoselective dihydroxylation yields a diol, after which It can be converted to the monotetrahydropyran protected compound 46-7. Acylation of the 2 ′ alcohol with phenyl chlorothionoformate provides a precursor for Robins deoxygenation. Subsequent deoxygenation yields compound 46-8 (Metteucci, MD et al. Tetrahedron Lett., (1987), 28, 22, 2459, Robins, MJ et al. J. Org. Chem., (1995), 60, 7902). If the initial protection proceeds exclusively at the 2 ′ position, the order of 3 ′ protected alcohol formation and thiocarbonate formation can be reversed. In that case, the 2 ′ thiocarbonate is formed first, after which the 3 ′ hydroxyl group is protected and finally Robins deoxygenation is performed. Removal of all three protecting groups by trifluoroacetic acid (TFA) mediated deprotection provides 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. Decarboxylative elimination is performed using dimethylformamide dineopentyl acetal in high temperature DMF (Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). . Once the furanoid glycal 46-11 was obtained, it was treated with phenylselenyl chloride to selenoether, followed by treatment with silver perchlorate in the presence of diethyl (hydroxymethyl) phosphonate (Philion, D. et al., Tetrahedron Lett., (1986), 27, 1477) phosphonate 46-12 is obtained (Kim, C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative elimination of selenide and subsequent dihydroxylation using osmium tetroxide yields the diol, which is converted to the monoprotected tetrahydropyranyl ether compound 46-13. Acylation of the 2 'alcohol with phenylchlorothionoformate provides a precursor for Robins deoxygenation, which is performed using tributyltin hydride to give compound 46-14 (Metteucci, MD). Et al., Tetrahedron Lett., (1987), 28, 22, 2459, Robins, MJ et al., J. Org. Chem., (1995), 60, 7902). Removal of all protecting groups using TFA provides compound 46-9 (Greene, T., Protective groups in organic synthesis, Wiley-Interscience, (1999)).

Example 47: Preparation of Exemplary Compounds of the Invention Using the examples shown in Schemes 47.2 and 47.4, making compounds of the invention as generally shown in Schemes 47.1 and 47.3. Can do.

N- (1-β-D-arabinofuranosyl-1,2-dihydro-2-oxo-4-pyrimidinyl) docosanamide (US Patent No. 3,991) in a solvent such as tetrahydrofuran or dimethylformamide 045, Akiyama, M. et al., Chem. Pharm. Bull., (1978), 26, 3, 981) is treated with a base such as sodium hydride. Upon defoaming, diethylphosphonomethyl triflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diesters 47-2, 47-3.

  (Scheme 47.3)

The preparation of compound 47-9 is described in Scheme 47.3. U. S. Patent No. Compound 47-1 is prepared according to 3,991,045. Protection of the 5 ′ hydroxyl group followed by protection of the 2 ′ and 3 ′ alcohols provides compound 47-4. Removal of the 5 ′ protecting group provides a free primary alcohol precursor for oxidation. Converting the primary alcohol to ester 47-6 using Corey's one-step oxidation procedure (Corey, EJ et al., J. Org. Chem., (1984), 49, 4735). Can do. 47-7 was converted to acetate 47-8 by oxidative decarbonylation using deesterification followed by a modified Husdiecker reaction (Chu, CK et al., Tetrahedron Lett., (1991), 32, 3791). Convert to Protection from group involvement at the 4 ′ position controls the stereochemical nature of Vorbruggen glycosylation under Lewis acid conditions. Final deprotection provides 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 Patent No. 3,991) , 045) is selectively protected with a t-butyldiphenylsilyl (TBDPS) group to give a 5'-O-TBDPS analog. Further protection of the 3 ′ and 4 ′ alcohols as benzoates provides compound 47-10 (Teng, K., Cook, DJ Org. Chem., (1994), 59, 278). Exposure of the fully protected compound 47-10 to the HF-pyridine reagent selectively deprotects the 5 ′ hydroxyl group, which can then be oxidized to the t-butyl ester using Corey-Samuelsson oxidation (Corey, EJ, Samuelsson, BJ Org.Chem., (1984), 49, 4735). Deesterification of the oxidation product using trifluoroacetic acid (TFA) provides compound 47-13. Acetate, which can be a mixture of anomers at the 5 ′ free acid by oxidative decarbonylation using a modified Husdiecker reaction (Chu, CK et al., Tetrahedron Lett., (1991), 32, 3791). Convert to 47-14. Although anomers can be separated by column chromatography, it is not necessary to do so. The stereochemical consequences of Vorbrugen glycosylation are controlled by the stereochemical nature of the 4'-benzoyl group due to neighboring group participation, without the need to separate isomers. Vorbruggen glycosylation using hydroxymethylphosphonic acid diethyl ester proceeds to give the protected phosphonate. Final deprotection using hydrolysis conditions completes the synthesis of compound 47-15.

Example 48: Preparation of Exemplary Compounds of the Invention Using the examples shown in Schemes 48.2 and 48.4, these compounds and the like are prepared according to the general route outlined in Schemes 48.1 and 48.3. Can be produced.

  (Scheme 48.1)

(Scheme 48.2)

U. S. Patent No. Appropriately protected 2-chloro-9- (2-deoxy-2-fluoro-β-D-arabinofuranosyl) -9H-purine-6 prepared according to 5,034,518 (also described in WO 0301877) -Treat amine 48-1 with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Protection of 2-chloro-9- (2-deoxy-2-fluoro-β-D-arabinofuranosyl) -9H-purin-6-amine with a pivaloyl group forms the pivaloyl compound 48-1. Greene, T., Protective groups in organic synthesis, Wiley-Interscience, (1999)). Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give protected products 48-2, 48-3. Removal of the pivaloyl group with sodium ethoxide provides the desired phosphonate diesters 48-2, 48-3.

  (Scheme 48.3)

The preparation of compound 48-8 is described in Scheme 48.3. Compound 48-4 (9- (2-deoxy-α-D-ribofuranosyl) -2-fluoroadenine) was prepared according to Montgomery, J. et al. et al. , J .; Med. Chem. , (1969), 12, 3,498. Oxidation of 5′-OH and subsequent elimination yields glycal 48-5 (see the procedure of Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). ) Protection of the chloroadenine at position 6 and subsequent selenoetherification affords the protected phosphonate 48-6 (Kim, C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative elimination of phenyl selenide (described in Kim, C. et al., J. Org. Chem., (1991), 56, 2642) followed by stereoselective dihydroxylation yields a diol, after which Can be converted to 2 'protected alcohol. Protection of the 3 ′ alcohol and subsequent removal of the protecting group at the 2 ′ hydroxyl group provides compound 48-7. Exposure of the compound to dimethylaminosulfur trifluoride (DAST) and pyridine allows simultaneous fluorination and inversion of the stereochemistry at the 2 'position (Pankiewicz, KW et al., J. Org). Chem., (1992), 57, 553, also see Pankiewicz, KW et al., J. Org. Chem., (1992), 57, 7315). Finally, the protecting group is removed to give compound 48-8.

  (Scheme 48.4)

Specifically, 9- (2-deoxy-α-D-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 performed using dimethylformamide dineopentyl acetal in high temperature dimethylformamide (Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). . Once furanoid glycal 48-5 is obtained, Greene, T .; First, the 6-position of 2-chloroadenosine is protected with pivaloyl chloride using PivCl conditions as described in, Protective groups in organic synthesis, Wiley-Interscience, 1999. Treatment of the protected glycal with silver perchlorate in the presence of diethyl (hydroxymethyl) phosphonate (Philion, D. et al., Tetrahedron Lett., 1986, 27, 1477) gives phosphonate 48-10 ( Kim, C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative elimination of selenide and subsequent dihydroxylation using osmium tetroxide yields the diol, which is first silylated with a 2′-OH group and then protected with a 3 ′ alcohol with an acetate group and The mono-protected acetate 48-12 can be converted by deprotection of the silyl group. DAST can be used to convert 2 ′ alcohols to 2 ′ fluorides with opposite stereochemical properties (Pankiewicz, WW et al., J. Org. Chem., (1992), 57. 553, Pankiewicz, KW et al., J. Org. Chem., (1992), 57, 7315). The 3 ′ acetate is removed under conditions for deprotecting the pivaloyl group (Greene, T., Protective groups in organic synthesis, Wiley-Interscience, (1999)) to give compound 48-13.

Example 49: Preparation of Exemplary Compounds of the Invention Representative examples of the invention according to the general route outlined in Schemes 49.1 and 49.3, using the examples shown in Schemes 49.2 and 49.4. Compounds can be made.

(1S) -1- (9-deazaguanine-9-yl) -1,4-dideoxy-1,4-meaning -D-ribitol (WO 9,919,338 and Evans, GB et al., Tetrahedron, (2000), 56, 3053, Evans, GB et al., J. Med. Chem. (2003), 46, 3412) and Greene, T., et al. Boc-protected (1S) -1- (9-deazaguanine-9-yl) -1,4-dideoxy-1 by stirring with BOC anhydride as described in, Protective groups in organic synthesis, Wiley-Interscience, (1999). , 4-imino-D-ribitol (compounds 49-1, 49-3) is prepared. The compounds 49-1 and 49-3 are then treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477)) was added and the desired phosphonate diester after deprotection of the BOC group using trifluoroacetic acid (TFA) 49-2 and 49-4 are obtained.

  (Scheme 49.3)

The preparation of compound 49-16 is described in Scheme 49.3. Evans, G.M. B. et al. Deprotection compound 49-5 ((1R) -1- (9-deazahypo) using di-tert-butyl dicarbonate in dichloromethane as described in U.S., Tetrahedron, (2000), 56, 3053. Xanthin-9-yl) -1,2,4-trideoxy 1,4-imino-D-erythro-pentitol (as hydrochloride)) is prepared. Oxidation of 5′-OH and subsequent elimination yields glycal 49-6 (see the procedure of Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). ) Selenoetherification gives the protected phosphonate 49-7 (Kim, C. et al., J. Org. Chem., (1991), 56, 2642). The desired diol 49-9 by oxidative elimination of phenyl selenide (described in Kim, C. et al., J. Org. Chem., (1991), 56, 2642) and subsequent stereoselective dihydroxylation. Is obtained. Finally, the protecting group is removed.

  (Scheme 49.4)

For details, see Evans, G. et al. B. et al. (1R) -1- (9-deazahypoxanthin-9-yl) -1,2,4-trideoxy 1,4- prepared as the hydrochloride salt as described in Tetrahedron, (2000), 56, 3053. Imino-D-erythro-pentitol is first protected and then oxidized with PtO ₂ to give carboxylic acid 49-11. Decarboxylation is performed using dimethylformamide dineopentyl acetal in high temperature dimethylformamide (Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). . Selenoetherification followed by treatment of the protected glycal with silver perchlorate in the presence of diethyl (hydroxymethyl) phosphonate (Philion, D. et al., Tetrahedron Lett., 1986, 27, 1477) leads to phosphonate 49 -13 is obtained (Kim, C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative elimination of selenide followed by dihydroxylation using osmium tetroxide provides diol 49-15. Greene, T .; , Protective groups in organic synthesis, Wiley-Interscience, (1999) to remove the amine protecting group to give compounds 49-16.

Example 50: Preparation of exemplary compounds of the invention (Scheme 50.1)

Using the examples shown in Schemes 50.5-50.7, compounds of the present invention can be made following the general route outlined in Schemes 50.2-50.4.

10-hydroxycamptothecin (prepared from commercial camptothecin according to J. Org. Chem., (1995), 60, 5739-5740) is dissolved in a mixture of sulfuric acid and nitric acid under ice cooling. After the reaction, the crude reaction solution is poured into ice. The precipitate is collected and washed with water, cold ethanol, and diethyl ether. If necessary, the product is further purified by recrystallization (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. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate ester. The product is further purified by chromatography.

  (Scheme 50.6: Modification of the nitro group at C9)

Ruvetican is dissolved in an organic solvent such as DMF or ethyl acetate and hydrogenated in the presence of Pd / C in a hydrogen atmosphere. After the reaction, the crude suspension is filtered through Celite, and the solvent is removed under reduced pressure. If necessary, the product is further purified by chromatography. J. et al. Org. The product of Step 1 is dissolved in an organic solvent such as THF, acetonitrile, or DMF as described in Chem, (1996), 61, 3849-3862, and (2-oxo-ethyl) -phosphonic acid diethyl ester (1 equivalent) and treatment with sodium triacetoxyborohydride. The reaction is quenched with aqueous sodium bicarbonate and the product is recovered as a precipitate. The product is further purified by chromatography.

  (Scheme 50.7: Modification with C7)

10-hydroxycamptothecin is converted to the corresponding C7 aldehyde according to literature protocols (J. Med. Chem., (2000), 43, 3963-3969). J. et al. Org. This product is dissolved in an organic solvent such as THF, acetonitrile, or DMF, as described in Chem, (1996), 61, 3849-3862, and aminoethylphosphonic acid diethyl ester (1 equivalent) and triacetoxyhydrogen. Treat with sodium borohydride. The reaction is quenched with aqueous sodium bicarbonate and the product is purified by chromatography. The product of this step is dissolved in a mixture of sulfuric acid and nitric acid under ice cooling. After the reaction, the crude reaction solution is poured into ice. The precipitate is collected and washed with water, cold ethanol, and diethyl ether. If necessary, the product is further purified by recrystallization (J. Med. Chem., (2001), 44, 1594-602).

  Further conversion to the C10 reduction product (according to J. Med. Chem., (1991), 34, 98-107).

The free C10 hydroxy compound synthesized as described above is dissolved in an organic solvent such as DMF under an inert gas atmosphere. A tertiary organic amine such as 2,6 lutidine is added, followed by N-phenyltrifluoromethanesulfonimide. The reaction mixture is stirred overnight at room temperature. After all starting material is consumed, a second tertiary organic amine base such as triethylamine is added, followed by a palladium (II) species such as Pd (OAc) ₂ , a phosphine such as triphenylphosphine, and concentrated formic acid. Add. The reaction mixture is heated to an elevated temperature of about 60 ° C. After completion of the reaction, the solvent is removed under reduced pressure and the crude 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 Use of a BAY-43-9006 analog prodrug that results in a drug with increased intracellular half-life by cleavage inside the target cell, resulting in dose reduction and / or An improvement in effectiveness is achieved. Such compounds are described below.

  (Scheme 51.1)

General examples outlined in schemes 51.2, 51.4, 51.6, and 51.8 using the specific examples illustrated in schemes 51.3, 51.5, 51.7, and 51.9 These compounds and the like can be prepared according to the route.

2-aminoethylphosphonic acid diethyl ester in a solvent such as dimethylformamide using standard reagents for the formation of secondary amines such as dicyclohexylcarbodiimide (DCC) and hydroxybenztriazole (HOBT) Coupling with (commercially available).

  (Scheme 51.4)

In the presence of a reagent such as phosgene in a solvent such as toluene, the aniline-carrying phosphonate moiety is converted to 4- (4-aminophenoxy) -pyridine-2-carboxylic acid methylamide (US Patent No. 2002/0165394). To form urea (see Bioorg. Med. Chem. Lett., (2001), 11, 2775).

  Alkylation of 4-hydroxypyridine-2-carboxylic acid methylamide with 4-fluoronitrobenzene using a base such as cesium carbonate in a solvent such as dimethylformamide followed by tin chloride (II in a solvent such as ethanol ) Reduction of the nitro group forms 4- (4-aminophenoxy) -pyridine-2-carboxylic acid methylamide.

  The synthesis of a suitable phosphonate bearing aniline is illustrated in Scheme 51.5.

  (Scheme 51.5)

Alkylation of 2-chloro-5-nitrophenol with excess E-1,4-dichlorobutene in a solvent such as dimethylformamide in the presence of a base such as potassium carbonate. The resulting monobromide is heated with triethyl phosphite in a solvent such as toluene (or other Arbuzov reaction conditions: see Engel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988). Finally, the nitro group is reduced with tin (II) chloride in a solvent such as ethanol.

  (Scheme 51.6)

In a manner similar to that shown in Scheme 51.4, 4-chloro-3-trifluoromethylaniline is coupled with a 4-phenoxy substituted aniline bearing a phosphonate moiety to form urea. The synthesis of a suitable phosphonate bearing aniline is illustrated in Scheme 51.7.

  (Scheme 51.7)

(3-Benzyloxy) phenol is treated with magnesium t-butoxide and diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) in a solvent such as tetrahydrofuran. Greene, T .; , Protective groups in organic synthesis, Wiley-Interscience, (1999), the benzyl group is removed by hydrogenation in the presence of a catalyst such as a palladium carbon catalyst in a solvent such as methanol. The resulting phenol is alkylated with 4-fluoronitrobenzene using a base such as potassium carbonate in the solvent. Finally, the nitro group is reduced as shown in Scheme 51.5.

  (Scheme 51.8)

In a manner similar to that shown in Scheme 51.4, 4-chloro-3-trifluoromethylaniline is coupled with a 4-phenoxy substituted aniline bearing a phosphonate moiety to form urea. The synthesis of a suitable phosphonate bearing aniline is illustrated in Scheme 51.9.

  (Scheme 51.9)

2-Chloro-5-nitrophenyl chloride is reacted with 2-aminoethylphosphonic acid diethyl ester. A biaryl ether motif is then obtained by displacement of the chloride by reaction 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. And reduction of the nitro group as in the previous example yields aniline for coupling in the urea formation step.

Example 52: Preparation of Exemplary Compounds of the Invention Use of SAHA analog prodrugs to obtain drugs with increased intracellular half-life by cleavage inside target cells, resulting in dose reduction and / or improved efficacy Is achieved. Such phosphonate prodrug compounds are described below.

  (Scheme 52.1)

Using the specific examples illustrated in Schemes 52.3 and 52.5, these compounds and the like are made following the general route outlined in Schemes 52.2 and 52.4.

  (Scheme 52.2)

(Scheme 52.3)

The synthesis of prodrugs 52-3, 52-13 is shown in Scheme 52.2 (WO 118,171 and WO 03,032,921). Differently protected octanedioic acid (reported in US Patent No. 23,232) can be deprotected to give 52-6, 52-11. Coupling of monoacid and 4-aminophenol using standard peptide coupling conditions provides compounds 52-7, 52-12. Hydrolysis of the remaining ester and subsequent formation of the protected hydroxyamide provides compound 52-9. The phenol moiety is used for conjugation of prodrug units late in the synthesis.
Specifically, octanedioic acid tert-butyl ester methyl ester is deprotected using trifluoroacetic acid (TFA) to give compounds 52-6, 52-11. Coupling of free acid to 4- (methylamino) phenol (Nag, A. et al., Indian J. Chem. Sect. B., (1989), 64, 1 and US Patent No. 2, 397,911) gives amides 52-7, 52-12. Hydrolysis of the methyl ester using LiOH provides the acid 52-8. Carbodiimides such _TBDPSO-NH 2, EDC, and the N-N-dimethylaminopyridine peptide coupling conditions using to form the TBDPS protective hydroxamic acid, compound 52-9 is formed. Phenol 52-9 can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the protected phosphonate diesters 52-3, 52-13. Removal of the TBDPS group using TFA gives compounds 52-3, 52-13.

  (Scheme 52.4)

Compounds 52-4, 52-16, 52-17 can be prepared from the advanced intermediate 52-14 reported in WO 0118171. Protection of the hydroxyamide and subsequent removal of the Cbz group gives compounds 52-15, 52-19. Reductive amination using aldehydes 52-18, 52-20 (Digital Specialty Chemicals) followed by removal of the protecting group on the hydroxyamide provides the prodrugs 52-4, 52-16, 52-17.

  (Scheme 52.5)

Cbz protection 52-14 can be prepared as described in WO 0118171. Blocking hydroxyamide using TBDPS (Greene, T., Protective groups in organic synthesis, Wiley-Interscience, (1999)) and subsequent removal of the Cbz group gives compounds 52-15, 52-19. The free amines of 52-15, 52-19 are available from Aldehyde 52-18, 52-20 (Digital Specialty Chemicals (Olson, GL et al., J. Med. Chem., (1995), 38). , 15, 2866)) to give the prodrugs 52-4, 52-16, 52-17.

Example 53 Preparation of Exemplary Compounds of the Present Invention Reduction of Dose and / or Improved Efficacy by Use of Prodrugs of Thalidomide Analogues that Obtain Drugs with Increased Intracellular Half-Life by Cleavage Inside Target Cells Is achieved. Such compounds are described below.

  (Scheme 53.1)

Using the example shown in Scheme 53.3, these compounds and the like are made according to the general route outlined in Scheme 53.2.

  (Scheme 53.2)

(Scheme 53.3)

Bioorg. Med. Chem. Lett. , (1999), 9, 1625, and 2-methyl-4-nitrobenzoic acid methyl ester (commercially available) is converted to 3- (5-amino-1-oxo-1,3-dihydro- Convert to isoindol-2-yl) -piperidine e-2,6-dione. This amine intermediate is subjected to reductive amination with diethylphosphonoacetaldehyde (obtained from ozonolysis of diethylallylphosphonate) in the presence of a reducing agent such as sodium triacetoxyborohydride to provide the desired amine linker. An analog is obtained (J. Org. Chem., (1996), 61, 3849). Alternatively, J. Org. Med. Chem. , (1982), 25, 960 and J. Am. Med. Chem. The amine is acylated with activated diethylphosphonoacetic acid to give the desired amide linker according to procedures such as those reported in, (1984), 27,600. Treatment with a coupling agent such as diethyl cyanophosphonate and a base such as diisopropylethylamide in a solvent such as dimethylformamide at room temperature can give activated diethylphosphonoacetic acid.

  Treatment of 2-methyl-3-nitrobenzoic acid methyl ester (commercially available) with N-bromosuccinimide in a solvent such as carbon tetrachloride in the light gives 2-bromomethyl-3-nitrobenzoic acid methyl ester. It is done. The benzylic bromide is converted to [2- (3-amino-2,6-dioxo-piperidin-1-yl) -ethyl] -diethylphosphonate in a solvent such as dimethylformamide in the presence of a base such as triethylamine. Treat with an ester (see below for the preparation of this compound). The coupled product is reduced by hydrogenation (Bioorg. Med. Chem. Lett., (1999), 9, 1625) to give the desired analog. J. et al. Med. Chem. , (2003) 46, 3793, etc. to give [2- (3-amino-2,6-dioxo-piperidin-1-yl) -ethyl] -phosphonic acid diethyl ester. It is done. Thus, benzyloxycarbonyl protected glutaric acid is treated with triethylamine, 1-hydroxybenzotriazole, diethyl 2-aminoethylphosphonate, and 1,3-dicyclohexylcarbodiimide in a solvent such as acetonitrile. After the reaction is complete, the solvent is removed and the residue is purified by chromatography to give the cyclic product, which is subjected to hydrogen in the presence of a palladium catalyst to give the desired intermediate.

Example 54: Preparation of Exemplary Compounds of the Present Invention Reduction of dose and / or efficacy by use of a prodrug of MS-275 analog that results in a drug with increased intracellular half-life by cleavage inside the target cell. Improvement is achieved. Such phosphonate prodrug compounds are described below.

  (Scheme 54.1)

Using the example shown in Scheme 54.3, these compounds and the like are made following the general route outlined in Scheme 54.2.

  (Scheme 54.2)

The preparation of a prodrug of MS-275 is shown in Scheme 54.2. Compound 54-4 (prepared according to CH 596714 and Chem Abstr. 78, 16049) was prepared via carbonate activation via formation of a carbonylimidazole intermediate followed by addition of 4- (aminomethyl) benzoic acid. Convert to 54-5. Subsequent coupling of 54-5 carboxylic acid with 2-aminoaniline proceeds to give compound 54-6. Hydrolysis of the ester and subsequent coupling of the acid with an aminophosphonate prodrug completes the synthesis of prodrug 54-2.

  (Scheme 54.3)

The preparation of prodrug linked MS-275 is shown in more detail in Scheme 54.3. Compound 54-7 is prepared according to reported methods (CH 567714 and Chem Abstr. 78, 16049). Condensation of 54-7 with 4- (aminomethyl) benzoic acid (Aldrich) using 1,1′-carbonyldiimidazole provides carboxylic acid 54-8 (Suzuki, T. et al., J. MoI. Med. Chem., (1999), 42, 3001). Treatment with oxalyl chloride converts the acid 54-8 to acyl chloride, followed by treatment with imidazole to form the acyl imidazole intermediate. This is then reacted with 2-aminoaniline in the presence of trifluoroacetic acid (TFA) to form 54-9. Hydrolysis of the methyl ester and subsequent coupling with diethylaminoethyl phosphonate (Fluka) provides the prodrug 54-10.

  Formation of prodrug 54-3 follows a similar procedure as described above. The starting material 5-hydroxymethylnicotinic acid methyl ester was prepared according to Hemel J. et al. V. et al. , Nucleosides Nucleotides, (1996), 15, 1203. The subsequent steps are shown in Scheme 54.3.

Example 55: Preparation of Exemplary Compounds of the Invention Using the example shown in Scheme 55.2, representative compounds of the invention are made according to the general route outlined in Scheme 55.1.

  (Scheme 55.1)

The preparation of prodrug 55-7 is shown in Scheme 55.1. Compound 55-1 (4-formylcinnamic acid) is first esterified to give aldehyde 55-2 (WO 03039599). Reductive amination of the aldehyde with 3- (2-aminoethyl) -1H-indol-5-ol (Aldrich) provides compound 55-3. Alkylation of the secondary amine in 55-3 using protected 2-bromoethanol provides compound 55-4. Phenol 55-4 can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, a dialkyl phosphonate such as diethylphosphonomethyl triflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diester 55-5. Formation of N-hydroxyamide using hydroxylamine in base gives compound 55-6. Final removal of the primary alcohol protecting group provides the prodrug 55-7.

  (Scheme 55.2)

A detailed synthesis of the prodrug of LAQ-824 is shown in Scheme 55.2. 4-Formylcinnamic acid is first esterified to give the methyl ester 52-14 (WO 03039599). Reductive amination of 52-14 aldehyde with 3- (2-aminoethyl) -1H-indol-5-ol (Aldrich) provides amine 55-8. Alkylation with (2-bromoethoxy) -tert-butyldimethylsilane gives compound 55-9. Alkylation of phenol 55-9 with phosphonomethyl triflate provides phosphonate 55-10. N-hydroxyamine is formed using hydroxylamine in a basic reaction medium. Final TBDMS removal yields prodrug 55-12.

Other syntheses can follow the same synthetic route as described above, for example, using 1H-indole-6-ol (sold by Toronto Research Chemicals) as the corresponding starting material.
Example 56: Preparation of Exemplary Compounds of the Invention Using the examples shown in Schemes 56.2 and 56.4, these compounds and the like are prepared according to the general route outlined in Schemes 56.1 and 56.3. Can be produced.

According to the procedure of arabinofuranosyl-2-fluoroadenine 56-1 (Montgomery, J. et al., J. Med. Chem., (1969), 12, 3, 498 in a solvent such as tetrahydrofuran or dimethylformamide. Preparation) is treated with a base such as sodium hydride. Upon defoaming, dialkylphosphonate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diester 56.2.

  (Scheme 56.3)

The preparation of compound 56-8 is described in Scheme 56.3. Compound 56-4 (9- (2-deoxy-α-D-ribofuranosyl) 2-fluoroadenine) was prepared according to Montgomery, J. et al. et. al. , J .; Med. Chem. , (1969), 12, 3,498 and U.S. Pat. S. Patent No. Prepared as described in US 4,210,745. Oxidation of 5′-OH and subsequent elimination yields glycal 56-5 (see the procedure of Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). ) Protection of the fluoroadenine at position 6 and subsequent selenoetherification affords the protected phosphonate 56-6 (Kim, C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative elimination of phenyl selenide (described in Kim, C. et al., J. Org. Chem., (1991), 56, 2642) followed by stereoselective dihydroxylation yields a diol. To monotriflate. Protection of the 3 ′ alcohol provides compound 56-7. Exposure of the compound to LiOA converts the stereochemical properties at the 2 ′ position to give the desired protected stereoisomer of the product. Finally, the protecting group is removed.

  (Scheme 56.4)

Specifically, 9- (2-deoxy-α-D-ribofuranosyl) 2-fluoroadenine (Compound 56-4) (Montgomery, J. et. Al., J. Med. Chem., (1969), 12, 3,498 and US Patent No. 4,210,745) are oxidized with PtO ₂ to give the carboxylic acid 56-9. Decarboxylative elimination is performed using dimethylformamide dineopentyl acetal in high temperature DMF (Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). . Once the furanoid glycal 56-5 is obtained, Greene, T .; First, protection at position 6 of 2-fluoroadenosine using PivCl conditions as described in, Protective groups in organic synthesis, Wiley-Interscience, (1999). Treatment of the protected glycal with silver perchlorate in the presence of diethyl (hydroxymethyl) phosphonate (Philion, D. et al., Tetrahedron Lett., 1986, 27, 1477) gives phosphonate 56.10. Kim, C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative elimination of selenide and subsequent dihydroxylation using osmium tetroxide yields the diol, which can be converted to the monoprotected triflate 56-12. Substitution of the triflate to the acetate group can reverse the conformation of the 2 ′ alcohol. Deprotection of the pivaloyl group (Greene, T., Protective groups in organic synthesis, Wiley-Interscience, (1999)) also removes the newly introduced 2 'acetate. Final deprotection of the THP group can be performed in an acidic medium.

Example 57: Preparation of Exemplary Compounds of the Invention Using the example shown in Scheme 57.2, the compounds of the invention are prepared as generally shown in Scheme 57.1.

The compound is prepared via reductive amination of the phosphonate containing aldehyde using pirarubicin itself. Such aldehydes are synthesized according to Synth. Commun. (1992), 22, 2219.

Example 58 Preparation of Exemplary Compounds of the Invention Compounds of the invention are prepared as generally described in the following schemes.

  (Scheme 58.1)

(Scheme 58.2)

Greene, T .; , Protective groups in organic synthesis, Wiley-interscience publication, (1999), using the Cbz protecting group to protect the amino sugar moiety of daunorubicin to give 58-7. The alcohol is treated with a base such as sodium hydride in a solvent such as dichloromethane, tetrahydrofuran, or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diester 58-6 after purification. Greene et. al. Final deprotection by hydrogenation in the presence of a catalyst, such as palladium on carbon, in a solvent such as methanol using the method of gives the desired product.

  Alkyl derivatives of amino sugar nitrogens have been reported (Farquar, D. et. Al., J. Med. Chem., (1998), 41, 6,965). The coupling of the phosphonate prodrug moiety onto this amine via alkylation is shown in Scheme 58.3. A specific example of the preparation of 58-9 is shown in Scheme 58.4.

  (Scheme 58.3)

Daunorubicin itself is used to prepare prodrug 58-9 via reductive amination of phosphonate-containing aldehydes. Such aldehydes are synthesized according to Synth. Commun. (1992), 22, 2219.

  The phosphonate moiety can be further manipulated before final deprotection. These conversion types are described in more detail below.

Example 59: Preparation of Exemplary Compounds of the Invention Representative compounds of formulations 59-4, 59-7, following the general route outlined in Scheme 59.1 using the examples shown in Scheme 59.2. Can be produced.

  (Scheme 59.1)

Greene, T .; , Protective groups in organic synthesis, Wiley-interscience publication, (1999), using the Cbz protecting group to protect the amino sugar moiety of idarubicin to give 59-5. The alcohol is treated with a base such as sodium hydride in a solvent such as dichloromethane, tetrahydrofuran, or dimethylformamide. Upon defoaming, diethylphosphonomethyl triflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diester 59-6 after purification. Greene et. al. Final deprotection by hydrogenation in the presence of a catalyst, such as palladium on carbon, in a solvent such as methanol using the method of gives the desired product.

  Alkyl derivatives of amino sugar nitrogens have been reported (Farquar, D. et. Al., J. Med. Chem., (1998), 41, 6,965). The coupling of the phosphonate prodrug moiety onto this amine via alkylation is shown in Scheme 59.3. A specific example of the preparation of 59-9 is shown in Scheme 59.4.

Prodrug 59-9 is prepared via reductive amination of phosphonate-containing aldehydes using idarubicin itself. Such aldehydes are synthesized according to Synth. Commun. (1992), 22, 2219.

Example 60 Preparation of Exemplary Compounds of the Present Invention Representative examples of the present invention according to the general route outlined in Schemes 60.1-60.3, using the examples shown in Schemes 60.4-60.6. Compounds can be made.

(Scheme 60.4: Modification with C7)

J. et al. Org. As described in Chem, ((1996)), 61, 3849-3862, exatecan is dissolved in an organic solvent such as tetrahydrofuran (THF), acetonitrile, or dimethylformamide (DMF) to give (2-oxo -Ethyl) -phosphonic acid diethyl ester (1 eq) and sodium triacetoxyborohydride. The reaction is quenched 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 at C9)

Exatecan is dissolved in an organic solvent such as carbon tetrachloride. N-bromosuccinimide (NBS) is added followed by azobisisobutyronitrile (AIBN) according to the procedure of Organikum, 17 ^th edition, Deutscher Verlag der Wissenschaften, (1988), 167. The reaction is heated to reflux temperature for several hours. After the reaction is complete, the mixture is cooled to room temperature. The reaction is filtered and the solvent removed in vacuo to give the crude product. The regioisomers are further separated by chromatography.

  The product of Step 1 is dissolved in an organic solvent such as acetonitrile or DMF and treated with aminoethylphosphonic acid diethyl ester (excess), sodium iodide (1 eq), and sodium carbonate (1 eq). The reaction mixture is heated to an elevated temperature of about 50-60 ° C. After the reaction is complete, the mixture is cooled to room temperature and filtered. The crude 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. The solvent is filtered and removed under reduced pressure to give the crude product. The product is further purified by chromatography.

  (Scheme 60.6: Modification with C10)

Exatecan is dissolved in an organic solvent such as DMF, DCM, or acetonitrile. After the addition of tert-butoxycarbonyl anhydride, a catalytic amount of 4-dimethylaminopyridine (DMAP) is added (Green and Wuts, Protective Groups in Organic Synthesis, Wiley and Sons, NY, (1999)). Continue stirring at room temperature. After the reaction is complete, water is added and the crude reaction product is extracted with an organic solvent such as DCM or chloroform and dried. Removal of the solvent gives a crude product. Further purification 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). Continue stirring at room temperature until conversion to the ring-opening lactone is observed. The solvent is removed under reduced pressure and the crude material is dissolved in an organic solvent such as methanol or DMF. J. et al. Am. Chem. Soc. , (1957), 79, 385-391, according to a modified procedure, aminoethylphosphonic acid diethyl ester is added and the reaction is heated to reflux for an extended period of time. After the reaction is complete, the mixture is cooled to room temperature and acidified with aqueous HCl. J. et al. Am. Chem. Soc. , (1966), 88, 3888-3890, continue to stir until lactone formation is observed.

  The solvent is removed under reduced pressure and the mixture is partitioned between an organic solvent such as chloroform or DCM and aqueous HCl (0.1 N). The organic phase is isolated and the solvent is removed under reduced pressure. 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 Synthesis, Wiley and Sons, NY, (1999)). After the reaction is complete, solid sodium bicarbonate is added and the reaction is filtered. The solvent is removed under reduced pressure. The product is further purified by chromatography.

Example 61 Preparation of Exemplary Compounds of the Present Invention Representative examples of the invention according to the general route outlined in Schemes 61.1-61.3 using the examples shown in Schemes 61.4-61.6. Compounds can be made.

(Scheme 61.4: Modification with ω guanidine nitrogen)

Synthesis of aromatic starting materials (1):
2-Cyanophenyl bromide (commercially available) is dissolved in an organic solvent such as N-methylpyrrolidinone (NMP) or dimethylformamide (DMF) under an inert gas atmosphere. After the addition of sodium carbonate, triphenylphosphine, and methyl acrylate, palladium (II) acetate (Pd (OAc) ₂ ) is added. Chem. Rev. , (2000), 100, 3009, the reaction mixture is heated to a high temperature of about 100 ° C to 140 ° C. After the reaction is complete, the mixture is cooled to room temperature and filtered through Celite. Removal of the solvent gives a crude product. Further purification by chromatography.

The crude material from step 1 is dissolved in a mixture of organic solvents such as benzene and ethanol under an inert gas atmosphere. J. et al. Org. Chem. Wilkinson catalyst [RhCl (PPh ₃ ) ₃ ] is added and the reaction mixture is placed under a hydrogen atmosphere of about 60-80 psi and heated to a high temperature of 60 ° C., according to the procedure described in, (1969), 34, 3684-3585. Heat. After completion of the reaction, the mixture is cooled to room temperature and the solvent is removed under reduced pressure. The crude material is wet triturated with diethyl ether and the catalyst removed by filtration through Celite. Removal of the solvent gives a crude material. Further purification by chromatography.

  Org. Lett. , (2001), 3, 279-281, the crude material from Step 2 is dissolved in polyphosphoric acid and heated to a high temperature of about 90 ° C. under an inert gas atmosphere. After 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. Removal of the solvent gives the crude product. Further purification by chromatography.

Synthesis of guanidine derivative (2):
J. et al. Org. Chem. , (2002), 67, 7553-7556, di (imidazol-1-yl) methanimide is dissolved in an organic solvent such as tetrahydrofuran (THF) and 2-aminoethylphosphonic acid diethyl ester at room temperature. React with. After completion of the reaction, water is added and the product is extracted with an organic solvent such as dichloromethane (DCM). The combined organic phases are washed with saturated aqueous ammonium chloride, water and brine and dried. Removal of the solvent gives a crude product. Further purification by chromatography.

  The product of this step is dissolved in an organic solvent such as DMF and reacted with hydrazine at a high temperature of about 100 ° C. in a sealed container according to a procedure slightly modified from the procedure cited above. After the reaction is complete, 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 phases are washed with saturated aqueous ammonium chloride, water and brine and dried. Removal of the solvent gives a crude product. Further purification by chromatography.

Final finish (3):
The products of reaction systems (1) and (2) are dissolved in an organic solvent such as ethanol and treated with a catalytic amount of concentrated sulfuric acid. J. et al. Med. Chem. (1993), 36, 46-54, the mixture is heated to reflux for a minimum time. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. The product is dissolved in an organic solvent such as ethyl acetate or chloroform and washed with water. The organic phase is dried and the solvent is removed under reduced pressure. Further purification 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 this temperature is maintained for a long time. After completion of the reaction, precipitation of the product is induced by addition of diethyl ether. The precipitate is collected and evaporated to dryness. The crude material is dissolved in an organic solvent such as ethanol and ammonium saturated ethanol is added. The mixture is heated to a high temperature of about 70 ° C. for several hours. After completion of the reaction, the mixture is cooled to room temperature and the solvent is removed under reduced pressure. The product is further purified either by recrystallization from an ethanol / diethyl ether mixture or by chromatography.

  (Scheme 61.5: Modification with α-guanidine nitrogen)

Synthesis of guanidine derivative (1).
J. et al. Org. Chem, (1996), 61, 3849-3862, tert-butylcarbazate (commercially available) with diethylphosphonatoethylcarbaldehyde and sodium triacetoxyborohydride in an organic solvent such as DCM or THF. To process. The reaction is quenched with sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Further purification by chromatography.

  J. et al. Org. Chem. , (2002), 67, 7553-7556, the product of this step is dissolved in an organic solvent such as THF and reacted with di (imidazol-1-yl) methanimine. After completion of the reaction, water is added and the product is extracted with an organic solvent such as DCM. The combined organic phases are washed with saturated aqueous ammonium chloride, water and brine and dried. Removal of the solvent gives a crude product. Further purification by chromatography.

  The product of this step is dissolved in an organic solvent such as DMF and reacted with ammonia at a high temperature of about 100 ° C. in a sealed container according to a slightly modified procedure derived from the above cited reference. After the reaction is complete, 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 phases are washed with saturated aqueous ammonium chloride, water and brine and dried. Removal of the solvent gives a crude product. Further purification by chromatography.

  Following the procedure from Green and Wuts, Protective Groups in Organic Synthesis, the product of this step is dissolved in an organic solvent such as DCM and treated with trifluoroacetic acid (TFA). After the reaction is complete, sodium bicarbonate is added and the reaction mixture is filtered. The solvent is removed under reduced pressure to give the crude product. Further purification by chromatography.

Final finish (3):
The product of the above reaction is dissolved in an organic solvent such as ethanol and treated with a catalytic amount of concentrated sulfuric acid. J. et al. Med. Chem. , (1993), 36, 46-54, the mixture is heated to reflux for a minimum time. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. The product is dissolved in an organic solvent such as ethyl acetate or chloroform and washed with water. The organic phase is dried and the solvent is removed under reduced pressure. Further purification 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 0 ° C. for a long time. After completion of the reaction, precipitation of the product is induced by addition of diethyl ether. The precipitate is collected and evaporated to dryness. The crude material is dissolved in an organic solvent such as ethanol and ammonium saturated ethanol is added. The mixture is heated to a high temperature of about 70 ° C. for several hours. After completion of the reaction, the mixture is cooled to room temperature and the solvent is removed under reduced pressure. The product is further purified either by recrystallization from an ethanol / diethyl ether mixture or by chromatography.

  (Scheme 61.6: Binding to C2)

The product (1) of the reaction system of Scheme 61.4 is dissolved in an organic solvent such as THF, and the solution is cooled to -78 ° C. Diisopropylamidolithium solution is added and the reaction mixture is stirred for several minutes. Upon completion of deprotection, an excess of E-1,4-dibromobutene is added and the reaction is allowed to warm to room temperature. The reaction is quenched with aqueous ammonium chloride and the product is extracted with an organic solvent such as ethyl acetate or chloroform. The solvent is removed by drying to obtain a crude product. Further purification by chromatography.

  Engel, R.A. The product of this step is heated to about 110 ° C. with triethyl phosphite in an organic solvent, such as toluene, according to the procedure outlined in S., Synthesis of carbon phosphorous bonds, CRC press (1988). After completion of the reaction, the mixture is cooled to room temperature and the solvent is removed under reduced pressure to obtain the crude product. Further purification by chromatography.

  The product of this reaction and aminoguanidine are dissolved in an organic solvent such as ethanol and treated with a catalytic amount of concentrated sulfuric acid. J. et al. Med. Chem. , (1993), 36, 46-54, the mixture is heated to reflux for a minimum time. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. The product is dissolved in an organic solvent such as ethyl acetate or chloroform and washed with water. The organic phase is dried and the solvent is removed under reduced pressure. Further purification 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 0 ° C. for a long time. After completion of the reaction, precipitation of the product is induced by addition of diethyl ether. The precipitate is collected and evaporated to dryness. The crude material is dissolved in an organic solvent such as ethanol and ammonium saturated ethanol is added. The mixture is heated to a high temperature of about 70 ° C. for several hours. After completion of the reaction, the mixture is cooled to room temperature and the solvent is removed under reduced pressure. The product is further purified either by recrystallization from an ethanol / diethyl ether mixture or by chromatography.

  The phosphonate moiety can be further manipulated before final deprotection. These conversion types are described in more detail below.

Example 62 Preparation of Exemplary Compounds of the Present Invention Representative compounds of formulations 62-4, 62-7 following the general route outlined in Scheme 62.1 using the examples shown in Scheme 62.2 Is made.

  (Scheme 62.1)

(Scheme 62.2)

Greene, T .; , Protective groups in organic synthesis, Wiley-interscience publication, (1999), using a Cbz protecting group to protect the amino sugar moiety of adriamycin. The protection of primary alcohols using an acetate protecting group to prepare 62-5 has been described (US Patent No. 4,303,785). The alcohol is treated with a base such as sodium hydride in a solvent such as dichloromethane, tetrahydrofuran, or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diester 62-6 after purification. Greene et. al. Final deprotection by hydrogenation in the presence of a catalyst, such as palladium on carbon, in a solvent such as methanol using the above method and subsequent exposure of the compound to potassium carbonate provides the desired product.

  Alkyl derivatives of amino sugar nitrogens have been reported (Farquar, D. et. Al., J. Med. Chem., (1998), 41, 6,965). The coupling of the phosphonate prodrug moiety onto this amine via alkylation is shown in Scheme 62.3. A specific example of the preparation of 62-9 is shown in Scheme 62.4.

Prodrug 62-9 is prepared via reductive amination of phosphonate-containing aldehydes using adriamycin itself. Such aldehydes are synthesized according to Synth. Commun. (1992), 22, 2219.

Example 63: Preparation of exemplary compounds of the invention Background and utility of scaffold compounds Certain triarylethylenes are useful in the treatment of hypercholesterolemia and osteoporosis by acting as selective estrogen receptor modulators. One such derivative, Ospemifene, is described in WO01 / 36360 page 3 line 5. The present invention provides a novel analog (63-1) of ospemifene. Such novel ospemiphene analogs described by structures 63-2, 63-3, and 63-4 have the full utility of AGI-1067 and optionally provide the following cellular accumulation To do.

Methods for preparing new compounds:
The synthesis of ospemiphen 63-1 is described in WO01 / 36360. As shown in Schemes 63.1-63.2, compound 63-1 is prepared in a non-basic solvent such as dichloromethane containing a solvent such as pyridine or a base such as triethylamine to provide an ether of 63-1. Treat with dialkylphosphonoalkyl trifluoromethylphosphonate. Using the phosphonate ester and amidate formation methods described below, the alkyl group is removed from the phosphonate moiety using trimethylsilyl bromide in a solvent such as DMF or acetonitrile and the resulting compound is converted to the desired prodrug 63-2, 63 -3, 63-4.

  Scheme 63.2 describes the synthesis of compound 63-9 (a specific member of the general class of compounds described in structures 63-2, 63-3, 63-4). Compound 63-1 is treated with diethylphosphonomethyl trifluorosulfonate 63-5 in pyridine to give ether 63-3. Compound 63-6 is treated with trimethylsilyl bromide in acetonitrile to give free phosphonic acid 63-7. Compound 63-7 is then treated with dichlorohexylcarbodiimide and phenol in DMF to give monophenol ester 63-8, then alanine using aldrithiol and triphenylphosphine in DMF. Is condensed with the isopropyl ester of to give the desired prodrug 63-9.

  (Scheme 63.1)

(Scheme 63.2)

Example 64: Preparation of Exemplary Compounds of the Invention A synthetic series of examples of such phosphonates is described in Scheme 64.1.

  (Scheme 64.1)

Bioorg. Med. Chem. Rapamycin (a synthetic precursor of everolimus) is O-arylated using the appropriate aryl bismuth reagent as described above according to the procedure reported in Lett, (1995), 5, 1035, etc. 3- (Dimethyl-t-butylsilyloxy) bromobenzene is treated with magnesium in diethyl ether or with butyllithium in tetrahydrofuran and the resulting organometallic reagent is reacted with bismuth trichloride to give triarylbis. A tribismuthine is obtained. After treatment with 1-1.2 equivalents of peracetic acid, the bismuth (V) reagent is mixed with rapamycin and copper (II) acetate. The desired 3- (dimethyl-t-butylsilyloxy) phenyl ether is obtained by refluxing as necessary and allowing the reaction to proceed for 1 day at room temperature. After removal of the dimethyl-t-butylsilyl protecting group, O-alkylation with diethyl (bromomethyl) phosphonate in the presence of silver oxide provides an everolimus analog containing the desired diethyl phosphonate. Silver ion assisted reactions have been used to mediate O-alkylation of immunosuppressive macrolides that are similar in structure to rapamycin (see J. Med. Chem., (1998), 41, 1764).

  (Scheme 64.2)

A phosphonate derivative of everolimus indolyl ether was prepared as described in J. Am. Org. Chem. (1998), 63, 6721, and prepared as shown in Scheme 64.2 in a manner similar to the previous example, except that the triindolyl bismuthine key intermediate is obtained from 5-bromoindole.

Example 65: Preparation of Exemplary Compounds of the Invention A synthetic series of examples of such phosphonates is described in Scheme 65.1.
(Scheme 65.1)

Bioorg. Med. Chem. Sirolimus is O-arylated using the appropriate aryl bismuth reagent as described above according to the procedure reported in Lett, (1995), 5, 1035, etc. 3- (Dimethyl-t-butylsilyloxy) bromobenzene is treated with magnesium in diethyl ether or with butyllithium in tetrahydrofuran and the resulting organometallic reagent is reacted with bismuth trichloride to give triarylbis. A tribismuthine is obtained. After treatment with 1-1.2 equivalents of peracetic acid, the bismuth (V) reagent is mixed with sirolimus and copper (II) acetate. The desired 3- (dimethyl-t-butylsilyloxy) phenyl ether is obtained by refluxing as necessary and allowing the reaction to proceed for 1 day at room temperature. After removal of the dimethyl-t-butylsilyl protecting group, O-alkylation with diethyl (bromomethyl) phosphonate in the presence of silver oxide provides a sirolimus analog containing the desired diethylphosphonate. Silver ion assisted reactions have been used to mediate O-alkylation of immunosuppressive macrolides that are similar in structure to sirolimus (see J. Med. Chem., (1998), 41, 1764).
(Scheme 65.2)

Phosphonate derivatives of sirolimus indolyl ether are prepared according to J. Org. Org. Chem. (1998), 63, 6721, and is prepared as shown in Scheme 65.2 in a manner similar to the previous example except that the triindolyl bismuthine key intermediate is obtained from 5-bromoindole.

Example 66: Preparation of Exemplary Compounds of the Invention Following the general route outlined in Schemes 66.1-66.3, methods for the synthesis of these compounds are described in WO 09/613266.

  (Scheme 66.1)

Synthesis examples of suitable phosphonate-containing phenylalanine derivatives are shown below.

  (Scheme 66.2)

The protected tricine derivative can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added and the desired phosphonate diester is obtained after purification. Subsequent selective hydrolysis of the carboxylic acid ester using a hydroxide ion source such as lithium hydroxide in a solvent such as ethanol yields a phosphonate-containing reagent in a form suitable for use in the synthesis of bortezomib analogs. It is done.

  (Scheme 66.3)

The protected tyrosine derivative can be treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. When defoaming, E-1,4-dibromobutene is added in excess. After quenching with aqueous ammonium chloride and extraction of the product with an organic solvent such as ethyl acetate, the monoalkylated product is isolated by chromatography. This is then heated in triethyl phosphite in a solvent such as toluene (or other Arbuzov reaction conditions: see Engel, R., Synthesis of carbon-phosphorus bonds, CRC press, 1988) and the desired phosphonic acid. Of the diethyl ester is obtained. Subsequent selective hydrolysis of the carboxylic acid ester using a hydroxide ion source such as lithium hydroxide in a solvent such as ethanol yields a phosphonate-containing reagent in a form suitable for use in the synthesis of bortezomib analogs. It is done.

Example 67: Preparation of Exemplary Compounds of the Invention Use of a VX-148 analog prodrug to obtain a drug with increased intracellular half-life by cleavage inside the target cell, resulting in dose reduction and / or efficacy. Improvement is achieved. Such compounds are described below.

  (Scheme 67.1)

Using the synthesis of the appropriate reagents shown in Schemes 67.3 and 67.6 to make these compounds etc. according to the general route outlined in Schemes 67.2, 67.4, and 67.5 Can do.

  (Scheme 67.2)

The 3,5-bifunctionalized nitrobenzene derivative allows the phenyl ring at the desired position to be prepared for incorporation into a VX-148 analog made entirely using the method developed for the parent compound. A suitable starting point is obtained for reagents containing a bound phosphonate moiety.

  (Scheme 67.3)

3-Hydroxy-5-nitro-benzoic acid is heated briefly in thionyl chloride to give the acid chloride. This is then condensed with O, N-dimethyl-hydroxyamine in the presence of a base such as triethylamine to give an acetophenone derivative. This is then treated with a base such as potassium carbonate in an amphoteric aprotic solvent such as dimethylformamide in the presence of excess E-1,4-dibromobutene. Monobromide is isolated by chromatography and treated with triethyl phosphite in a solvent such as toluene (or other Arbuzov reaction conditions: see Engel, R., Synthesis of carbon-phosphorous bonds, CRC press, 1988). The diethyl ester of the desired phosphonic acid is obtained. Thereafter, the carbonyl of acetophenone is enantioselectively reduced using an appropriate homochiral oxazaborolidine such as described in Corey (J. Am. Chem. Soc., (1987), 109, 5551). The resulting alcohol is replaced with azide using a method described by Mitsunobu (Bull. Chem. Soc. Japan., (1971), 44, 3427) and the like. 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 nitrobenzene provides the desired aniline.

  (Scheme 67.4)

A suitable reagent for use in phosphonate analog synthesis is made by a route analogous to Scheme 67.3 starting from 2-hydroxy-5-nitro-benzoic acid.

  (Scheme 67.5)

U. S. Patent No. 6,054,472 and U.S. Pat. S. Patent No. An example of the synthesis of a suitable reagent for the coupling reaction at 6,344,465 is shown in Scheme 67.6 below.

  (Scheme 67.6)

2-Aminoethylphosphonic acid diethyl ester (commercially available) using standard reagents for the formation of secondary amides such as dichlorohexylcarbodiimide (DCC) and hydroxybenztriazole (HOBT) in solvents such as dimethylformamide Coupling with The reduction of the nitro group then proceeds in a manner similar to that described in Scheme 67.3.

Example 68: Preparation of exemplary compounds of the invention General synthesis outlined in Schemes 68.1, 68.3, and 68.4 using the synthesis of the appropriate reagents shown in Schemes 68.2 and 68.5. These compounds and the like can be prepared according to the route.

  (Scheme 68.1)

The 3,5-difunctionalized nitrobenzene derivative allows the phenyl ring at the desired position to be prepared for incorporation into a fully prepared merime positive analog using the method developed for the parent compound. A suitable starting point is obtained for reagents containing a bound phosphonate moiety.

  (Scheme 68.2)

3-hydroxy-5-nitro-benzoic acid is heated briefly in acidic methanol to give the methyl ester. This is then treated with a base such as potassium carbonate in an amphoteric aprotic solvent such as dimethylformamide in the presence of excess E-1,4-dibromobutene. Monobromide is isolated by chromatography and treated with triethyl phosphite in a solvent such as toluene (or other Arbuzov reaction conditions: see Engel, R., Synthesis of carbon-phosphorous bonds, CRC press, 1988). The diethyl ester of the desired phosphonic acid is obtained. The benzoate is then saponified and reduced, and the resulting alcohol is replaced with azide using the method 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 nitrobenzene provides the desired aniline.

  (Scheme 68.3)

Reagents suitable for use in type II phosphonate analog synthesis can be made by a route analogous to Scheme 68.2 starting from 2-hydroxy-5-nitro-benzoic acid.

  (Scheme 68.4. General route to type III analogs)

U. S. Patent No. 6,054,472 and U.S. Pat. S. Patent No. An example of the synthesis of a suitable reagent for the coupling reaction at 6,344,465 is shown in Scheme 68.5 below.

  (Scheme 68.5)

As shown, 3-nitrobenzaldehyde is reacted with a Grignard reagent to derive a tether bearing a protected alcohol to give a benzylic alcohol. In a manner similar to Scheme 68.2, the alcohol is replaced with an azide. After deprotection, the free alcohol is alkylated with diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) using a base such as magnesium tert-butoxide in a solvent such as tetrahydrofuran. To do. Subsequent conversion of the azido and nitro groups proceeds in a manner similar to 68.2.

Example 69: Preparation of Exemplary Compounds of the Invention Methods for the synthesis of these compounds are described in Batt et al, Bioorg. Med. Chem. Lett. , (1995), 5, 1549. A typical general route is outlined in Scheme 69.1.

  (Scheme 69.1)

Examples of suitable phosphonate-containing analogs are shown below.
(Scheme 69.2)

As shown, the initial Pfitzer condensation is classically performed in one step using potassium hydroxide using a work-up. Alternatively, the initial aldol condensation can be performed using diethylamine and the quinoline ring can be formed in a second step mediated by an acid such as hydrochloric acid in a solvent such as 1,4-dioxane. After removal of the benzyl protecting group by hydrogenation, the phenol can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diester. The carboxylate is deprotected by treatment with lithium hydroxide in ethanol.

  (Scheme 69.3)

Similar to the synthesis of Scheme 69.2, except that an excess of E-1,4-dibromobutene is added after deprotonation of the phenol. After quenching with aqueous ammonium chloride and extraction of the product with an organic solvent such as ethyl acetate, the monoalkylated product is isolated by chromatography. The resulting bromide is heated with triethyl phosphite in a solvent such as toluene to give the desired phosphonic acid diethyl ester, deprotecting the carboxylic acid as described above.

Example 70 Preparation of Exemplary Compounds of the Invention Dexamethasone 70-1 (US Patent No. 3,007,923) The structure of phosphonate ester 70-4 is shown in Scheme 70.1 (substituent R ¹ is H, alkyl, alkenyl, aryl, or aralkyl). Compound 70-4 incorporates a phosphonate moiety (R ¹ O) ₂ P (O) linked to the nucleus by a variable linking group shown as “link” in the bond structure.

  Schemes 70.2-70.12 illustrate the synthesis of phosphonate compounds of the present invention and intermediate compounds useful for the synthesis thereof.

(Protection of reactive substituents)
Depending on the reaction conditions used, it may be necessary to protect certain reactive substituents from undesired reactions by protection prior to the described series and then deprotect the substituents, depending on the reaction conditions used. Functional group protection and deprotection are described, for example, in Protective Groups in Organic Synthesis, by T .; W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990. Protection and deprotection of steroidal ketones and alcohols are described in Organic Reactions in Steroid Chemistry, Vol. 1, J. Fried and J.H. A. Edwards, van Nostrand Reinhold, (1972), p. 375ff. Reactive substituents that can be protected are described in the accompanying schemes (eg, [OH], [O], etc.). For example, Scheme 70.1 shows a protection-deprotection series that protects the steroid side chain as a bis-methylenedioxy (BMD) moiety. In the series, Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition (1990), p. As described in H.223, dexamethasone 70-1 is reacted with an acid catalyst such as paraformamide and hydrochloric acid to give BMD derivative 70-2. The phosphonate moiety is then introduced using the following procedure to give the phosphonate ester 70-3. Then, Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition (1990), p. As described in H.223, for example, the BMD moiety is hydrolyzed by treatment with 50% aqueous acetic acid to give triol 70-4.

Preparation of phosphonate esters 70-7, 70-14, 70-18, 70-20, 70-120, 70-22, and 70-27 Scheme 70.2-70.6 is an imino group or iminoxy group and variability. 2 shows the preparation of a phosphonate linked to the phosphonate by a carbon chain. In this procedure, the BMD protected derivative 70-2 is converted to an amine or hydroxyamine 70-5 where R ² is an alkyl, alkenyl, cycloalkyl, or cycloalkenyl group (optionally a heteroatom O, S or N is incorporated), or a functional group such as an amide, ester group, oxime group, sulfoxide group, or sulfone group, or optionally a substituted aryl group, heteroaryl group, or aralkyl group (optionally Heteroatoms O, S, or N are incorporated) and X is a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxy, and the like. Reacting equimolar amounts of the reactants in an aprotic solvent such as pyridine or xylene or an alcohol solvent such as ethanol, optionally in the presence of an acid catalyst, provides an imine or oxime. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. 1978, 86, 133. and in J.J. Mass. Spectrom. (1995), 30,497. The BMD protected side chain compound 70-6 is then converted to the triol 70-7 as described in Scheme 70.1.

  Schemes 70.2-70.6 also illustrate the preparation of hydroxylamine ethers incorporating phosphonate groups. In this procedure, phosphonate 70-8 (where Lv is a free radical such as bromo or trifluoromethylsulfonyloxy) is reacted with BOC-hydroxylamine 70-9 (Aldrich) to give ether 70-10. Is obtained. The equimolar amounts of the reactants are reacted in a polar solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as potassium hydroxide or dimethylaminopyridine. For example, deprotection by treatment with trifluoroacetic acid provides hydroxylamine ether 70-11.

  (Scheme 70.2 Phosphate A2)

Scheme 70.3 illustrates the preparation of phosphonate 7-14 where the phosphonate is linked by an iminoxy group. In this procedure, substrate 70-2 was prepared as described above with dialkylphosphonomethylhydroxylamine 70- prepared from dialkyltrifluoromethylsulfonyloxymethylphosphonate (Tet. Lett., 1986, 27, 1477) and BOC-hydroxylamine as described above. 12 to give oxime 70-13, which is deprotected to give triol 70-14. The oxime formation reaction is performed between equimolar amounts of reactants in an ethanol-acetic acid solution at ambient temperature. Using the above procedure, but using a different oxime ether 70-5 instead of hydroxylamine ether 70-12, the corresponding product 70-7 is obtained.

  (Scheme 70.3)

Scheme 70.4 illustrates the preparation of compounds 70-18, 70-20, and 70-180 in which the phosphonate group is linked by a pyridylmethoxy group. In this procedure, 0- (3-bromo-5-pyridylmethyl) hydroxylamine 70-15 and dienone 70-2 prepared from 3-bromo-5-bromomethylpyridine (WO 95/28400) as described above were combined with the above. To give oxime 70-16 after side chain deprotection. The product is then reacted with dialkyl phosphite 70-17 in the presence of a palladium catalyst to give phosphonate 70-18. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and alkyl phosphites is described in J. Am. Med. Chem. , 35, 1371, (1992). The reaction is carried out in the presence of a base such as triethylamine and a catalytic amount of tetrakis (triphenylphosphine) palladium (0) in an inert solvent such as toluene.

  Alternatively, bromo compound 70-16 is coupled with dialkyl vinyl phosphonate 70-19 (Aldrich) to give phosphonate 70-20. Coupling of aryl halides and olefins by the Heck reaction is described, for example, in Advanced Organic Chemistry, by F.M. A. Carey and R.C. J. et al. Sundberg, Plenum, (2001), p. 503ff and in Acc. Chem. Res. 12, 146, (1979). Dimethylformamide 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 optionally a base such as triethylamine or potassium carbonate Alternatively, aryl bromide and olefin are coupled in a polar solvent such as dioxane. Optionally, the styrenoid double bond present in product 70-20 is reduced, for example by reaction with diimide, to give saturated analog 70-120. Reduction of olefinic bonds is described in Comprehensive Organic Transformations, by R.C. C. Larock, VCH, (1989), p. 6ff. For example, conversion by catalytic hydrogenation using a palladium carbon catalyst and hydrogen or a hydrogen donor or the use of diimide or diborane.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkenyl phosphonates instead of bromopyridyloxy reagent 70-15, compounds 70-18, 70-20, and 70 A product similar to -120 is obtained.

  (Scheme 70.4)

Scheme 70.5 shows the preparation of phosphonate 70-22 linked to the phosphonate by an imino group. In this procedure, substrate 70-2 is reacted with dialkyl 2-aminophenylphosphonate 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 in the presence of a basic catalyst such as sodium methoxide or an acidic catalyst such as p-toluenesulfonic acid under azeotropic conditions at reflux temperature.

  Using the above procedure, but using a different amino-substituted aryl or heteroaryl phosphonate instead of 2-aminophenyl phosphonate 70-21 gives a product similar to 70-22.

  (Scheme 70.5)

Scheme 70.6 shows the preparation of phosphonate 70-27 with the phosphonate linked by an oximino group and an amide bond. In this procedure, dienone 70-2 is reacted with O- (2-carboxyethyl) hydroxylamine 70-23 (J. Med. Chem., 1990, 33, 1423) to give oxime 70-24. The reaction of steroidal 1,4-dien-3-ones with substituted hydroxylamines is described in J. Am. Steroid Bioch. (1976), 7, 795 (optionally reacting equimolar amounts of reactants in a polar organic solvent such as pyridine in the presence of acetic acid or sodium acetate). The oxime is then reacted with dialkylaminomethylphosphonate 70-25 (AsInEx) to give amide oxime 70-26. Preparation of amines from carboxylic acids and derivatives is described, for example, in Organic Functional Group Preparations, by S .; R. Sandler and W.M. Karo, Academic Press, (1968), p. 274 and Comprehensive Organic Transformations, by R.C. C. Larock, VCH, (1989), p. 972ff. An aprotic solvent in the presence of an activator (such as dicyclohexylcarbodiimide or diisopropylcarbodiimide), optionally in the presence of, for example, hydroxybenztriazole, N-hydroxysuccinimide, or N-hydroxypyridone The amide is obtained by reacting the carboxylic acid with an amine (eg, pyridine, DMF, or dichloromethane).

  Alternatively, the carboxylic acid is first converted to an activated derivative such as an acid chloride, anhydride, mixed anhydride, and imidazolide, and then reacted with an amine in the presence of an organic solvent such as pyridine to give an amide. . Treatment of the carboxylic acid with a reagent (eg thionyl chloride or oxalyl chloride) in an inert organic solvent such as dichloromethane, optionally in the presence of a catalytic amount of dimethylformamide, converts the carboxylic acid to the corresponding acid chloride. Convert.

  The amino product 70-26 is then converted to the triol 70-27 as described in Scheme 70.1.

  Using the above procedure, but using carboxy-substituted hydroxylamine and / or amino-substituted phosphonate instead of hydroxylamine 70-25, a product similar to 70-27 is obtained.

  (Scheme 70.6)

(Preparation of phosphonate esters 70-33, 70-35, 70-40, 70-41, 70-47, 70-147, and 70-48)
Schemes 70.7-70.9 illustrate the preparation of phosphonate esters in which a phosphonate group is attached to the 1 'or 2' position of the pyrazole ring by an aromatic or heteroaromatic group, a heteroatom, and a variable carbon chain. In this procedure, the BMD protected dienone 70-2 is reduced to give the 1,2-dihydro product 70-74. For example, J. et al. Med. Chem. , (2001), 44, 602, the catalytic hydrogenation reaction is carried out by the use of tris (triphenylphosphine) rhodium (I) chloride. Then, J.H. Am. Chem. Soc. , 1964, 86, 1520, the product is reacted with a base such as ethyl formate and sodium hydride in an inert solvent such as toluene or dimethylformamide to give 2-formyl product 70-28. It is done. This compound is then reacted with an alkyl, aralkyl, aryl, or heteroaryl hydrazine 70-29, where substituent X is either a phosphonate group or a group that subsequently converts to a phosphonate-containing substituent. For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl, and the like. The reaction yields isomers 2'- and 1'-arylpyrazoles 70-30 and 70-31. J. et al. Am. Chem. Soc. 1964, 86, 1520, a pyrazole forming reaction is carried out between equimolar amounts of reactants in an acidic solvent such as acetic acid. The pyrazoles 70-30 and 70-31 are then converted to the phosphonates 7-35 and 70-33 via the BMD protected intermediates 70-34 and 70-32, for example, by the procedure described in Schemes 70.8-70.9. Convert to

  (Scheme 70.7 phosphoric acid M3 and M4)

Scheme 70.8 illustrates the preparation of phosphonates linked by a phosphonate via a phenyl ring and an alkoxy or acetylene linkage. In this procedure, the ketoaldehyde 70-28 above is reacted with 3-hydroxyphenylhydrazine 70-36 (Japan patent JP 03011081) to give 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 an ambient temperature chloromethane solution to give the triflate 70-39. The product is then reacted with a dialkylpropynylphosphonate 70-71 (Syn (1999), 2027), triethylamine, and a catalytic amount of tetrakis (triphenylphosphine) palladium (0) in a toluene solution to give an acetylene product 70 -73 is obtained. The palladium-catalyzed coupling reaction of aryl triflate and terminal acetylene is described in WO 0230930. The BMD protecting group is then removed to give triol 70-41.

  Alternatively, 1 'substituted pyrazole 70-37 is reacted with dialkyl 2-hydroxyethylphosphonate 70-72 (Epsilon) in a Mitsonobu reaction to give ether 70-38. Preparation of aromatic ethers by Mitsonobu reaction is described in, for example, Comprehensive Organic Transformations, by R.M. C. Larock, VCH, 1989, p. 448, Advanced Organic Chemistry, Part B, by F.M. A. Carey and R.C. J. et al. Sundberg, Plenum, (2001), p. 153-4, and Org. React. (1992), 42, 335. For example, the phenol and alcohol components are reacted together in the presence of a dialkylazodicarboxylate and a triarylphosphine in an aprotic solvent such as tetrahydrofuran to give an ether or thioether product. The procedure is described in Org. React. (1992), 42, 335-656. The product 70-38 is then deprotected to give the triol 70-40.

  Using the above procedure, but using different acetylene or hydroxyl substituted phosphonates, products similar to 70-41 and 70-40 are obtained. Functionalization procedures are interchangeable between pyrazole substituents 70-70 and 70-37.

  (Scheme 70.8)

Scheme 70.9 illustrates the preparation of phosphonates in which the phosphonate group is linked by a benzyl group or a benzyl group and a saturated or unsaturated carbon chain. In this procedure, ketoaldehyde 70-28 is reacted with 3-bromobenzylhydrazine 70-75 (US Patent No. 4,370,339) as described to give pyrazoles 70-42 and 70-43. Is obtained. Coupling the 1 'substituted isomer 70-42 with a dialkyl vinyl phosphonate 70-76 (Aldrich) in the presence of a palladium catalyst provides the phosphonate 70-46. The product is then deprotected to give triol 70-47. Optionally, as described above, the styrenoid double bond present in product 70-47 is reduced to provide saturated analog 70-147.

  Alternatively, 2'-substituted pyrazole 70-43 is coupled with dialkyl phosphite in the presence of a palladium catalyst to prepare phosphonate 70-44, which is deprotected to give triol 70-48. The preparation of aryl phosphonates by coupling aryl bromides with dialkyl phosphites is described in J. Am. Med. Chem. , 35, 1371, (1992). This reaction is carried out in an inert solvent such as toluene in the presence of a base such as triethylamine and tetrakis (triphenylphosphine) palladium (0).

  Using the above procedure, but using a different bromo-substituted aralkyl, aryl, or heteroarylalkoxyhydrazine and / or different dialkylalkenyl phosphonate instead of bromobenzyl reagent 70-75, compounds 70-47, 70-147, And products similar to 70-48 are obtained.

  (Scheme 70.9)

Schemes 70.10 to 70.12 illustrate the preparation of phosphonate esters in which the phosphonate is linked by a variable carbon bond. In this procedure, ketoaldehyde 70-28 is reacted with hydrazine to give pyrazole derivative 70-49. The reaction of steroidal 2-formyl-3-ketones with hydrazine is described in J. Am. 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 where R ² and X are as defined above to give alkylated products 70-50 and 70-51. Alkylation of substituted pyrazoles is described, for example, in Heterocyclic Chemistry, by T .; L. Gilchrist, Longman, (1992), p. 309. The reaction is carried out between equimolar amounts of the substrate in a polar solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as dimethylaminopyridine and lithium hexamethyldisilazide. Products 70-50 and 70-51 are converted to phosphonates 70-52 and 70-53, followed by deprotection using the procedures described herein, except when X is a dialkylphosphono. Thus, triols 70-54 and 70-55 are obtained.

  (Scheme 70.10 phosphoric acid M3 and M4)

As shown in Scheme 70.11, pyrazole 70-49 was reacted with 1 molar equivalent of dialkyl bromoacetonyl phosphonate 70-78 (Tet., 1978, 34, 649) as described above to produce alkylated pyrazole 70-49. 82 and 70-83 can be selected. Deprotection then yields triols 70-84 and 70-85.

  (Scheme 70.11)

As shown above, pyrazole 70-49 is reacted with 1,4-bis (bromomethyl) benzene 70-86 to give pyrazoles 70-87 and 70-56, as shown in Scheme 70.12. The product is subjected to an Arbuzov reaction (converting the bromomethyl substituent to a dialkylphosphomethyl substituent) by reaction with a trialkyl phosphite at 120 ° C., and after deprotection of the side chain, the phosphonates 70-57 and 70-58 Is obtained. The Arbuzov reaction is described in Handb. Organophosphorus Chem. (1992), 115-72. In the procedure, the substrate is heated from 60 ° C. to about 160 ° C. with a 5-50 fold molar excess of trialkyl phosphite.

  Using the above procedure, but using a different dibromide instead of dibromide 70-86, products similar to 70-57 and 70-58 are obtained.

Example 72: Preparation of Exemplary Compounds of the Invention Methods for the synthesis of these compounds are described in Westwood et al, J., et al., According to the general route outlined in Scheme 72.1. Med. Chem. (1996), 39, 4608-4621.

  (Scheme 72.1)

An example of the synthesis of a suitable phosphonate-containing aniline is shown below.

  (Scheme 72.2)

Example 73: Preparation of Exemplary Compounds of the Invention Compounds of the invention are prepared according to the general route outlined in Scheme 73.1 according to Westwood et al, J. MoI. Med. Chem. (1996), 39, 4608-4621, as generally described.

  (Scheme 73.1)

An example of the synthesis of a suitable phosphonate-containing aniline is shown below.

  (Scheme 73.2)

Alkylation of 3-nitrophenol with E-1,4-dibromobutene and heating the resulting monobromide with triethyl phosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., Synthesis) of carbon-phosphorus bonds, CRC press, 1988), the diethyl ester of the desired phosphonic acid is obtained. Finally, the desired aniline is obtained by tin (II) mediated reduction of nitrobenzene.

  (Scheme 73.3)

Treatment of the methyl ester of 3-nitro-4-triurlomethylbenzoic acid with tin (II) chloride provides the aniline. Treatment with diazotized and potassium iodide provides 3-iodobenzoic acid. A diethyl phosphonate is coupled via an acetylene linker using a palladium catalyst and, after saponification of the benzoate, the Curtius rearrangement of the acyl azide provides an aniline suitable for introduction into the synthesis of teriflunomide analogs.

  Example 74: Preparation of exemplary compounds of the present invention

In a solvent such as DMF or NMP at room temperature, Am. Chem. Soc. (1948), 70, 1922-1926, treated with a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as diisopropylethylamine (DIEA) (J. Med. Chem. (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). After completion of activation, 2-aminoethylphosphonic acid diethyl ester (commercially available) is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 74.3)

Treat the starting carboxylic acid with a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as diisopropylethylamine (DIEA) in an organic solvent such as DMF or NMP at room temperature (J. Med. Chem. (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Upon completion of activation, the base of (2-amino-ethylsulfanylmethyl) -phosphonic acid diethyl ester (2-aminoethanethiol and diethylphosphonomethyltriflate prepared by Tetrahedron Lett., (1986), 27, 1477) Prepared by catalytic coupling). After consumption of the activated species is observed, the solvent is removed under reduced pressure and the intermediate is isolated by chromatography. Alternatively, the intermediate can be isolated 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 a hydrogen peroxide solution (excess). After removal of the solution, the product is isolated by chromatography. Alternatively, the intermediate can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 74.4)

Treat the starting carboxylic acid with a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as DIEA in an organic solvent such as DMF or NMP at room temperature (J. Med. Chem., (1982). 25, 960-964, and J. Med. Chem., (1984), 27, 600-604). Upon completion of activation, (L) -2-amino-6- (diethylphosphonato) -hexanoic acid is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the product is isolated by chromatography. Alternatively, the product can be isolated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

  (Scheme 74.5)

Treat the starting carboxylic acid with a coupling reagent such as diethyl cyanophosphonate or isobutyl chloroformate and a base such as DIEA in an organic solvent such as DMF or NMP at room temperature (J. Med. Chem., (1982). 25, 960-964, and J. Med. Chem., (1984), 27, 600-604). Upon completion of activation, 4-amino-4- (diethylphosphonato) butyric acid tertbutyl ester (J. Am. Chem. Soc., (1995), 117, 10879-10888) is added. After consumption of the activated species is observed, the solvent is removed under reduced pressure and the intermediate is isolated by chromatography. Alternatively, the intermediate can be isolated 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 solution, the product is isolated by chromatography. Alternatively, the product can be isolated 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 melime positive analog 75-2 is synthesized from the parent compound by alkylation. U. S. Patent No. 6,054,472 and U.S. Pat. S. Patent No. Merimeposib 75-1 is obtained by the procedure described in US Pat. Schemes 75.1-75.2 show procedures for 75-2 and 75-4. The methoxy group of melimeposib 75-1 is demethylated to phenolic OH using a suitable reagent such as boron tribromide. The phosphonate moiety is introduced into the phenolic OH in a suitable aprotic solvent such as DMF, followed by leaving groups (eg bromine, mesyl, tosyl, or trifluoromethane) in the presence of a suitable organic or inorganic base. Treatment with phosphonate reagents 75-40, 75-41 carrying sulfonyl).

  (Scheme 75.1)

For example, treatment of 75-1 in dichloromethane with boron tribromide provides demethylated compound 75-3. Compound 75-3 is then treated with cesium carbonate and 1 equivalent of (trifluoromethanesulfonyl) methylphosphonic acid diethyl ester 75-41 to form a merimeposive-phosphonate 75-4 in which the bond is a methylene group as shown in Scheme 75.2. Is obtained. Using the above procedure, but using different phosphonate reagents 75-40, the corresponding product 75-2 carrying different linking groups can be obtained.

  (Scheme 75.2)

Merime positive analogs 75-2, 75-12, and 75-13 are shown in schemes 75.3-75.4. Shih in Tetrahedron Lett. (1993), 34, 595, imidazole-containing intermediate 75-7 is synthesized from aldehyde 75-6. U. S. Patent No. 5,807,876, U.S. Pat. S. Patent No. 6,054,472, and U.S. Pat. S. Patent No. Compound 75-6 is prepared by the two-step procedure described in 6,344,465. A suitable reagent (eg, 2- (trimethylsilyl) ethoxymethyl (SEM) chloride) is used to protect the imidazole and S. Patent No. 6,054,472 and U.S. Pat. S. Patent No. Compound 75-8 is converted to 75-10 by a similar procedure described for the synthesis of 75-1 in 6,344,465. As shown in Scheme 75.4, after removing the protecting group on the imidazole of 75-10, the phosphonate containing moiety is introduced into the imidazole.

  (Scheme 75.3)

For example, treating compound 75-10 with tetrabutylammonium fluoride in THF at reflux and alkylating the resulting 75-11 with 75-41, 75-42 using sodium hydride as the base, Two isomers 75-12 and 75-13 are obtained, which are separated by chromatography.

  (Scheme 75.4)

Schemes 75.5-75.6 show the preparation of melime positive analog 75-17. The literature procedure (Ichikawa and Ichibagase Yakugaku Zashi (1963), 83, 103; Norio, A. et al. Tetrahedron Lett. (1992), 33 (37), 5403) gives trisubstituted benzene derivatives. Protecting the phenolic OH with a suitable protecting group (eg, a benzyl group); S. Patent No. 6,054,472 and U.S. Pat. S. Patent No. Compound 75-16 is synthesized by the same 75-1 synthetic procedure as 6,344,465. After removal of the protecting group, the phosphonate containing moiety is introduced into the phenolic OH using a phosphonate reagent 75-45 carrying an appropriate leaving group.

  For example, Norio et al. 75-18 solution obtained by the procedure of (Tetrahedron Lett. (1992), 33 (37), 5403) is treated with sodium hydride and 1 equivalent of benzyl bromide in DMF to give 75-19. . For the synthesis from 75-1 to 75-6, see U.S. Pat. S. Patent No. 6,054,472 and U.S. Pat. S. Patent No. Compound 75-19 is converted to 75-20 by a series of steps reported in US 6,344,465. After removal of the 75-20 benzyl protecting group by catalytic hydrogenation, alkyl of the resulting phenol in DMF using sodium hydride and 1 equivalent of (trifluoromethanesulfonyloxy) methylphosphonic acid diethyl ester 75-42 The phosphonate-bearing moiety is coupled by isomerization to give 75-21.

The synthesis of merime positive analog 75-26 is shown in Schemes 75.7-75.8. Compound 75-22 (synthetic intermediate for 75-1) is treated with carbonyldiimidazole or triphosgene followed by compound 75-23 with a handle to attach the phosphonate moiety. Compounds 75-23 bearing an excess of substituents are commercially available or can be obtained from literature procedures (Zolfigor, MA et al. Indian J. Chem. Sect. B (2001), 40, 1191; De Jongh, R.O. et al.Recl.Trav.Chim.Pays-Bas (1968), 87, 1327) is synthesized from a trisubstituted phenol having a cyano group and a nitro group. For the synthesis of 75-1. S. Patent No. 6,054,472 and U.S. Pat. S. Patent No. The obtained 75-24 is converted to 75-25 using the procedure described in 6,344,465. After deprotection of the 75-25 benzyl group, the 75-26 phosphonate moiety is attached.

  For example, De Jong, R.A. O. et al. (Recl. Trav. Chim. Pays-Bas (1968), 87, 1327), the bromine substituent of compound 75-27 was substituted with a cyano group, and the methoxy group was converted to a benzyloxy group as a protecting group. Compound 75-28 is obtained. After selective reduction of the cyano group to an aminomethyl group with borane, the amino group is protected with Boc and the nitro group is reduced using tin (II) chloride to give compound 75-29. Then, for the synthesis of 75-1, U.S. Pat. S. Patent No. 6,054,472 and U.S. Pat. S. Patent No. This substituted aniline 75-29 is treated with a reaction mixture of compound 75-22 and carbonyldiimidazole to form urea 75-30, as described in US Pat. No. 6,344,465. Compound 75-30 is readily converted to 75-31 (an analog of 75-1 carrying a benzyloxy group). Catalytic hydrogenation followed by conjugation of the phosphonate moiety using 75-41, 75-42 in the presence of cesium carbonate provides 75-32.

  (Scheme 75.7)

(Scheme 75.8)

Example 76 Preparation of Exemplary Compounds of the Invention Preparation of Phosphonate Prodrugs of Tamoxifen and Toremifene Citrate

A number of tamoxifen analogs have been prepared and tested. High mobility has been observed due to substitution of the aminoethyl moiety of the compound (Meegan et al. Anti-Cancer Drug Design, (2001), 16, 57). Based on the available SAR, this position is selected as one binding handle for the prodrug moiety. A number of tamoxifen analogs have been reported and many have favorable profiles. For a review of numerous tamoxifen analogs, see Meegan, M .; J. et al. Lloyd, D .; G. , Current Medicinal Chemistry, (2003), 10, 181. Considering that these analogs are similar to tamoxifen, a prodrug approach at the same site as tamoxifen can be applied to them. A number of additional sites on the tamoxifen core are available for attachment of prodrug groups. Considering the well-established expansion method with tamoxifen, we also consider prodrug binding via the aminoethanol group on the B ring. The original synthesis of tamoxifen (Harper et al., GB 1064629, and Harper et al., GB 1013907) has recently been modified (Smyth, T.P., Corby, B.W., Organic Process Research & Development, (97). ), 1,264). This new method was developed for mass preparation. Furthermore, the introduction of the aminoethyl group bonded to the B ring is carried out later in the synthesis, which is advantageous for prodrug synthesis.

  (Scheme 76.1 (all compound numbers in this scheme are for this example only))

The synthesis of compounds such as phosphonate 1 (of Scheme 76.1) is illustrated above. Smith et al. , Organic Process Research & Development, (1997), 1,264, consider compounds 1.1 and 1.2 (of Scheme 76.1) using trifluoroacetic anhydride. Replacement of the halogen with an amino-linker-phosphonate gives compound 1.4 (Scheme 76.1). A final Grignard reaction to introduce the last aromatic group and subsequent deprotection in acidic medium gives compound 1 (of Scheme 76.1). The order of the last two steps can be exchanged. First, a Grignard reaction to introduce a tetra-substituted olefin can be carried out, followed by halogen substitution (McCague R., J. Chem. Res., 1986, 0771). The final product is a mixture of cis and trans separated by crystallization. It can also be further diversified on the aromatic A ring 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 for this example only))

In particular, the preparation of compound 1.3 (of scheme 76.2) is completed as described in the literature. Alkylation with aminoethylphosphonate to displace the chloride in 1.3 gives 1.4 (Scheme 76.2). Grignard reaction with bromobenzene gives compound 1.5 (of scheme 76.2), which is dehydrated under acidic conditions to give compound 1 (of scheme 76.2) as the hydrochloride salt. Citrate is another useful compound. Other salts can also be produced.

  (Scheme 76.3 (all compound numbers in this scheme are for this example only))

A number of toremifene analogs are described in U.S. Pat. S. Patent No. 4,696,949. The synthesis of toremifene prodrug is shown in Scheme 76.3 above. Prodrug is introduced at the beginning of synthesis. It is possible to protect 4-hydroxybenzophenone first and remove the protecting group near the end of the synthetic sequence. In that case, a prodrug group is introduced near the end of the synthesis. The preparation shown in Scheme 76.3 uses 4-hydroxybenzophenone as the starting material. Two carbon linkers are attached, after which the synthesis of compound 2.3 (of Scheme 76.3) is activated. At this stage, the introduction of aminophosphonate 2.1.1 (of scheme 76.3) is completed in the left-half of the molecule. Addition of cinnamaldehyde to lithium aluminum hydride followed by the addition of benzophenone 2.4 yields diol 2.5 (both scheme 76.3). Dehydration of 2.5 and conversion of 4-OH to chloride by addition of thionyl chloride gives compound 2.6 (of Scheme 76.3). The final product 2 (Scheme 76.3) is prepared by formation of the desired salt.

  (Scheme 76.4 (all compound numbers in this scheme are for this example only))

Specifically, 4-hydroxybenzophenone is reacted with 1-mesylethanediol in CH ₂ Cl ₂ to give 2.2 (of Scheme 76.4). Activation of alcohol 2.2 (Scheme 76.4) to mesylate 2.3 (Scheme 76.4) is accomplished by the use of mesyl chloride in CH ₂ Cl ₂ using TEA as a scavenger. Alkylation of mesylate 2.3 with N-methylaminoethylphosphonate 2.1.1 (Scheme 76.4) in EtOH at 80 ° C. sufficiently produced compound 2.4 (Scheme 76.4). Proceed to. Addition of 2.4 (1 equivalent) to a mixture of cinnamaldehyde (1 equivalent) and lithium aluminum hydride in THF gave compound 2.5 (of Scheme 76.4) after 30 minutes of stirring at room temperature. It is done. Dehydration of 2.5 (Scheme 76.4) using thionyl chloride in toluene is complete after 3 hours at 80 ° C. to give compound 2.6 (Scheme 76.4). Various salts can then be prepared. Toremifene citrate is an example of a compound. As illustrated above, the phosphonate prodrug can be further modified to a phosphonate diester, bisamidate, or monoamidate.

Example 77 Preparation of Exemplary Compounds of the Invention Preparation of Phosphonate Prodrugs of Raloxifene Hydrochloride A number of structural modifications of roxifene have been investigated and the SAR for this drug group is well established. Briefly, the hydroxyl substituent on the aryl ring of raloxifene is important for the potent activity of the compound as expected. C-6 OH is positioned to bind to the ER residue pair Arg394 / Glu343 in the same manner as estradiol 3-OH. In addition, as evidenced by crystal structure studies (Anzo, et al., J. Natl. Cancer Inst., (1996), 88, 123), 4′-OH that mimics 17β-OH of estradiol is converted to His524. Join. The amine of the piperidine ring is also important in binding the estrogen receptor to aspartic acid 351. This amine also plays a role in tissue specificity. However, many N, N-dialkyl analogs of raloxifene are isopotent with the parent compound. Therefore, substitution of the prodrug group at this end of the compound is a preferred embodiment of this work.

  Three substituent types are described herein. There are two variations of the prodrug attachment to the tertiary amine region (Scheme 77.1). Another binding site on raloxifene is the carbonyl position. Considering that the carbonyl moiety can be replaced with a simple oxygen, this position can be used as a potential handle for phosphonate prodrugs (Palkowitz, et al., J. MoI. Med. Chem., (1997), 40, 10, 1407).

  The first phosphonate prodrug is prepared according to general schemes 77.2 to 77.3. A suitably protected diol is attached to the phenolic position of 4-hydroxylbenzoic acid methyl ester by the Williamson ether synthesis method. Removal of the protective term gives compound 77-5. Conversion of the hydroxyl group to an appropriate free radical such as mesyl, bromide, etc. of trifluoromethylsulfonyl followed by addition of an aminophosphonate prodrug provides compounds 77-6, 77-50. As reported in the literature (Jones, et al. J. Med. Chem., 1984, 27, 1057), acid activation proceeds by liberation of the methyl ester and subsequent acid chloride formation. Friedal-Crafts aroylation (Kost et al., Zh. Org. Khim, 1970, 6, 1503) with compounds 77-7, 77-33, 77-25 which are rearrangement products, (Jones, CD. , EP 0062503), the desired protected compound is obtained. Final deprotection gives compound 77-9. Different salts can be prepared to aid solubility of the final compound.

A specific example of the general route is shown in Scheme 77.3. Compound 77-4 is alkylated with TMS protected diol 77-23 using K ₂ CO ₃ in DMF. TFA is used to ensure the removal of the silyl protecting group to give precursor 77-5. Activation of 77-5 by formation of mesylate using MsCl and TEA in CH ₂ Cl ₂ and subsequent addition of aminoethylphosphonate 77-22, 77-32 yields amine 77-6, 77-50. Progresses sufficiently. Removal of the methyl ester protecting group of 77-6, 77-50, followed by Friedal-Crafts aroylation deprotection using thioethanol, followed by a one-pot, two-step reaction of the final compounds 77-10, 77-35 hydrochloride Generation proceeds reliably.

Piperazylphosphonate prodrugs are produced in the same manner as compounds 77-10 and 77-35. Regioprotective piperazine and 2-hydroxyethylphosphonate are used to proceed with the synthesis of 77-24, 77-40. Subsequent synthetic steps are performed as described in Schemes 77.2-77.3. In particular, by the addition of 77-24,77-40 to 77-5 in _CH 2 Cl ₂ using TEA as scavenger, 77-12,77-42 are obtained. Deprotection of the mesyl ester, activation of the acid with thionyl chloride, and Friedal-Crafts aroylation proceed as described above. In situ deprotection of methyl ether using triethylsilane gives compounds 77-15, 77-16. Conversion of the final product to bis-HCl improves solubility.

Phosphonate prodrugs 77-18, 77-19 are produced from commercially available raloxifene hydrochloride. Reductive amination with aminophosphonate gives the desired product. Use CH ₂ Cl 77-15,77-16 equivalents _disodium cyanoborohydride in and reacted. The two enantiomers obtained are separated by chiral chromatography.

  (Scheme 77.1)

Example 78 Preparation of Exemplary Compounds of the Invention Preparation of Phosphonate Prodrug of Mycophenolate Mofetil As shown in compounds 78-1 to 78-4 (Scheme 78.1), the phosphonate prodrug to mycophenolic acid was prepared. Three regions of mycophenolate mofetil are used for conjugation. Also, as in compound 78-3, the carboxylic acid is substituted with a phosphonic acid that is part of the prodrug moiety.

  As shown in Schemes 78.2-78.3, the morpholinoethyl moiety, which acts as a prodrug to improve bioavailability, is replaced with a phosphonate prodrug handle. Mycophenolic acid is described in, for example, Sigma Chemical Company, St. Commercially available from Louis, Mo. Activation of the carboxylic acid 78-5 in the presence of free phenol and subsequent addition of an alcohol carrying a phosphonate group forms the desired product (US Patent No. 4,786,637). . Specifically, mycophenolic acid 78-5 is dissolved in dichloromethane. Thionyl chloride is added followed by a catalytic amount of DMF. 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 at 4 ° C. on an ice bath. Mycophenolic acid chloride 78-7 is dissolved in dichloromethane and added to the cooled solution. After stirring for 90 minutes at 4 ° C., the reaction mixture is washed with water and then with aqueous sodium bicarbonate. The organic solution is dried under reduced pressure to give phosphonate prodrugs 78-6, 78-8.

  The C-4 phenol position provides a reaction handle for additional analogs (Schemes 78.4-78.5). Once the carboxylic acid is blocked by morpholinoethyl, such as in compound 78-9, or by a phosphonate prodrug such as compounds 78-6, 78-8, the phenol is alkylated under basic conditions. A base such as pyridine, potassium carbonate, or triethylamine is used. A free radical such as trifluoromethyl sulfonate, mesylate, bromide, or iodide is attached 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 either directly or in salt form. Of the many salts that can be prepared, chloride and bisulfate are particularly preferred.

  The preparation of compounds 78-10, 78-11 is outlined in more detail in Scheme 78.5. Compound 78-7 is prepared as described in Scheme 78.3. Cool the morpholinoethanol in dichloromethane to 4 ° C. Mycophenolic acid chloride 78-7 is dissolved in dichloromethane and added to the cooled solution. This solution is stirred for 90 minutes to give compound 78-9. The reaction mixture is washed with water and dried over sodium sulfate. Removal of the solvent gives compound 78-9. The phenol position of 78-9 is alkylated by suspension of 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. Removal of the organic phase gives compounds 78-2, 78-45. The hydrochloride salt of 78-2, 78-45 is also prepared. Compounds 78-2, 78-45 are dissolved in isopropanol and the solution is added to a mixture of hydrochloric acid and isopropanol. The hydrochlorides 78-10, 78-11 are collected by filtration and dried in vacuo.

  The carboxylate of mycophenolic acid is replaced with a phosphonic acid that also serves as a prodrug handle. In order to remove the carboxylic acid containing the side chain, the acid chloride 78-7 is converted to the esters 78-13, 78-33. Protection of the phenol with a silyl group followed by dihydroxylation and cleavage of the diol gives aldehydes 78-15, 78-19 (Pankiewicz, et al., J. Med. Chem., (2002), 45, 703), (Patterson et al., US Patent No. 5,444,072) (Schemes 78.6-78.7). A wittig reaction using ylides 78-50, 78-31 carrying appropriately protected phosphonates gives the desired compounds 78-16, 78-20. Final deprotection provides compound 78-17.

  The mycophenolate esters 78-13, 78-33 are prepared by stirring the acid chloride 78-7 with MeOH. Next, the phenol position of mycophenolic acid ester is protected with a silyl group such as TBS to obtain compounds 78-14 and 78-18. Once the phenolic position is protected, dihydroxylation using osmium tetroxide and subsequent cleavage of the periodate affords aldehydes 78-15, 78-19. The aldehydes 78-15, 78-19 and excess ylides 78-50, 78-31 are heated to reflux in benzene for 24 hours. The reaction mixture is concentrated and the residue is generated by column chromatography to give olefins 78-16, 78-20 (Pankiewicz et al., J. Med. Chem., (2002), 45, 703). Final deprotection using HF-pyridine gives the final product 78-17.

  After demethylation of mycophenolate ester 78-9 (Schemes 78.8-78.9), another point of attachment of the compound is not masked. For this purpose, 4-OH is masked with a protecting group such as a silyl group. Once 6-MeO is demethylated and alkylated, the 4-position protecting group is removed to yield the final product. Initially, a morpholethanol group is introduced to complete the alkylation step. Different groups acting as protecting groups are first introduced and then removed. In that case, the last step is the formation of a morpholino ethyl ester prodrug.

The synthesis of compound 78-4 is shown in Scheme 78.9. Use imidazole as base to protect the phenol 78-9 with TBS group in _CH 2 Cl _2. Demethylation using a thiolate nucleophile gives compounds 78-2, 78-22. Various other methods in the literature are also available, such as described in Greene and Wuts' protective groups in organic synthesis. K ₂ CO ₃ or TEA is used to fully proceed the alkylation of 6-OH using the phosphonate prodrug triflate. Final deprotection to remove the TBS group gives the products 78-27, 78-24.

  Prior to the final deprotection, the phosphonate moiety can be further manipulated. These conversion types are further described in the following section.

  (Scheme 78.1)

(Scheme 78.2)

(Scheme 78.9)

Example 79 Preparation of Exemplary Compounds of the Invention Derivatization at the C-21 hydroxyl group by alkylation of dexamethasone 79-1 with the appropriate phosphonate provides an analog of type 79-2 (Scheme 79.1). .

  (Scheme 79.1)

After sodium hydride extraction of the primary hydroxy proton in 79-1, diethyl phosphonate triflate is added to give ether 79-3 (Scheme 79.2).

  (Scheme 79.2)

The protecting group of dexamethasone 79-1 is used to attach phosphonate appendages to the C-11 hydroxyl group (Scheme 79.3). After protection of the initial hydroxyl group, protected intermediate 79-4 is alkylated at the more exposed C-11 hydroxyl site. Final deprotection gives the desired product 79-6.

  (Scheme 79.3)

Standard TBSCl and imidazole conditions are used to protect dexamethasone 79-1 as a silyl ether (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 the diol 79-9.

  (Scheme 79.4)

The synthesis of a C-21 phosphonate analog of type 79-12 is shown in Scheme 79.5. This protection of dexamethasone 79-1 at the two unconstrained sites gives alcohol 79-10 in which only the exposed hydroxyl group is alkylated with the appropriate phosphonate. Removal of the protecting group completes the construction of analog 79-12.

  (Scheme 79.5)

Dexamethasone 79-1 is protected again as its TBS ether, but with harsher conditions for bis protection (Scheme 79.6). After alkylation with diethylphosphonate triflate, the resulting intermediate 79-14 is treated with TBAF to give the desired phosphonate 79-15.

  (Scheme 79.6)

Example 81 Preparation of Exemplary Compounds of the Invention Experimental Results of Phosphonate-containing PNP Inhibitors

Divalent acid (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) were dissolved in pyridine (5 mL). The mixture was heated at 60 ° C. for 5 minutes. To this reaction mixture was added triphenylphosphine (560 mg, 2.14 mmol) and Aldrithiol (2) (470 mg, 2.13 mmol) in pyridine (5 mL). The reaction was then heated at 60 ° C. for 12 hours. The reaction mixture was diluted with EtOAc and washed with H ₂ O, saturated NaHCO ₃ (aq), and brine. The organic phase was dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (1% MeOH / CH ₂ Cl ₂ → 10% MeOH / CH ₂ Cl ₂ ) to purify monoamidate 81-1 (5 mg, 3%). And diamidate 81-2 (5 mg, 3%) was obtained. About 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.Calculated for C ₂₃ H ₃₄ N ₆ O ₅ P on MS (MH ⁺ ): 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 Calculated for MS of C ₂₂ H ₃₉ N ₇ O ₆ P (MH ⁺ ): 528.3.

Dissolve 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) in pyridine (1.25 mL). The mixture was heated at 60 ° C. for 5 minutes. To this mixture was added a solution of triethylphosphine (140 mg, 0.534 mmol) and aldolthiol (2) (119 mg, 0.540 mmol) in pyridine (1.25 mL). The reaction was then heated at 60 ° C. for 12 hours. Another batch of diacid (12 mg, 0.035 mmol) was treated as described above. The reaction mixtures from both batches were combined, diluted with EtOAc, washed with H ₂ O, saturated NaHCO ₃ (aq), and brine. The organic phase was dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (1% MeOH / CH ₂ Cl ₂ → 10% MeOH / CH ₂ Cl ₂ ) to purify monoamidate 81-3 (3 mg, 8%) And diamidate 81-4 (8 mg, 20%) was obtained. 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.Calculated for MS of C ₂₅ H ₂₈ N ₆ O ₅ P (MH ⁺ ): . 523.2 the measurements ^{523.2.81-4: 1 H NMR (300 MHz} , CD 3 OD) δ 8.15 (1H, d ), 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. calculated for _{C 24 H 33 N 7 O 6} P of MS ^(MH +):. 546.2 measurements 546.2.

Prodrug cleavage assay Isolation of PBMC extracts:
Fresh human PBMCs were obtained from patients undergoing leukophoresis; cells were transported to plasma and processed within 26 hours of blood collection. Purification was performed using the Ficoll-Paque method: PBMC cells were harvested by centrifugation at 1200 × g for 5 minutes and placed in RBC lysis buffer (155 mM NH ₄ Cl, 0.1 mM EDTA, 10 mM KHCO ₃ ). Washed 3 times by resuspension. Washed cells are suspended in lysis buffer (0.2 × 10 ⁹ cells in 1 ml 10 mM Tris (pH 7.4), 150 mM NaCl, 20 mM CaCl ₂ , 1 mM DTT, and 1% NP40) and incubated on ice for 20 minutes. did. The PBMC crude extract was centrifuged at 1000 × g for 30 minutes to remove non-lysed cells, and the supernatant was centrifuged at 100,000 × g for 1 hour. 100,000 × g supernatant (PBMC extract: P0) was collected, snap frozen in liquid nitrogen and stored at -70 ° C.

Protocol for measuring prodrug cleavage by PBMC extract:
The reaction mixture contained 25 mM MesNa (pH 6.5), 100 mM NaCl, 1 mM DTT, 0.1% NP-40, 30 μM substrate, and various amounts of enzyme in a final volume of 100 μl. The enzyme reaction is carried out at 37 ° C. for 10 to 120 minutes, and the reaction is stopped with 180 μl of ice-cold methanol at each of 3 to 4 measurement points. Samples are incubated at −20 ° C. for 30 minutes and centrifuged at 13,000 RPM for 30 minutes (4 ° C.). The supernatant is transferred to a 96 well plate and evaporated under reduced pressure using a speedvac. The precipitate is dissolved in 100 μl of 20 mM CH ₃ COONH ₄ + 5% AcCN. Prodrug disappearance is measured by HPLC monitored at 260 nm. The specific activity of the PBMC extract relative to the prodrug tested is defined as v (cleavage rate) / μg protein = pmoles / min / μg.

  result

Example 82 Preparation of Exemplary Compounds of the Invention A series of inhibitors of PNPs are rationally designed to mimic the transition state of an enzyme. This whole class is called Immucillin. Depending on the enzyme used for the rational design of the inhibitor, a slightly different structure is proposed and synthesized. A very potent analog (structure below) that inhibits the PNP enzyme from Mycobacterium tuberculosis (MtPNP) called DADMe-ImmG has recently been prepared. (Lewandowics A. et al., Biochemistry, (2003), 42, 6057).

  (Scheme 82.1)

Use of the prodrug DADMe-ImmG, which results in a drug with increased intracellular half-life by cleavage inside the target cell, achieves dose reduction and / or improved efficacy. Such phosphonate prodrug compounds are shown below (Scheme 82.2).

  (Scheme 82.2)

Using the example shown in Scheme 82.4, compounds such as 82-1 are made according to the general route outlined in Scheme 82.3.

DADMe-ImmG is a product of Lewandoics A.M. et al. , Biochemistry, (2003), 42, 6057. The tertiary nitrogen of the ring cannot inhibit the alkylation of the secondary alcohol and in such a case does not need to be protected, but if necessary, Greene, T .; Standard protection and deprotection protocols described in Protective groups in organic synthesis, Wiley-Interscience, (1999) can be used. Reaction of the primary alcohol 82-3 with a base followed by addition of a suitably activated phosphonate provides the protected product. Overall deprotection yields the desired phosphonate 82-4.

  Using the example shown in Scheme 82.6, compounds such as 82-2 are made following the general route outlined in Scheme 82.5.

  (Scheme 82.5)

The preparation of DADMe-ImmG was prepared by the method described in Lewandowics A.D. et al. , Biochemistry, (2003), 42, 6057. Greene, T .; , Protective groups in organic synthesis, Wiley-Interscience, (1999) can block primary alcohols. Reaction of the secondary alcohol in a base followed by addition of a suitably activated phosphonate gives the desired protected product. Deprotection yields the desired phosphonate.

  (Scheme 82.6)

Specifically, the protected DADMe derivative can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the desired phosphonate diester. Greene, T .; , Protective groups in organic synthesis, Wiley-Interscience, (1999) to remove the protecting group to give the desired phosphonate ester.

Example 83: Preparation of exemplary compounds of the invention (Scheme 83.1)

Synthetic schemes for specific targets 83-8 and 83-9 are outlined below.

  (Scheme 83.2)

References for these reactions: Med. Chem. (1996), 39, 4608.
The synthesis of additional compounds: targets 83-13 and 83-14 is described below.

  (Scheme 83.3)

Example 84 Preparation of Exemplary Compounds of the Invention Leflunomide (structures below with its active metabolites) (see US Patent No. 4,284,786) is shown by inhibition of dihydroorotic acid dehydrogenase. It is a derivative of isoxazole that inhibits various T lymphocyte functions (Copeland et al, Biochem., (1996), 35, 1270).

  (Scheme 84.1)

The active metabolite of leflunomide (A771726, also known as teriflunomide, see US Patent No. 6,288,098) has a very long half-life in humans, which is noted for the compound. Reasons for concern for a given side effect, including skin rash, pruritus, diarrhea, abdominal pain, nausea, vomiting, weight loss, hypertension, dizziness, and reversible alopecia. The more serious side effects reported include several cases involving the pleura, vasculitis, and hepatotoxicity. Rare cases such as Steven-Johnson syndrome and toxic epidermal necrosis have also been described.

  Reduced dose and improved efficacy are achieved through the use of prodrugs of leflunomide analogs that result in drugs with increased intracellular half-life by cleavage inside the target cell. The same concept can be applied to FK778 (MNA-715) (see US Patent No. 5,308,865). Such compounds are described below.

  (Scheme 84.2)

Following the general route outlined in Schemes 84.3-84.5, methods for the synthesis of these compounds are described in Westwood et al, J. MoI. Med. Chem. (1996), 39, 4608-4621.

  (Scheme 84.3)

The synthesis of a suitable phosphonate-containing aniline is shown below.

  (Scheme 84.4)

Example 85: Preparation of Exemplary Compounds of the Invention Brequinal (see structure below; see US Patent No. 4,680,299 and US Patent No. 5,032,597) It is an inhibitor of dihydroorotic acid dehydrogenase (Biochemical Pharmacology 1990, 40, 709-714).

  (Scheme 85.1)

A clinical investigation of compounds as immunosuppressive or anticancer drugs has been disappointing due to the narrow therapeutic threshold, possibly resulting from an excessively long half-life that prevents higher doses. there were.

  These problems are addressed by the use of prodrugs of brequinar analogs and other quinoline inhibitors of dihydroorotate dehydrogenase that yield active substances that, when cleaved in the target cell, have a sustained intracellular half-life compared to plasma levels. Tackle. The therapeutic index of such drugs can be significantly improved over brequinar itself. Such compounds are described below.

  (Scheme 85.2)

Methods for synthesizing these compounds are described in Batt et al, Bioorg. Med. Chem. Lett. , (1995), 5, 1549. A typical general route is outlined in Schemes 85.3-85.5.

  (Scheme 85.3)

Examples of the synthesis of suitable phosphonate-containing 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] -benzoylamino} -methyl) -Phosphonic acid diethyl ester)

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (67.0 mg, 177 μmol) in DMF (3.0 mL) was added diethylcyanophosphonate. (34.8 μL, 230 μmol) and diisopropylethylamine (Hunig base, DIEA, 30.4 μL, 177 μmol) were added. Diethyl (aminomethyl) -phosphonate (45.4 mg, 177 μmol) was added and the solution was stirred at ambient temperature for 4 hours. The solution was stirred for an additional 4 hours after the starting material was completely consumed. The reaction was worked up by removal of the solvent under reduced pressure and purification of the residue by silica gel chromatography using MeOH—CH ₂ Cl ₂ (10-30%). The product recovered from this chromatography step was sufficiently pure to proceed with the next reaction. A small amount of product (20 mg) was re-purified by RP HPLC on a _C18 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 ) d 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 (brs, 1H), 8.61 (s, 1H). ³¹ P (121.4 MHz, DMSO-d ₆ ) d 23.4. MS (m / z) 475.2. [M + H] ⁺ , 597.2 [M + Na] ⁺ .

  (Scheme 86.2: (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -methyl) -phosphonic acid)

Drying of crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid diethyl ester (60 mg, 126 mmol) after silica gel chromatography To a DMF (0.90 mL) solution, 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 hours, after which the reaction mixture was cooled to room temperature. The solvent volume was reduced to about 700 μL under reduced pressure and diluted with H ₂ O (100 μL). The solution was purified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 26.8 mg (51%) of the desired compound as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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, 1H), 8.56 (s, 1H); MS (m / z) 419.2 [M + H] ⁺ .

  (Scheme 86.3: (2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid diethyl ester)

To 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) was added diethylcyanophosphonate. (31.8 mL, 210 mmol) and DIEA (27.8 mL, 161 mmol) were added. Diethyl (aminomethyl) -phosphonate (43.8 mg, 161 μmol) was added and the solution was stirred at ambient temperature for 4 hours. The solution was stirred for an additional 3 hours after the starting material was completely consumed. The reaction was worked up by removal of the solvent under reduced pressure and purification of the residue by silica gel chromatography using MeOH—CH ₂ Cl ₂ (10-30%). The product recovered from this chromatography step was sufficiently pure to proceed with the next reaction. A small amount of product (32 mg) was repurified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 19 mg (70%) of pure product. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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 (app 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, 1H). ³¹ P (121.4 MHz, DMSO-d ₆ ) d 28.9. MS (m / z) 489.2 [M + H] &lt; ⁺ &gt;, 511.2 [M + Na] &lt; ⁺ &gt;.

  (Scheme 86.4: (2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid)

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl-phosphonic acid diethyl ester (61 mg, 125 mmol) after silica gel column chromatography at ambient temperature. ) In dry DMF (1.00 mL) was added TMSBr (129.0 μL, 999.2 mmol), and the reaction was heated at 70 ° C. for 5.5 hours, at which time 90% of the reaction was complete by LCMS analysis. The reaction mixture was cooled to room temperature and stirred for an additional 12 hours The reaction was completed by removal of the solvent in vacuo and dissolution in DMF / H ₂ O (800 mL, 1: 1) and 1N aqueous NaOH (15 mL). was _.H 2 O / acetonitrile (2-95%) product by RP HPLC on _{C 18} column using Purified to the desired compound of 29 mg (53%) as a yellow solid was ^{obtained. 1 H NMR (300MHz, DMSO} -d 6) d 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) d 23.0.MS} (m / z) 431.3 [M-H] -.

  (Scheme 86.5: (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzylamino} -propyl) -phosphonic acid diethyl ester)

To 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) was added diethylcyanophosphonate. (31.8 mL, 210 mmol) and DIEA (27.8 mL, 161 mmol) were added. Diethyl (aminopropyl) phosphonate (34.9 mg, 122.6 mmol) was added and the solution was stirred at ambient temperature for 3 hours. The solution was stirred for another 2 hours after the starting material was completely consumed. The reaction was worked up by removal of the solvent under reduced pressure and purification of the residue by silica gel chromatography using MeOH—CH ₂ Cl ₂ (10-30%). The product recovered from this chromatography step (65.5 mg) was pure enough to proceed to the next reaction. A small amount (32.8 mg) was repurified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 23.2 mg (75%) pure product. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 1.20 (t, 6H, J = 7.2 Hz), 1.64-1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H), 3.98 (app 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, 1 H), 8.70 (s, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 31.9; MS (m / m z) 503.2 [M + H] ⁺ .

  (Scheme 86.6: (2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzylamino} -propyl) -phosphonic acid)

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzylamino} -propyl) -phosphonic acid diethyl ester (32.2 mg) after silica gel column chromatography at ambient temperature , 66.2 mmol) in dry DMF (0.50 mL) was added TMSBr (68.0 μL, 529.6 mmol). The reaction was heated at 70 ° C. for 1.0 hour, at which time LCMS analysis proved complete. The reaction mixture was cooled to room temperature and water (60 μL) and methanol (60 μL) were added. The crude reaction mixture was purified by RP HPLC on a _C18 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 ) d 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 (brs, 1H), 8. 69 (s, 1H). ³¹ P (121.4 MHz, DMSO-d ₆ ) d 26.3. MS (m / z) 447.3 [ M-H] -.

  (Scheme 86.7: 2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] benzoylamino} -ethyl) phenoxyphosphinoyloxy] propionic acid ethyl ester [in phosphorus A mixture of diastereomers])

To 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) was added diethyl. Cyanophosphonate (31.2 mL, 205.7 mmol) and DIEA (81.8 mL, 474.9 mmol) were added. The solution was stirred at ambient temperature for 3.5 hours, at which time (S) -2-[(2-aminoethyl) phenoxyphosphinoyloxy] -propionic acid ethyl ester monoacetate (57.1 mg, 158.3 mmol). A mixture of diastereomers with phosphorus) in DMF (200 mL) was added. The solution was stirred for an additional 1.5 hours, immediately after completion of starting material consumption was observed. The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography using MeOH—CH ₂ Cl ₂ (10-30%). A small amount of product (24.8 mg) was re-purified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 15.8 mg (65%) pure product. It was. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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 ) d 26.6, 27.4. MS (m / z) 609.2 [M + H] &lt; ⁺ &gt;.

  (Scheme 86.8: 2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] benzoylamino} -ethyl) phenoxyphosphinoyloxy] -propionic acid [in phosphorus Diastereomeric mixture])

2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methyl-amino] benzoylamino} ethyl) phenoxyphosphinoyloxy] propionic acid ethyl ester (diastereomeric mixture at phosphorus; To a solution of 40.0 mg, 65.7 mmol) DMF (0.4 mL), acetonitrile (0.2 mL), and water (0.2 mL) was added aqueous sodium hydroxide (1N, 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 _C18 column using H ₂ O / acetonitrile (2-95%) to yield 23.7 mg (71.3%) pure product. Got. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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, 1 H), 8.63 (s, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 25.1. MS (m / z) 505.2 [M + H] &lt; ⁺ &gt;.

  (Scheme 86.9: 2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] -benzoylamino} ethyl) phenoxyphosphinoyloxy] propionic acid ethyl ester [in phosphorus Diastereomerically pure])

To 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) was added diethyl cyanophosphonate. (53.0 mL, 349.5 mmol) and DIEA (138.0 mL, 806.7 mmol) were added. The solution was stirred at ambient temperature for 2.5 hours, at which time (S) -2-[(2-aminoethyl) phenoxyphosphinoyloxy] -propionic acid ethyl ester monoacetate (phosphorus diastereomerically). Pure; 268.9 mmol) in DMF (500 mL) was added. The solution was stirred for an additional 30 minutes immediately after completion of starting material consumption was observed. The solvent was removed under reduced pressure 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 _C18 column using H ₂ O / acetonitrile (2-95%) to give 28.7 mg (75.1%) pure product. Got. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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, 1 H), 8.71 (s, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 26.6. MS (m / z) 609.2 [M + H] &lt; ⁺ &gt;.

  (Scheme 86.10: 2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] -benzoylamino} -ethyl) -phenoxyphosphinoylamino] propionic acid ethyl ester ( A mixture of diastereomers with phosphorus))

To 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) was added diethyl. Cyanophosphonate (20.6 mL, 136.1 mmol) and DIEA (36.0 mL, 209.4 mmol) were added. The solution is stirred at ambient temperature for 3 hours, at which time (S) -2-[(2-aminoethyl) phenoxyphosphinoylamino] propionic acid ethyl ester monoacetate (mixture of diastereomers with phosphorus; 104. 0 mmol) of DMF (200 mL) was added. The solution was stirred for an additional 30 minutes, at which point completion of starting material consumption was observed. The reaction aliquot (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 mg) was re-purified by RP HPLC on a _C18 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 ) d 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 (brs, 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 ) d 29.5, 30.1. MS (m / z) 608.2 [M + H] &lt; ⁺ &gt;.

  (Scheme 86.11: 2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6- (diethoxy-phosphoryl) -hexanoic acid)

To 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) was added diethyl. Cyanophosphonate (30.8 mL, 199.4 mmol) and DIEA (85.8 mL, 498.6 mmol) were added. The solution was stirred at ambient temperature for 3.5 hours, at which time (L) -2-amino-6-diethylphosphonatohexanoic acid (44.3 mg, 166.2 mmol) was added. The solution was stirred for an additional 48 hours. The reaction was worked up by removal of the solvent under reduced pressure and purification of the residue by silica gel chromatography using MeOH—CH ₂ Cl ₂ (10-30%). The product recovered from this chromatography step (87 mg) was sufficiently pure to proceed to the next reaction. An aliquot of the product (51.0 mg) was re-purified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 24.7 mg (44%) of pure product. It was. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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 (brs, 1H), 6.81 (d, 2H) , J = 9 Hz), 7.73 (d, 2H, J = 9 Hz), 8.14 (d, 1H, J = 7.8 Hz), 8.56 (s, 1H); ³¹ P (121 .4 MHz, DMSO-d ₆ ) d 31.8; MS (m / z) 574.3 [M] ⁺ .

  (Scheme 86.12: 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})-2 '(L)-(6'- after silica gel column chromatography at ambient temperature TMSBr (18.0 μL, 139.2 μmol) was added to a solution of (phosphonic acid diethyl ester) hexanoic acid) (20 mg, 34.6 mmol) in dry DMF (0.60 mL). The solution was then heated at 70 ° C. for 18 hours, after which the reaction mixture was cooled to room temperature. The solution was removed under reduced pressure and dissolved in DMF (400 mL) and water (60 mL). The solution was purified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 8.9 mg (49%) of product as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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, 1 H), 8.55 (s, 1 H); MS (m / z) 519.2 [M + H] ⁺ . (Scheme 86.13: 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 ′-(monophenylphosphonate) hexanoic acid)

Hydrolysis of the ethyl-TMS ester under suitable conditions provides the corresponding acid of the present invention.

  Intermediate 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 ′-(monophenyl-phosphonate) -hexanoic acid TMS ethanol ester is Can be prepared.

  (A. (L) -2-Cbz-amino-hexanoic acid-6-phosphonic acid)

To a solution of (L) -2-amino-6- (diethoxyphosphonyl) hexanoic acid (106 mg, 396.8 mmol) in dry DMF (2.00 mL) at ambient temperature was added TMSBr (307.0 μL, 2,381. 0 mmol) was added. The solution was then heated at 70 ° C. for 2 hours, after which the reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The crude material was dissolved in water (0.25 mL) and NaOH (1-N, 2.50 mL). Benzyl chloroformate (79.3 mL, 555.5 mmol) was added and stirring was continued at room temperature. After 2 hours, the solution was washed with ether (2 mL) and the aqueous phase was acidified to pH 1 with aqueous HCl. The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phases were dried with sodium sulfate. Filtration and evaporation of the solvent gave the crude product, which was pure enough for further conversion. ¹ H NMR (300 MHz, DMSO-d ₆ ) d1.42-1.65 (m, 8H), 3.90 (m, 1H), 5.02 (s, 2H), 7.32 (s, 5H) ), 7.55 (m, 1 H), 7.94 (s, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 26.5; MS (m / z) 345.6 [M + H] ⁺ .

  (B. (L) -2-Amino-hexanoic acid 2'TMS ethyl ester-6-phosphonic acid monophenyl ester)

Acetyl chloride (50 mL) was added 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). Stirring was continued at room temperature. Full conversion was observed after 22 hours. The solvent was removed under reduced pressure. The crude material was sufficiently pure for the next step.

  Half of the crude material (198.9 mmol) is 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 to 70 ° C. (oil bath). After 4 hours, the reaction was cooled to room temperature and the solvent 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 mL, 389.0 mmol) in methylene chloride (1.0 mL) was added. . Stirring was continued at room temperature. After 4 hours, the solvent was removed under reduced pressure.

  The crude material was dissolved in tetrahydrofuran (THF) (3.0 mL) and aqueous sodium hydroxide (1N, 0.885 mL) was added. Stirring was continued at room temperature. After 14 hours, the solvent was removed under reduced pressure to give crude phosphonate monophenyl ester (63.8 mg). This material was dissolved in 2-TMS ethanol (1.0 mL) and acetyl chloride (20 mL) was added. Stirring was continued at room temperature. After 22 hours, complete conversion to the carboxylic acid ester was observed. The solvent was removed under reduced pressure. The material was sufficiently pure for the next step.

  Half of the crude material (75 mmol) was dissolved in ethanol (1.5 mL). Pd / C (5%, 20 mg) was added and the reaction was placed under a hydrogen gas atmosphere. After 1.5 hours, Celite was added and the crude reaction mixture was filtered through Celite. The solvent was evaporated under reduced pressure and the crude material was used in the next step without further purification.

  (C. 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 '-(monophenyl-phosphonate) -hexanoic acid TMS ethanol ester)

To 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), Diethyl cyanophosphonate (12.4 mL, 78.0 mmol) and DIEA (31.0 mL, 180.0 mmol) were added. The solution was stirred for 1 hour at ambient temperature, at which time (L) -2-amino-6-monophenoxyphosphonatohexanoic acid 2′TMS ethyl ester (70.5 mmol) dissolved in DMF (0.2 mL) was added. did. The solution was stirred for an additional 3.5 hours. The crude reaction mixture was purified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (5-95%) to give 19.4 mg (46%) of 2- {4-[(2,4-diamino- Pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6- (monophenylphosphonate) -hexanoic acid TMS ethanol ester was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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, 1 H, J = 7.8 Hz), 8.71 (s, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 26.2; MS (m / z) 695. 2 [M] ⁺ .

  (Scheme 86.14: 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) methylamino] -benzoylamino} -6 ′-(monophenylmono (S) ethyl lactate-phosphonate) hexanoic acid )

Hydrolysis of the ethyl-TMS ester under suitable conditions provides the corresponding acid of the present invention.

  Intermediate 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 ′-(monophenylmono (S) ethyl lactate-phosphonate) -hexanoic acid TMS The ethanol ester can be prepared as follows.

  (2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 ′-(monophenylmono (S) ethyl lactate-phosphonate) -hexanoic acid TMS ethanol ester)

2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 ′-(monophenyl-phosphonate) -hexanoic acid TMS ethanol ester (14.5 mg, 20 .8 μmol, Example 225) in DMF (0.70 mL), PyBOP (32.4 mg, 62.4 μmol), DIEA (21.4 mg, 166.4 μmol), and (S) ethyl lactate (19.6 mg, 166.4 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was purified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (5-95%) to give pure product as a mixture of diastereomers with phosphoric acid (about 4: 1) Got. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (brs, 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, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 30.5, 29.2; MS (m / z) 795.2 [M] ⁺ .

Example 87 Preparation of Exemplary Compounds of the Present Invention The recent PNP inhibitor PNP-405 (also referred to as PNU-405) is disclosed in ACS meeting, (2000). This compound inhibits purine nucleotide phosphorylase with an IC ₅₀ of 20 nM (structure below).

  (Scheme 87.1)

Use of the prodrug PNP-405, which results in an agent with increased intracellular half-life by cleavage inside the target cell, achieves dose reduction and / or improved efficacy. Such phosphonate prodrug compounds are shown below (Scheme 87.2).

  (Scheme 87.2)

Using the example shown in Scheme 87.4, compounds such as 87-2, 87-5 are made according to the general route outlined in Scheme 87.3.

  (Scheme 87.3)

Littler, B.M. J. et al. et al. ^{, 7 th International Conference on Organic Process} Research and Development, New Orleans, LA, March 16-19, according to the method of (2003), to prepare a PNP-405. Treat PNP-405 with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give compound 87-6 as the desired product.

Littler, B.M. J. et al. et al. , 7 ^th International Conference on Organic Process Research and Development, New Orleans, LA, March 16-19, (2003), to prepare compounds of Scheme 87.2 (X = O, Z = CH ₂ OH). (Schemes 87.5 and 87.6). The starting material (2-benzyloxyphenylacetic acid (provided by Avodado)) can be acylated with oxazolidinone through a mixed anhydride at 80-85 ° C. using triethylamine as the base. Low temperature alkylation with bromoacetonitrile forms compound 87-9 with a good diastereomeric ratio. Removal of the chiral auxiliary under reducing conditions gives compound 87-10 without racemization. Protection of the resulting alcohol with the trityl group gives compound 87-11. Subsequent pyrrole ring construction and cyclo-guanidination reaction to prepare a 6-membered 2-aminopyrimidone ring can be prepared as illustrated in Scheme 87.6.

  (Scheme 87.5)

The compound of Scheme 87.2 (X═O, Z═H) can be prepared according to the general route illustrated above. The starting material 3- (2-benzyloxy-phenyl) -propionitrile is described in U.S. Pat. S. Patent No. 2,789,995 can be utilized by Lewis acid mediated reaction of phenol with acrylonitrile. Intermediate 87-11 can follow the synthetic steps outlined herein to obtain compounds of Schemes 87.1 and 87.1.

  The construction of the pyrrole ring can be completed in 3 steps from 3- (2-benzyloxy-phenyl) -propionitrile. Exposure of 87-12 to LDA and ethyl formate can form 3-hydroxy-acrylonitrile 87-13. Condensation of this product 87-14 with 2-amino-malonic acid diethyl ester in EtOH and sodium acetate gives pyrrole 87-15. In some syntheses, the trityl protecting group on benzyl alcohol is removed at this stage. Subsequent guanidinylation using cyanamide provides compound 87-16 by treatment with sodium hydroxide and cyclization to form the 2-aminopyrimidone ring (compound 87-17). Removal of the phenolic protecting group under hydrogenation conditions yields the free phenol that is used as the attachment site for the prodrug group. A variety of linkers can be used to attach the prodrug moiety to the backbone molecule. A specific example using diethylphosphonomethyl triflate as a starting material is illustrated below. Accordingly, compound 87-18 is treated with a base such as sodium hydride or cesium carbonate in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., (1986), 27, 1477) is added to give the compound of Scheme 87.2.

  (Scheme 87.6)

The compound of Scheme 87.2 (X═O, Y═H, Z═CH ₂ OH) can be prepared from 4-benzyloxyphenylacetic acid (commercially available from Aldrich). Intermediate 87-24 can be prepared following a series similar to Scheme 87.7 (Scheme 87.7). The sequence shown in Scheme 87.6 can be performed to convert 87-24 to the desired product of Scheme 87.2.

  (Scheme 87.7)

Example 88 Preparation of Exemplary Compounds of the Invention Phosphorus-containing triazolidinedione derivatives 88-2 are synthesized from the parent compound by alkylation. U. S. The parent compound 88-1 is obtained by the procedure described in Patent 4,572,912. Scheme 88.1 shows the attachment of a phosphonate linkage to the phenolic OH of 88-1 to give a compound of formula 88-2. A phosphonate that dissolves a compound in a suitable aprotic solvent such as DMF and then carries a leaving group (eg, bromine, methyl, tosyl, or trifluoromethanesulfonyl) in the presence of a suitable organic or inorganic base Treat with reagent (88-30). In the scheme of this example, A ^o -LG refers to a phosphonate compound described herein bonded to a leaving group such as, for example, halogen, triflate, mesylate, or toluenesulfonate.

  (Scheme 88.1)

For example, a solution of 88-3 in DMF can be treated with cesium carbonate and 1 equivalent of (trifluoromethanesulfonyloxy) methylphosphonic acid diethyl ester 88-18, 88-25, so that the bond is a methylene group as shown in Scheme 88.2. Certain troglitazone-phosphonates 88-4 are obtained. Using the above procedure, different 88-1 and phosphonate reagents 88-30, 88-40 can be used to obtain the corresponding product 88-2 carrying different substituents and linking groups.

  (Scheme 88.2)

Scheme 88.3 shows the preparation of phosphorus containing triazolidinedione derivatives of type 88-7, 88-20. U. S. Patent No. The parent compound 88-5 is obtained by the procedure described in 4,572,912. The phenolic OH and triazolidinedione units are protected with a suitable protecting group (eg, SEM group), and the C4 of the chroman alcohol analog by reduction of the carbonyl group using a suitable reducing agent (eg, sodium borohydride). A hydroxyl group is obtained at the position. The alcohol is then treated with a carbonate such as 88-6 with a suitable chloroformate such as phenyl chloroformate or p-nitrophenyl chloroformate or bis (p-nitrophenyl) carbonate to give the active carbonate. The resulting activated carbonate is reacted with a phosphonate reagent 88-35 carrying an amino group, followed by deprotection of the protecting group to give type 88-7, 88-20 phosphonates.

  (Scheme 88.3)

For example, a solution of 88-8 in THF is treated with diisopropylethylamine and 2 equivalents of 2- (trimethylsilyl) ethoxymethyl chloride to protect the phenolic OH and triazolidinedione units. The methanol solution of the protected product is then reduced using sodium borohydride to give alcohol 88-9. Alcohol 88-9 is treated with phenyl chloroformate to give phenyl carboxylate, which is reacted with 2-aminoethyl-phosphonic acid diethyl ester 88-12 to give the protected phosphonate derivative, and fluorinated tetrafluoride in THF. Protection with butylammonium gives 88-10. Using the above procedure, different 88-5 and phosphonate reagents 88-35 can be used to obtain the corresponding products 88-7, 88-20 carrying different substituents and linking groups.

  (Scheme 88.4)

Scheme 88.5 shows the preparation of phosphorus-containing thiazolidinedione derivatives. A thiazolidinedione having a phosphorus-containing moiety 88-13 is made by alkylation of thiazolidinedione 88-11 in a suitable aprotic solvent such as DMF to produce a leaving group (eg, bromine, mesyl, tosyl, or trifluoro). Treatment in the presence of phosphonate reagents 88-30, 88-40 bearing (romethanesulfonyl) and a suitable organic or inorganic base. Compound 88-13 is then reacted with benzaldehyde 88-14 having a protected phenol in the para position. The protecting group R ⁸⁸ can be any protecting group for phenolic OH (eg, an alkoxyalkyl group such as a methoxymethyl group; an aralkyl group such as a benzyl group; a 2-tetrahydropyranyl group; and an acetyl group or a benzoyl group; Acyl group), but a benzyl group is preferred. The reaction is suitably carried out in an aprotic solvent such as toluene at an elevated temperature (such as the reflux temperature of the solvent), preferably in the presence of a suitable catalyst (such as piperidinium acetate or benzoate). Preferably, the water produced by the reaction is removed from the reaction mixture, for example by a Dean and Stark apparatus. 88-15 is reduced to 88-16 by catalytic reduction using a suitable catalyst such as a palladium on carbon catalyst, preferably a 10% palladium on carbon catalyst (US Patent 6,288,095). Using Mitsunobu conditions, J. American Oil Chemical Society (1974), 51, 200 or U.S. Pat. S. Patent No. 4,572,912 and U.S. S. Patent No. Coupling of chroman alcohol homologs 88-17 and 88-16 with appropriately protected functional groups as described in US Pat.

  (Scheme 88.5)

For example, a solution of 88-11 in DMF is treated with sodium hydride and 1 equivalent of (trifluoromethanesulfonyloxy) methylphosphonic acid diethyl ester 88-18, 88-25, and the linkage is the methylene group shown in Scheme 88.6. Triazolidinedione-phosphonate 88-19 is obtained. The thiazolidinedione-phosphonate 88-19 is then reacted with benzaldehyde 88-20 bearing a benzoyl substituent under reflux conditions in toluene in the presence of catalytic piperidinium acetate using a Dean and Stark apparatus. 21 is obtained. Reaction of 88-22 with the chroman alcohol analog 88-23 in the presence of diethyl azodicarboxylate and triphenylphosphine and subsequent deprotection of the SEM group with TBAF provides 88-24. Using the above procedure, but using different chroman alcohol analogs and phosphonate reagents 88-30, 88-40, the corresponding products 88-2 carrying different substituents and linking groups are obtained.

  (Scheme 88.6)

Example 89: Preparation of Exemplary Compounds of the Invention Scheme K2-K4 illustrates the synthesis of phosphonate compounds K2-K4 of the invention and the synthesis of intermediates required for the synthesis.

(Protection of reactive substituents)
Depending on the reaction conditions used, with knowledge of the skilled person, it may be necessary to protect certain reactive substituents from undesired reactions by protection before the described series of reactions and then deprotect the substituents. Functional group protection and deprotection are described, for example, in Protective Groups in Organic Synthesis, by T .; W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990. Protection and deprotection of steroidal ketones and alcohols are described in Organic Reactions in Steroid Chemistry, Vol. 1, J. Fried and J.H. A. Edwards, van Nostrand Reinhold, (1972), p. 375ff. Reactive substituents that can be protected are shown in the accompanying schemes (eg, [OH], [O], etc.).

  (Scheme K1.)

For example, Scheme K1 shows a protection-deprotection series that protects the steroid side chain as a bis-methylenedioxy (BMD) moiety. In this series, Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition (1990), p. 6α, 9α-difluoro-16β-methyl-11β, 17α, 21-trihydroxypregn-1,4-diene-3,21-dione K1.1 (US Patent 4, 619,921) is reacted with an acid catalyst such as paraformamide and hydrochloric acid to give the BMD derivative K1.2. The phosphonate moiety is then introduced using the following procedure to give the phosphonate ester K1.3. Then, Protective Groups in Organic Synthesis, by T. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition (1990), p. As described in H.223, for example, the BMD moiety is hydrolyzed by treatment with 50% aqueous acetic acid to give triol K1.4. Then, Chem. Pharm. Bull. , 1986, 34, 1613 is used to convert the latter compound to the 17,21-cyclic orthoester K1.5. The substrate is reacted in dimethylformamide at 70 ° C. with 2 molar equivalents of triethyl orthopropionate and a catalytic amount of p-toluenesulfonic acid. The product is then reacted with excess trimethylsilyl chloride in dimethylformamide at ambient temperature to give the 21-chloro-17-propionate product K1.6.

  Alternatively, J. Org. Med. Chem. (1987), 30: 1581, convert the substrate K1.4 to the product K1.6. In this procedure, the 21-hydroxyl group is converted to 21-mesylate by reaction with mesyl chloride in pyridine, followed by substitution of the mesylate group by reaction with lithium chloride in dimethylformamide to yield the 21-chloro intermediate. The 17-hydroxyl group is esterified to give 21-chloro-17-propionate derivative K1.6. Selective acylation of the 17α hydroxyl group in the presence of the 11β hydroxyl group is described in J. Am. Med. Chem. (1987), 30: 1581.

(Preparation of phosphonate ester K2)
(Scheme K2. Phosphonate K2.)

Scheme K2 shows the preparation of phosphonate K2 linked to the phosphonate by an imino or iminoxy group and a variable carbon chain. In this procedure, the BMD protected derivative K1.2 is converted to an amine or hydroxyamine K2.1 where R ² is an alkyl, alkenyl, cycloalkyl, or cycloalkenyl group (optionally a heteroatom O, S or N is incorporated), or a functional group such as an amide, ester group, oxime group, sulfoxide group, or sulfone group, or optionally substituted aryl group, heteroaryl group, or aralkyl group (optionally Heteroatoms O, S, or N are incorporated) and X is a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxy, and the like. Reacting equimolar amounts of the reactants in an aprotic solvent such as pyridine or xylene or an alcohol solvent such as ethanol, optionally in the presence of an acid catalyst, provides an imine or oxime. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. 1978, 86, 133. and in J.J. Mass. Spectrom. (1995), 30,497. The BMD protected side chain compound K2.2 is then converted to triol K2.3a and then to 21-chloro 17-propionate product K2.3b as described in Scheme K1.

  K2 also illustrates the preparation of hydroxylamine ethers incorporating phosphonate groups. In this procedure, phosphonate K2.4 (wherein Lv is a free radical such as bromo or trifluoromethylsulfonyloxy) is reacted with BOC-hydroxylamine K2.5 (Aldrich) to give ether K2.6. Is obtained. The equimolar amounts of the reactants are reacted in a polar solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as potassium hydroxide or dimethylaminopyridine. For example, deprotection by treatment with trifluoroacetic acid provides hydroxylamine ether K2.7.

  (Scheme K2)

Scheme K2 (Example 89-A) illustrates the preparation of phosphonate K2 with the phosphonate attached by an iminoxy group. In this procedure, the substrate K1.2 was prepared as described above from dialkyl trifluoromethylsulfonyloxymethylphosphonate (Tet. Lett., 27: 1477 (1986)) and dialkylphosphonomethylhydroxylamine K2 prepared from BOC-hydroxylamine. To give oxime K2.9. Deprotection then yields the triol K2.10a from which the 21-chloro-17-propionate compound K2.10b is prepared. The oxime formation reaction is performed between equimolar amounts of reactants in an ethanol-acetic acid solution at ambient temperature.

  Using the above procedure, but using a different oxime ether K2.1 instead of hydroxylamine ether K2.8, the corresponding product K2.3b is obtained.

  (Scheme K2)

Scheme K2 (Example 89-B) illustrates the preparation of compound K2 having a phosphonate group attached through a thienylmethoxyoxime group. In this procedure, 0- (4-bromo-2-thienylmethoxy) hydroxylamine K2.11 prepared from 4-bromo-2-bromomethylthiophene (WO9420456) as described above and BOC protected hydroxylamine with dienone K1.2. Can be reacted as described above to give oxime K2.12 after side chain deprotection. The product is then reacted with a dialkyl phosphite K2.13 in the presence of a palladium catalyst to give the phosphonate K2.14a. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. , 35, 1371, (1992). The reaction is carried out in the presence of a base such as triethylamine and a catalytic amount of tetrakis (triphenylphosphine) palladium (0) in an inert solvent such as toluene. The 21-hydroxy compound K2.14a is then converted to the 21-chloro-17-propionate derivative K2.14b as described in Scheme K1.

  Alternatively, bromo compound K2.12 is coupled with dialkylbutenyl phosphonate K2.15 (Org. Lett. 3: 217 (2001)) to give phosphonate K2.16a. Coupling of aryl halides and olefins by the Heck reaction is described in, for example, A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry 503ff (Plenum, 2001) and in Acc. Chem. Res. 12: 146 (1979). Dimethylformamide 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 optionally a base such as triethylamine or potassium carbonate Alternatively, aryl bromide and olefin are coupled in a polar solvent such as dioxane. Optionally, the double bond present in product K2.16a is reduced, for example by reaction with diimide, to give saturated analog K2.17a. Reduction of olefinic bonds is described in R.A. C. Larock, Comprehensive Organic Transformations 6ff (VCH 1989). For example, conversion by catalytic hydrogenation using a palladium carbon catalyst and hydrogen or a hydrogen donor or the use of diimide or diborane. The products K2.16a and K2.17a are then converted to the 21-chloro-17-propionate analogs K2.16b and K2.17b.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromothienylmethoxy reagent K2.11, compounds K2.14b, K2.16b, and K2 A product similar to .17b is obtained.

  (Scheme K2, Example 89-C)

Scheme K2 (Example 89-C) shows the preparation of phosphonate K2 linked to the phosphonate by an imino group. In this procedure, the substrate K1.2 is prepared as described above by the palladium-catalyzed coupling of 4-amino-2-bromothiophene (Tet. 43: 3295 (1987)) with a dialkyl phosphite. Reaction with amino-2-thienylphosphonate K2.18 gives the imine product K2.19a after deprotection. The imine formation reaction is carried out in a hydrocarbon solvent such as toluene or xylene in the presence of a basic catalyst such as sodium methoxide or an acidic catalyst such as p-toluenesulfonic acid under azeotropic conditions at reflux temperature. The product is then converted to 21-chloro 17-propionate compound K2.19b.

  Using the above procedure, but using a different amino-substituted aryl or heteroaryl phosphonate instead of 4-aminothienyl phosphonate K2.18 gives a product similar to K2.19b.

  (Scheme K2, Example 89-D)

Scheme K2 (Examples 89-D) shows the preparation of phosphonate K2 with the phosphonate linked by an oximino group and an amide bond. In this procedure, dienone K1.2 is reacted with O- (4-aminobutyl) hydroxylamine K2.20 (Pol. J. Chem. 55: 1163 (1981)) to give oxime K2.21. The reaction of steroidal 1,4-dien-3-ones with substituted hydroxylamines is described in J. Am. Steroid Bioch. 7: 795 (1976) (reacting equimolar amounts of reactants in a polar organic solvent such as pyridine or methanol, optionally in the presence of acetic acid or sodium acetate). The product is then coupled with 2-hydroxyethylphosphonate K2.22 (Epsilin) and carbonyldiimidazole to give the carbamate oxime K2.23. The preparation of the carbamate is described in A. R. Katritzky, Comprehensive Organic Functional Group Transformations, 6: 416ff (Pergamon, 1995) and S.K. R. Sandler and W.M. Karo, Organic Functional Group Preparations, 260ff (Academic Press, 1986). In this procedure, phosgene or a functional equivalent thereof (carbonyldiimidazole, triphosgene, pentafluorophenyl carbonate, etc.) is reacted with an amine in an inert aprotic solvent such as dichloromethane or tetrahydrofuran to give the corresponding activated acylamine. It is done. The latter compound is then reacted with an alcohol to give the carbamate. The carbamate product K2.23 is then converted to the 21-chloro-17-propionate product K2.24b as described in Scheme K1.

  Using the above procedure, but using amino-substituted hydroxylamine and / or hydroxy-substituted phosphonate instead of hydroxylamine K2.22, products similar to K2.24b are obtained.

(Preparation of phosphonate esters K3 and K4)
(Scheme K3. Phosphonates K3 and K4)

Scheme K3 illustrates the preparation of phosphonate esters K3 and K4 in which a phosphonate group is attached to the 1 ′ or 2 ′ position of the pyrazole ring by an aromatic or heteroaromatic group, a heteroatom, and / or a variable carbon chain. In this procedure, the BMD protected dienone K1.2 is reduced to give the 1,2-dihydro product K3.1. For example, J. et al. Med. Chem. 44: 602 (2001), the catalytic hydrogenation reaction is carried out by the use of tris (triphenylphosphine) rhodium (I) chloride. Then, J.H. Am. Chem. Soc. 86: 1520 (1964) reacting the product with a base such as ethyl formate and sodium hydride in an inert solvent such as toluene or dimethylformamide to give 2-formyl product K3.2. It is done. This compound is then reacted with an alkyl, aralkyl, aryl, or heteroaryl hydrazine K3.3, where substituent X is either a phosphonate group or a group that subsequently converts to a phosphonate-containing substituent. For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl, and the like. The reaction gives isomers 2'- and 1'-arylpyrazoles K3.4 and K3.5. J. et al. Am. Chem. Soc. 86: 1520 (1964), pyrazole formation reactions are carried out between equimolar amounts of reactants in an acidic solvent such as acetic acid. The pyrazoles K3.4 and K3.5 are then converted to 21-chloro-17-pro via the BMD protected intermediates K3.6 and K3.7, for example by the procedure described in Examples 89-E and 89-F. Convert to Pionate Phosphonate K3.8b and K3.9b.

  (Scheme K5, Example 89-E)

Scheme K3 (Examples 89-E) illustrates the preparation of phosphonates K3 and K4 where the phosphonate is attached by an amide bond. In this procedure, ketoaldehyde K3.2 was reacted with 3-carboxypropylhydrazine K3.10 (Ind. J. Exp. Biol. 32: 218 (1994)) as described above to give pyrazoles K3.11 and K3. .12 is obtained. Reaction of 2'-substituted isoform K3.11 with 1 molar equivalent of dialkyl 4-aminophenylphosphonate K3.13 (Epsilon) and didichlorocarbodiimide in dimethylformamide solution at ambient temperature to give amide K3.14. . Preparation of amides from carboxylic acids and derivatives is described, for example, in S.H. R. Sandler and W.M. Karo, Organic Functional Group Preparations, 274 (Academic Press, 1968); C. Larock, Comprehensive Organic Transformations, 972ff (VCH, 1989). An aprotic solvent in the presence of an activator (such as dicyclohexylcarbodiimide or diisopropylcarbodiimide), optionally in the presence of, for example, hydroxybenztriazole, N-hydroxysuccinimide, or N-hydroxypyridone The amide is obtained by reacting the carboxylic acid with an amine (eg, pyridine, DMF, or dichloromethane).

  Alternatively, the carboxylic acid is first converted to an activated derivative such as an acid chloride, anhydride, mixed anhydride, and imidazolide, and then reacted with an amine in the presence of an organic base such as pyridine to give an amide. It is done.

  Treatment of the carboxylic acid with a reagent (eg thionyl chloride or oxalyl chloride) in an inert organic solvent such as dichloromethane, optionally in the presence of a catalytic amount of dimethylformamide, converts the carboxylic acid to the corresponding acid chloride. Convert.

  The BMD protecting group is then removed and the product is converted to the 21-chloro-17-propionate product K3.16b.

  Alternatively, as described above, 1'-substituted pyrazole K3.12 is coupled with dialkylaminomethylphosphonate K3.17 (Interchim) to give amide K3.18. Product K3.18 is deprotected to give triol K3.19a, which is converted to 21-chloro-17-propionate K3.19b.

  Using the above procedure, but using different amino substituted phosphonates and / or different carboxy substituted hydrazines, K3.16b and K3.19b are obtained. The functionalization procedures between the pyrazole substituents K3.11 and K3.12 are interchangeable.

  (Scheme K3, Example 89-F)

Scheme K3 (Examples 89-F) illustrates the preparation of phosphonates K3 and K4 where the phosphonate is linked by an aryl ring and a propenyl linkage. In this procedure, ketoaldehyde K3.2 was reacted with allylhydrazine K3.20 (Zh. Org. Khim., 3: 983 (1967)) to give pyrazoles K3.21 and K3.22 as described above. It is done. As described in Scheme K2, the 1′-substituted isomer K3.21 is coupled with dialkyl 3-bromophenylphosphonate K3.23 (Epsilon) to give phosphonate K3.24.

The product is then deprotected to give triol K3.25a, which is converted to 21-chloro-17-propionate compound K3.25b.

  Alternatively, as described above, 2′-substituted pyrazole K3.22 is coupled with dialkyl 5-bromo-2-thienylphosphonate K3.26 (Syn., 455 (2003)) and deprotected to give phosphonate K3.27. The product obtained is converted to the 21-chloro-17-propionate analog K3.28b.

  Using the above procedure, but using an alkyl hydrazine and / or a different dialkyl bromo-substituted phosphonate instead of propenyl hydrazine K3.20, products similar to K3.25b and K3.28b are obtained.

(Scheme K4. Phosphonates K3 and K4)
(Method)

Scheme K4 shows the preparation of phosphonate esters K3 and K4 where the phosphonate is linked by a variable carbon bond. In this procedure, ketoaldehyde K3.2 is reacted with hydrazine to give pyrazole derivative K4.1. The reaction of steroidal 2-formyl-3-ketones with hydrazine is described in J. Am. Am. Chem. Soc, 86: 1520 (1964). The reaction is carried out in acetic acid at ambient temperature. The pyrazole product is then reacted with bromomethyl compound K4.2 (wherein R ² and X are as defined above) to give alkylated products K4.3 and K4.4. Alkylation of substituted pyrazoles is described, for example, in T.W. L. Gilchrist, Heterocyclic Chemistry, 309 (Longman, 1992). The reaction is carried out between equimolar amounts of the substrate in a polar solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as dimethylaminopyridine and lithium hexamethyldisilazide. Products K4.3 and K4.4 are converted to phosphonates K4.5 and K4.6, followed by deprotection using the procedures described herein, except when X is a dialkylphosphono. / Chlorination / acylation gives 21-chloro-17-propionate compounds K4.7b and K4.8b.

(Scheme K4)
(Example 89-G)

As shown in Scheme K4 (Example 89-G), K4.1 is reacted with 2-bromobenzyl bromide K4.9 to give pyrazoles K4.10 and K4.11. The product is then coupled with a dialkyl phosphite as described above to give 21-chloro-17-propionate K4.12b and K4.13b after deprotection and modification of the above side chains.

As shown in Scheme K4 (Example 89-H), pyrazole K4.1 was reacted with 4-bromomethylchlorohexanone K4.14 (WO 9737959) as described above to produce alkylated products K4.14 and K4. .15 is obtained. The 1′-substituted isomer K4.15 is then converted to the dialkylaminomethylphosphonate K. in a reductive amination reaction. Reaction with 19 (Interchim) and sodium cyanoborohydride gives 21-chloro-17-propionate K4.17b after deprotection and side chain modification.

  Preparation of amines by reductive amination procedures is described, for example, in R.A. C. Larock, Comprehensive Organic Transformations, 421 (VCH, 1989) and F.M. A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry, Part B, 269 (Plenum, 2001). In this procedure, J.M. Org. Chem. 55: 2552 (1990), the amine component and the aldehyde or ketone component together with a reducing agent (such as borate, sodium cyanoborohydride, sodium triacetoxyborohydride, or diisobutylaluminum hydride). Optionally in the presence of a Lewis acid such as titanium tetraisopropoxide.

  The 2'-substituted pyrazole K4.16 is subjected to the same series of reactions to give amine phosphonate K4.18b.

  Using the above procedure, but using different bromomethyl-substituted aldehydes or ketones and / or different amino-substituted phosphonates, products similar to K4.17b and K4.18b are obtained.

Example 90: Preparation of Exemplary Compounds of the Invention Schemes 1 and 2 illustrate the synthesis of phosphonate compounds M1 and M2 of the invention and the synthesis of intermediate compounds required for the synthesis.

(Protection of reactive substituents)
Depending on the reaction conditions used, one skilled in the art may need to protect certain reactive substituents from undesired reactions by the described pre-series protection and then deprotect the substituents. Functional group protection and deprotection are described, for example, in T.W. W. Greene and P.M. G. M.M. Wuts, Protective Groups in Organic Synthesis (Second Edition, Wiley, 1991). The protection and deprotection of steroidal ketones is described in J. Org. Fried and J.M. A. 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 (eg, [OH], [O], etc.).

  (Preparation of M1 phosphonate ester M1)

Scheme 1 shows the preparation of phosphonate M1 (Compound 1 of Scheme 1). Scheme 1 (Example 90-A) shows an example of Scheme 1. In Scheme 1 (Example 90-A), 5-hydroxy-1-bD-ribofuranosyl-1H-imidazole-4-carboxamide 1.1 (prepared according to US Pattn No. 3888843) was prepared in tetrahydrofuran or dimethylformamide. Can be treated with a base such as sodium hydride in a solvent such as Upon defoaming, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986, 27, 1477) is added to give the desired phosphonate diester 1.

  (Preparation of phosphonate ester M2)

Scheme 2 illustrates the preparation of phosphonate ester M2 (Compound 2 of Scheme 2). Compound 2.1 (5-hydroxy-1- (4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-ylmethyl) -1H-imidazole-4-carboxylic acid amide) was converted to 3,5-bis protected 2- Deoxy-D-erythro-pentofuranosyl chloride (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) can be prepared by addition of an imidazole base (JP Kokai 76 88965). it can. The imidazol-4-ol of compound 2.1 is then protected. Oxidation of 5′-OH and subsequent elimination yields glycal 2.3 (see the procedure of Zemlicka J. et al., J. Am. Chem. Soc., 1972, 94, 9, 3213). ). Selenoetherification gives the protected phosphonate 2.4 (Kim, C. et al., J. Org. Chem., 1991, 56, 2642). Oxidative elimination of phenyl selenide (described in Kim, C. et al., J. Org. Chem., 1991, 56, 2642) and subsequent stereoselective hydroxylation yields diol 2.6. . Finally, the protecting group is removed to give compound 2.

  (Scheme 2, Example 90-C)

Scheme 2 (Example 90-C) illustrates the preparation of phosphonate M2 (Compound 2 of this example). Specifically, 3,5-bis-protected 2-deoxy-D-erythro-pentofuranosyl chloride (Hayashi, M. et al., Chem. Pharm. Bull., 1975, 23, 1,245; Montgomery, J. et al. A. et al., J. Med. Chem., 1969, 12, 3,498; and Iwamoto, RH et al., J. Med. Chem., 1963, 6, 684) (JP) Compound 2.1 (5-Hydroxy-1- (4-), which can be prepared by the addition of Kokai 76 88965; also Sipper, E. et al., J. Am. Chem. Soc., 1952, 74, 350). Hydroxy-5-hydroxymethyl-tetrahydrofuran-2-ylmethyl) -1H-imidazo Le 4-carboxylic acid amide), to protect the scratch using TBS group. Subsequent oxidation with PtO ₂ proceeds to give carboxylic acid 2.2. Decarboxylative elimination is performed using dimethylformamide dineopentyl acetal in DMF at high temperature (Zemlicka J. et al., J. Am. Chem. Soc., 1972, 94, 9, 3213). Once the furanoid glycal 2.3 is obtained, it is treated with silver perchlorate in the presence of diethyl (hydroxylmethyl) phosphonate (Philion, D. et al., Tetrahedron Lett., 1986, 27, 1477). To obtain phosphonate 2.4 (Kim, C. et al., J. Org. Chem., 1991, 56, 2642). Oxidative elimination of selenide followed by dihydroxylation using osmium tetroxide provides diols with the desired stereochemistry. TBAF can be used to deprotect the TBS group to give compound 2.

  Example 91: Preparation of exemplary compounds of the invention

(Example 91-A)
([2- (4- {4- [4-Methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenylcarbamoyl] -benzyl} -piperazin-1-yl) -ethyl]- Phosphonic acid diethyl ester)
N- [4-Methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenyl] -4-piperazin-1-ylmethyl-benzamide (30 mg, 0.06 mmol, Zimmermann et al., Bioorg Med. Chem. Lett. 1996, 6, 1221), diethyl 2-bromoethylphosphonate (30 mL, 0.12 mmol), and 2.5 mL of DMF containing K ₂ CO 3 (20 mg, 0.16 mmol) in 110 mL. Heated at 0 ° C. for 8 hours, at which point most of the starting material was consumed as judged by LCMS analysis. Solid material was filtered. The filtrate was diluted with water and then extracted with EtOAc. The organic phase 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 give 28 mg (55%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 ) d 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} -piperazin-1-yl) -ethyl]- Phosphonic acid)
[2- (4- {4- [4-Methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenylcarbamoyl] -benzyl} -piperazin-1-yl) -ethyl] -phosphone TMSBr (15 mL, 0.12 mmol) was added to a solution of acid diethyl ester (8 mg, 0.012 mmol) in DMF (1 mL) at room temperature. The reaction was allowed to proceed for 14 hours at room temperature. Another portion of TMSBr (20 mL) was added and heated at 110 ° C. for 12 hours, at which time completion of the reaction was detected by LCMS. The reaction was cooled to room temperature and quenched by the addition of MeOH. The reaction mixture was dried under reduced pressure, _H 2 O-acetonitrile gradient residue 20 minutes (5-100%) to give RP HPLC using a C18 column with a mono -TFA of 4.2 mg (50%) Salt was obtained. ¹ H NMR (300 MHz, CD ₃ OD) d 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, possible overlap 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, 1 H), 8.58 (d, 1 H, J = 5 Hz), 8.89 (d, 1 H, J = 2 Hz), 9.22 (dd, 1 H, J = 2) , 5 Hz), 9.63 (s, 1 H); ³¹ P (121.4 MHz, CD ₃ OD) d 21.9; MS (m / z) 588 [M + H] ⁺ .

(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-benzamide (20 mg, 0.04 mmol) and 2-[(2 -Oxo-ethyl) -phenoxy-phosphinoyloxy] -propionic acid ethyl ester (60 mg, 0.2 mmol) in 1% acetic acid / DMF (1.5 mL) was stirred at room temperature for 7 h, then NaCNBH ₃ (30 mg 0.24 mmol) was added. The resulting mixture was stirred for an additional 30 minutes, at which point LCMS showed the reaction was complete. After evaporation of the solvent, the residue was taken up in CH ₂ Cl ₂ and extracted with saturated aqueous NaHCO ₃ solution. 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 product. _{^{31 P NMR (121.4MHz, CDCl 3}} ) d27.2,28.6; 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) -phenylcarbamoyl] -benzyl} -piperazin-1-yl) -ethyl To a 2: 1 acetonitrile / water (0.3 mL) solution of] -phenoxy-phosphinoyloxy} -propionic acid ethyl ester (6 mg, 0.008 mmol) was added 1N NaOH (50 mL, 0.048 mmol). The solution was stirred at room temperature for 1 hour, at which time the reaction was complete by LCMS. The reaction was acidified with 1N HCl (50 mL) solution and purified by RP HPLC using a C18 column with a 20 minute H ₂ O-acetonitrile gradient (5-100%) to yield 2 mg (38%). I got a thing. ¹ H NMR (300 MHz, CD ₃ OD) d1.51 (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, possible 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, 1 H, J = 2 Hz), 9.10 (dd, 1 H, J = 2, 5 Hz), 9.59 (s, 1 H); ³¹ P (121.4 MHz, CD ₃ OD) d 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- Enic acid methyl ester)
6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester (222 mg , 0.66 mmol), PPh ₃ (260 mg, 0.996 mmol), and diethylazocarboxylate (173 mg, 0.996 mmol) in THF (3 mL) to trimethylsilylethanol (142 mL, 0.996 mmol) in THF (3 mL). The solution was added. The resulting yellow solution was warmed to room temperature and stirred overnight. The reaction was completed by concentrating the solution to dryness and adding ether and hexane. Triphenylphosphine oxide was removed by filtration 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 ) d 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, 1H).

(Example 92-B)
([6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde)
Smith, D.M. B. et al. , J .; Org. Chem. , 1996, 61, 6, 2236, 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 (618 mg, 1.42 mmol) MeOH in _{(10mL), CH 2 Cl 2} (10mL), and (50 mL, 0.618 mmol) was treated with dry ice / Cooled to -70 ° C using an acetone bath. The reaction was bubbled through a stream of ozone with a gas dispersion tube until the reaction turned blue (15 minutes). The ozone line was replaced with a stream of nitrogen and continued to bubble for an additional 15 minutes until the blue color disappeared. To this solution at −70 ° C., thiourea (75.7 mg, 0.994 mmol) was added in one portion and the cooling bath was removed. The reaction was warmed to room temperature and stirred for 15 hours. The reaction was worked up by partitioning between filtration and subsequent CH ₂ Cl ₂ and water to remove solid thiourea S- dioxide. The organic phase was removed. The aqueous phase was washed once more with CH ₂ Cl ₂ and the organic extracts were combined. The organic phase was washed with 1N HCl, saturated NaHCO ₃ , and brine. The organic extract was dried in vacuo and the residue purified by silica gel chromatography to give 357 mg (75%) of product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) d -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] -acetaldehyde (70 mg, 0 in toluene (2 mL). .21 mmol) was heated with 2- (triphenylphosphanylidene) -propionaldehyde (72.9 mg, 0.23 mmol) at 100 ° C. overnight. A second portion of 2- (triphenylphosphanylidene) -propionaldehyde (33 mg, 0.11 mmol) was added and the reaction mixture was heated for an additional day. After concentration, the residue was purified by silica gel chromatography to give 54 mg (83%) of the desired product as a pale yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 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-enyl) -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] -2-methyl-but-2-enal A solution of (103 mg, 0.27 mmol) in methanol (5 mL) 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 THF solution). The ice bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture was stirred for an additional 40 minutes, immediately after which completion of starting aldehyde consumption was observed by TLC. The reaction was worked up by the addition of 1N aqueous HCl (0.5 mL) and extracted with CH ₂ Cl ₂ . The organic phase was washed with saturated sodium bicarbonate solution and brine. The organic phase is concentrated under reduced pressure and the residue is purified by silica gel chromatography to give 100 mg (97%) of product as a clear liquid. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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)
(Mono- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] phosphite] -2- Methyl-but-2-enyl} ester)
Shadid, B.M. et al. , Tetrahedron, 1989, 45, 12, 3889, 6- (4-hydroxy-3-methyl-but-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl- To a solution of ethoxy) -3H-isobenzofuran-1-one (75 mg, 0.20 mmol) and DIEA (49 mL, 0.28 mmol) in dioxane (2 mL) was added 2-chloro-4H-1,3,2-benzodi. Oxaphospholin-4-one (56.7 mg, 0.28 mmol) was added. After 10 minutes, another 2-chloro-4H-1,3,2-benzodioxaphospholin-4-one (40 mg, 0.20 mmol) and DIEA (35 mL, 0.20 mmol) were added. The reaction was allowed to proceed for an additional hour at room temperature and then stopped by the addition of H ₂ O. The solution was stirred for an additional 10 minutes and concentrated in vacuo to a small volume. The product was wet triturated with diethyl ether and coevaporated with acetonitrile (4 × 10 mL) to give the product. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (brs, 1H); ³¹ P (121.4 MHz, CDCl ₃ ) d 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 phosphate -But-2-enyl} ester)
Phosphorous acid mono- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl -But-2-enyl} ester (27 mg, 0.06 mmol) in dioxane (1 mL) was diluted with DIEA (21 mL, 0.12 mmol) and N, O-bis (trimethylsilyl) acetamide (29 mL, 0.12 mmol) at room temperature. For 3 hours. To the reaction solution was added 2,2′-dipyridyl disulfide (16 mg, 0.072 mmol) and the mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was diluted by the addition of H ₂ O and the solution was stirred for an additional 2 hours and 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 in vacuo 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) d 1.87 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.79 (s, 3H), 4.28 (d, 2 H, J = 6 Hz), 5.26 (s, 2 H), 5.50-5.61 (m, 1 H); ³¹ P (121.4 MHz, CD ₃ OD) d 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] -acetaldehyde (97 mg, 0.29 mmol) in THF ( To the solution, an aliquot of 2M LiBH ₄ in THF (150 mL, 0.300 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, at which point TLC showed complete consumption of starting material. The reaction mixture was worked up by addition of 1N aqueous HCl and extraction with EtOAc. The organic phase was dried under reduced pressure and the residue was purified by silica gel chromatography to give the product. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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)
A mixture of 6- (2-hydroxy-ethyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (79 mg, 0.23 mmol) was added to DMF. (2 mL) was heated with bromomethylphosphonic acid diisopropyl ester (120 mg, 0.46 mmol) in the presence of lithium t-butoxide (22 mg, 0.27 mmol) at 70 ° C. overnight. The reaction mixture is purified by reverse phase HPLC to give the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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) -1,3-dihydro-isobenzofuran-5-yl] -ethoxymethyl} -phosphonic acid diisopropyl ester To a solution of (7.5 mg, 0.014 mmol) in acetonitrile (2 mL) and 2,6-lutidine (25 mL, 0.21 mmol) was added trimethylsilyl bromide (27 mL, 0.21 mmol) at room temperature. The reaction was allowed to proceed for 18 hours, at which time LCMS indicated the reaction was complete. The reaction was quenched by the addition of MeOH and concentrated. The residue was purified by reverse phase HPLC using a C18 column. The recovered product was suspended in 10% TFA / CH ₂ Cl ₂ solution to completely cleave the TMSE group. The reaction mixture was lyophilized to give the desired product. ¹ H NMR (300 MHz, CD ₃ OD) d2.12 (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-enyl) -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-enyl) -5-methoxy-4-methyl-3H-isobenzofuran-1-one (100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) was added continuously and the mixture was shaken for 1 hour at room temperature. Additional carbon tetrabromide (143 mg, 0.43 mmol) was added and the mixture was shaken for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (0% to 60% ethyl acetate / hexane) to give 6- (4-bromo-3-methyl-but-2-enyl) -7-hydroxy-5-methoxy-4-methyl as an oil. -3H-isobenzofuran-1-one was obtained (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).

(Example 92-K)
([4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl] -phosphonic acid dimethyl ester )
6- (4-Bromo-3-methyl-but-2-enyl) -7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one (33 mg, 0.097 mmol) trimethyl phosphite The (1.0 mL, 8.5 mmol) solution was heated at 100 ° C. for 1 hour, immediately after which LCMS indicated completion of the reaction. Finish the reaction by removing excess trimethyl phosphite under reduced pressure and purify the residue by silica gel chromatography using EtOAc-hexane (20-100%) to give 20 mg (60%) of the desired product. It was. ¹ H NMR (300 MHz, CDCl ₃ ) d 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, 6 H, J = 11 Hz), 3.72 (s, 3 H), 5.14 (s, 2 H), 5.33 (q, 1 H, 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-enyl] -phosphonic acid (LC -2095-49): [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl] TMSBr (63 mL, 0.49 mmol) and 2,6-lutidine (85 mL, 0.73 mmol) were added to a solution of phosphonic acid dimethyl ester (18 mg, 0.049 mmol) in acetonitrile (2 mL) at 0 ° C. The solution was allowed to warm to ambient temperature and the solution was stirred at room temperature for 2 h, at which time LCMS indicated the reaction was complete, the reaction was cooled to 0 ° C. and MeOH was added. The reaction was stopped Te. The reaction mixture was dried under reduced pressure for 20 minutes _H 2 O-acetonitrile gradient (5-0%) and the residue was purified by RPHPLC using a C18 column using, 12.2 mg (73 ¹ H NMR (300 MHz, CD ₃ OD) d 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-enyloxymethyl] -diisopropylphosphonate Ester: 7-hydroxy-6- (4-hydroxy-3-methyl-but-2-enyl) -5-methoxy-4-methyl-3H-isobenzofuran-1-one (50 mg, 0.18 mmol, Pankiewicz et al , J. Med. Was heated to 70 ° C. for 5 hours. The reaction was quenched with 1N HCl. The mixture was poured into 5% aqueous lithium chloride solution, extracted with ethyl acetate and concentrated. The residue was purified by silica gel chromatography to give [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-butoxy as an oil. -2-enyloxymethyl] -phosphonic acid diisopropyl ester (25 mg, 32%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ1.25 (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-enyloxymethyl] -phosphonic acid )
[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -diisopropylphosphonate To an acetonitrile solution of 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 room temperature and stirred for 4 hours. The reaction was quenched with methanol at 0 ° C. and the resulting mixture was concentrated. The residue was purified by separation reverse phase HPLC and [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-as an oil after removal of the solvent 2-Methyl-but-2-enyloxymethyl] -phosphonic acid (17 mg, 83%) was obtained. ¹ H NMR (300 MHz, CD ₃ OD) δ1.81 (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-enyloxymethyl] -phosphonic acid Monophenyl ester and [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -Phosphonic acid diphenyl ester)
[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid ( 49 mg, 0.13 mmol) in DMF (0.4 mL) and phenol (62 mg, 0.65 mmol) in DMF containing dicyclohexylcarbodiimide (107 mg, 0.52 mmol) and DMAP (8 mg, 0.065 mmol) at 0 ° C. 0.6 mL) was added slowly. The reaction was warmed to room temperature and heated at 140 ° C. for 10 minutes. After cooling to room temperature, the mixture was filtered and extracted with 1N aqueous NaOH. The aqueous phase was acidified with 1N HCl and extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by reverse phase HPLC to yield 18.5 mg of [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl as a pale yellow solid. ) -2-methyl-but-2-enyloxymethyl] -phosphonic acid monophenyl ester (main product) and 4.1 mg of [4- (4-hydroxy-6-methoxy-7-methyl-) as a pale yellow solid 3-Oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid diphenyl ester (byproduct) was also obtained. Main products: ¹ H NMR (300 MHz, CD ₃ OD) d 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) d17.3; MS (m / z) 449.0 [M + H] ⁺ , 471.2 [M + Na] ⁺ . By-products: ¹ H NMR (300 MHz, CD ₃ OD) d1.82 (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) d16.3; 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-enyloxymethyl] -Phenoxy-phosphinoyloxy} -propionic acid ethyl ester)
[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid mono To a solution of phenyl ester (18.5 mg, 0.040 mmol) and (S)-(−)-ethyl lactate (47 mL, 0.040 mmol) in pyridine (0.5 mL) was added PyBOP (32 mg, 0.060 mmol). . The solution was stirred at room temperature for 1 hour and additional PyBOP (21 mg, 0.040 mmol) was added. The solution was stirred for an additional 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) d 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, 1 H), 7.15-7.27 (m, 3 H), 7.33-7.41 (m, 2 H); ³¹ P (121.4 MHz, CD ₃ OD) d 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 )
Butyllithium (1.6 M hexane solution, 1 mL) was added to the same volume of THF at −20 ° C. A solution of diethyl methylphosphonate (220 mg, 1.45 mmol) in THF (1 mL) was then 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-enyl) -7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one (50 mg, 0.15 mmol) in THF (1 mL) The solution was added and the mixture was warmed at 0 ° C. for 2 hours, after which 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 subjected to silica gel chromatography (40% -100% ethyl acetate / hexane) to give [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1] as an oil. , 3-Dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -phosphonic acid diethyl ester (27 mg, containing starting diethyl methylphosphonate). 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] -phosphonic acid diethyl ester ( A mixture of 27 mg, 0.066 mmol), LiOH (200 mg), MeOH (3 mL), and (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 separated reverse phase HPLC (acetonitrile and 0.1% aqueous CF ₃ COOH) to give [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).

  (II. 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 tetramethylmethylene 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-methyl-but-2-enal (30 mg , 0.11 mmol, Pankiewicz, et al., J. Med. Chem. 45, 703) in THF (2.5 mL) was added and stirring continued for an additional 15 minutes. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with acetic acid. After evaporation of the solvent, the residue was purified by silica gel chromatography eluting with ethyl acetate (50-100%) / hexane to give [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo- as an oil. 1,3-Dihydro-isobenzofuran-5-yl) -3-methyl-penta-1,3-dienyl] -phosphonic acid dimethyl ester (30 mg, 71%) was obtained. 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-1,3-dienyl] -dimethylphosphonate To an acetonitrile solution of ester (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) at 0 ° C. The mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched with methanol at 0 ° C. and the resulting mixture was concentrated. The residue was purified by separation reverse phase HPLC, the solvent was removed and [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl as a solid] ) -3-Methyl-penta-1,3-dienyl] -phosphonic acid (13 mg, 65%) was obtained. 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-enyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4- Methyl-hex-4-enoic acid methyl ester)
To a cooled (−78 ^° C.) mycophenolic acid methyl ester (138 mg, 0.41 mmol) in THF (2.5 mL) was added sodium bis (trimethylsilyl) amide (1.0 M, 0.98 mL) in THF. 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 was continued for 10 minutes. The resulting mixture was warmed to −30 ° C. and this temperature was maintained for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate and a residue was obtained after evaporation of the solution, which was purified by silica gel chromatography eluting with ethyl acetate (0% to 40%) / hexane to give 2- (4-bromo-butene as an oil. -2-enyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl The ester (150 mg, 78%) is obtained. 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-enyl] -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-enyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5 Yl) -4-methyl-hex-4-enoic acid methyl ester (490 mg, 1.05 mmol) in trimethyl phosphite (2.5 mL, 21.1 mmol) was heated at 120 ° C. for 1 h. The reaction was cooled to room temperature. The reaction mixture was worked up by removal of the solvent in vacuo and chromatography using EtOAc-hexanes to give 460 mg (88%) of product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 1.77 (s, 3H), 2.081-2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H, J = 22Hz), 2.54 (d, 1H, J = 22Hz), 2.55-2.63 (m, 1H), 3.36 (d, 2H, J = 7Hz), 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 ) d 30.1; MS (m / z) 497.2 [M + H] ⁺ , 519. 2 [M + Na] ⁺ .

(Example 92-U)
(2- [4- (Dimethoxy-phosphoryl) -but-2-enyl] -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-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) 4-methyl - hex-4-enoic acid methyl ester (460 mg, 0.927 mmol) in _H 2 O / MeOH / THF containing 1: 1: 2 solution (8 mL) and _{LiOH · H 2 O (78mg,} 1. 86 mmol) and ambient temperature for 12 hours. A second batch of LiOH.H ₂ O (40 mg, 0.952 mmol) was added. The reaction mixture was stirred at room temperature for an additional 16 hours, after which time the reaction did not proceed further. The reaction was quenched by the addition of saturated aqueous NH ₄ Cl. The organic phase was removed under reduced pressure and the product was extracted from the aqueous phase acidified with EtOAc by oxidation 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 ) d 1.79 (s, 3H), 2.08-2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J = 22 Hz), 2.60 (d, 1 H, J = 22 Hz), 2.57-2.64 (m, 1 H), 3.38 (d, 2 H, J = 7 Hz), 3.72 (d, 6 H, 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 ) d 30.5; MS (m / z) 481.2 [M−H] ⁻ .

(Example 92-V)
(2- [4- (2- [4- (Dimethoxy-phosphoryl) -but-2-enyl] -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-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) To a solution of -4-methyl-hex-4-enoic acid (25 mg, 0.052 mmol) in acetonitrile (2 mL) was added 2,6-lutidine (60 mL, 0.52 mmol) and TMSBr (67 mL, 0.52 mmol). . The reaction was allowed to proceed for 45 minutes, at which point the reaction was complete as judged by LCMS. The reaction mixture was concentrated under reduced pressure and quenched with aqueous NaOH (1 mL). The product was purified by reverse phase HPLC on a C18 column to give 14.2 mg (60%) of product as a solid. ¹ H NMR (300 MHz, CD ₃ OD) d1.81 (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) d25. 4; MS (m / z) 453 [M−H] ⁻ .

(Example 92-W)
(2- [4- (Dimethoxy-phosphoryl) -but-2-enyl] -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-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) A solution of -4-methyl-hex-4-enoic acid (160 mg, 0.332 mmol) and trimethylsilylethanol (160 mg, 1.36 mmol) in THF (8.00 mL) was stirred with triphenylphosphine (345 mg, 1.33 mmol). did. To this solution was added diethyl azocarboxylate (230 mL, 1.33 mmol) at 0 ° C. The mixture was warmed to room temperature and stirred for 16 hours. Additional triphenylphosphine (180 mg, 0.692 mmol), trimethylsilylethanol (160 mg, 1.36 mmol), and diethyl azocarboxylate (115 mL, 0.665 mmol) were added and the reaction mixture was stirred at room temperature for an additional day. The reaction was worked up by removal of the solvent under reduced pressure and purification of the residue by silica gel chromatography to give 192 mg (85%) of product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (app t, 2H, J = 8 Hz), 4.30 (app t, 2H, J = 8 Hz), 5.12 (s, 2H), 5.15-5 ^{.25 (m, 1H), 5.36-5.63} (m, 2H); 31 P (121.4MHz, CDCl 3) d29.3; MS (m / z) 705. [M + Na] ^+.

(Example 92-X)
(2- [4- (hydroxy-methoxy-phosphoryl) -but-2-enyl] -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-enyl] -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 (184 mg, 0.270 mmol) in tert-butylamine (2.8 mL, 27 mmol) For 24 hours. The solution was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography using MeOH / CH ₂ Cl ₂ (0-30%) to give 75 mg of product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (brt, 1H, J = 6 Hz) ^{), 5.33-5.56 (m, 2H)} , 8.49 (br s, 1H); 31 P (121.4MHz, CDCl 3) d 2.1; MS (m / z) 667.4 [M + Na] +.

(Example 92-Y)
(2- {4-[(1-Ethoxycarbonyl-ethoxy) -methoxy-phosphoryl] -but-2-enyl} -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsila Nyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester)
2- [4- (Hydroxy-methoxy-phosphoryl) -but-2-enyl] -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 (67 mg, 0.10 mmol), PyBOP (234 mg, 0.450 mmol) in DMF (1. 5 mL) solution was stirred with (S)-(−)-ethyl lactate (53 mg, 0.45 mmol) and DIEA (174 mL, 1.00 mmol) at ambient temperature, at which point the starting material consumption was complete. Admitted. The reaction was completed by the addition of saturated aqueous sodium chloride and ethyl acetate. The organic phase was separated and washed with 5% aqueous lithium chloride. The organic phase 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 ) d 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, 2H, J = 9 Hz), 4.85-4.99 (m, 1H), 5. 2 (s, 2H), 5.19 (br t, 1H, J = 6Hz), 5.33-5.61 (m, 2H); 31 P (121.4MHz, CDCl 3) d28.9,29. 9; MS (m / z) 791.4 [M + Na] ⁺ .

(Example 92-Z)
(2- {4-[(1-Ethoxycarbonyl-ethoxy) -methoxy-phosphoryl] -but-2-enyl} -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-enyl} -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 (14 mg, 0.018 mmol) in THF (1 mL) Stir with 1M TBAF in THF (55 mL, 0.055 mmol) for 1 h. The reaction mixture was worked up by concentration of the reaction mixture under reduced pressure and extraction of the product from aqueous 1N HCl with EtOAc. The organic phase was washed with brine and dried. The product was purified by silica gel chromatography with EtOH-EtOAc (0-10%). Further purification was obtained by dissolving the product in CH ₂ Cl ₂ and passing the product through a 13 mm Acrodisc syringe filter equipped with a 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 (brt, 1H, J = 7 Hz), 5.33-5.55 (m, 2H) ^{), 7.51-7.56 (m, 1H)} , 7.68-7.74 (m, 1H); 31 P (121.4MHz, CDCl 3) d 29.0,3 .1; MS (m / z) 569.2 [M + H] +, 591.3 [M + Na] +.

(Example 92-AA)
(2- {4-[(1-carboxy-ethoxy) -hydroxy-phosphoryl] -but-2-enyl} -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-enyl} -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl) -Ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanylethyl ester (12 mg, 0.016 mmol) in tert-butylamine (1 mL, 9 .6 mmol) solution was heated at 65 ° C. for 16 hours. The solution was cooled to room temperature and concentrated to give the 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 = 7Hz), 3.76 (s, 3H), 4.08 (appt t, 2H, J = 9Hz), 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 ) d 28.9; MS (m / z) 725.3 [M−H] ⁻ .

(Example 92-AB)
(2- {4-[(1-carboxy-ethoxy) -hydroxy-phosphoryl] -but-2-enyl} -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-enyl} -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 (AC-2101-59) and tetrabutylammonium fluoride A solution of THF (1M, 54 mL, 0.054 mmol) was stirred in THF (1 mL) at ambient temperature for 2 hours, at which point, THF (54 mL, 0.054 mmol) solution containing excess tetrabutylammonium fluoride. Was added. The reaction was stirred for an additional 16 hours at which time the reaction was complete. The reaction mixture was concentrated under reduced pressure and reverse using a Phenomenex Synergi 5m Hydro RP 80A column (50 × 21.2 mm) with an eluent of H ₂ O, 0.1% TFA-CH ₃ CN, 0.1% TFA. The product was purified by phase HPLC to give 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 (brs, 1H), 5. 20 (s, 2H), 5.21-5.30 (m, 1H), 5.33-5.63 (m, 2H); 31 P (121.4MHz, CDCl 3) d 27.7; MS ( m / z) 525.2 [M−H] ⁻ .

  (Scheme II)

(Example 92-AC)
(2- {4-[(1-Ethoxycarbonyl-ethylamine) -methoxy-phosphoryl] -but-2-enyl} -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsila Nyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester)
2- [4- (Hydroxy-methoxy-phosphoryl) -but-2-enyl] -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 (20 mg, 0.030 mmol), PyBOP (62.4 mg, 0.120 mmol) in DMF ( 1.0 mL) solution was stirred with L-alanine ethyl ester hydrochloride (18 mg, 0.12 mmol) and DIEA (26 mL, 0.15 mmol) for 1 hour at ambient temperature, at which point the starting material consumption was complete. It was. The reaction was completed by adding water until the reaction solution became cloudy. A minimum amount of DMF was added until the reaction was clear again. The reaction mixture was filtered through Acrodisc (13 mm syringe filter with 0.45 mm nylon membrane) and by reverse phase HPLC using a Phenomenex Synergi 5m Hydro RP 80A column (50 × 21.2 mm) eluting with water and acetonitrile. Purified. Fractions containing product were pooled and dried in vacuo to remove acetonitrile. The aqueous phase 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 ) d 0.03 (s, 9H), 0.05 (s, 9H), 0.923 (appt, 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 = 8Hz), 5.12 (s , 2H), 5.18-5.28 (m, 1H), 5.33-5.67 (m, 2H); 31 P (121.4MH _{, CDCl 3) d30.4,31.2; MS (} m / z) 790.4 [M + Na] +.

(Example 92-AD)
(2- {4-[(1-Ethoxycarbonyl-ethylamine) -methoxy-phosphoryl] -but-2-enyl} -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-enyl} -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 (7.2 mg, 9.38 mmol) in THF (1 mL) To the solution was added TBAF (40 mL, 1M THF solution) at room temperature. The reaction mixture was stirred for 20 minutes, at which point the stirring material was completely converted to the desired product as determined by LCMS. The reaction mixture was dried under reduced pressure and redissolved in DMF. The product was purified by RP HPLC using a Phenomenex Synergi 5m Hydro RP 80A column (50 × 21.2 mm) with the eluent H _{2 O-CH} 3 CN. The fractions containing the desired product were _{pooled, H 2 O-MeOH (1} : 1) was further purified by Dowex 50WX8-400 was packaged into 4.5 cm × 2 cm column to elute the sodium salt, 3.2 mg of the desired product was obtained. ¹ H NMR (300 MHz, CD ₃ OD) d 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 (121.4MHz, CD 3 OD) d33.8,34.2 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 -Enyl] -4-methyl-hex-4-enoic acid)
2- [4- (Hydroxy-methoxy-phosphoryl) -but-2-enyl] -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3 -Dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanylethyl ester (11 mg, 0.016 mmol) in THF (1 mL) at room temperature with TBAF (50 mL, 1 M THF solution) was added. The solution was stirred for 16 hours and concentrated. The solution was dried in vacuo 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 Phenomenex Synergi 5m Hydrode using an eluent of H ₂ O, 0.1% TFA-CH ₃ CN, 0.1% TFA. Purified by RP HPLC using an RP 80A column (50 x 21.2 mm). 6. The product from the column was subjected to ion exchange chromatography (Sodium salt form of Dowex 50WX8-400) using a 2 × 4.5 cm column eluting with H ₂ O—MeOH (1: 1) as an oil. 5 mg of the desired product was obtained. 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 ) d 23.5; MS (m / z) 469.2 [M + H] ⁺ , 491.3 [M + Na] ⁺ .

  (Scheme III)

(Example 92-AF)
(2- [4- (Diethoxy-phosphoryl) -but-2-enyl] -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-enyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl A solution of -hex-4-enoic acid methyl ester (140 mg, 0.30 mmol) and triethyl phosphite (600 mg, 3.6 mmol) in toluene (30 mL) was stirred at reflux for 20 hours. The mixture was concentrated and chromatographed on silica gel eluting with ethyl acetate (60% to 100%) / hexane to give 2- [4- (diethoxy-phosphoryl) -but-2-enyl] -6- (4- Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester (70 mg, 43%) was obtained. 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-enyl] -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-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) A mixed solvent of THF (6 mL) and water (1 mL) containing a mixture of -4-methyl-hex-4-enoic acid methyl ester (33 mg, 0.063 mmol) and lithium hydroxide (44 mg) was stirred at room temperature for 6 hours. did. The organic solvent was removed and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous phase was acidified with 2N HCl and extracted with sodium acetate. The ethyl acetate extract is concentrated to give 2- [4- (diethoxy-phosphoryl) -but-2-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1, as an oil. 3-Dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid (30 mg, 100%) was obtained. 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-enyl] -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-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) A mixed solvent of methanol (3 mL) and water (1 mL) containing a mixture of -4-methyl-hex-4-enoic acid methyl ester (25 mg, 0.048 mmol) and lithium hydroxide (200 mg) was stirred at 70 ° C. for 2 hours. Stir. The organic phase was removed, acidified with 2N HCl and extracted with ethyl acetate / acetonitrile. The organic phase is concentrated and the residue is purified by reverse phase HPLC (acetonitrile and 0.1% aqueous CF ₃ COOH) to give 22- [4- (ethoxy-hydroxy-phosphoryl) -but-2-enyl]-as an oil. 6- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid (15 mg, 89%). Obtained. 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 (Figure 1)

Using the example shown in Scheme 2, compounds such as 1 can be made following the general route outlined in Scheme 1.

(1S) -1- (9-deazaguanine-9-yl) -1,4-dideoxy-1,4-imino-D-ribitol (WO 9,919,338 and Evans, GB et al., Tetrahedron , 2000, 56, 3053, Evans, GB et al., J. Med. Chem. 2003, 46, 3412) and Greene, T. Boc-protected (1S) -1- (9-deazaguanine-9-yl) -1,4-dideoxy-1,4 by agitation with BOC anhydride as described in, Protective groups in organic synthesis, Wiley-Interscience, 1999. -Prepare imino-D-ribitol (compound 1.1.1). Compound 1.1.1 is then treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyl triflate (prepared according to Tetrahedron Lett., 1986, 27, 1477) is added to give the desired phosphonate 1 after deprotection of the BOC group using trifluoroacetic acid (TFA) .

  Using the example shown in Scheme 4, compounds such as 2 and 3 can be made following the general route outlined in Scheme 3.

(1S) -1- (9-deazaguanine-9-yl) -1,4-dideoxy-1,4-imino-D-ribitol (WO 9,919,338 and Evans, GB et al., Tetrahedron , 2000, 56, 3053, Evans, GB et al., J. Med. Chem. 2003, 46, 3412) and Greene, T. Boc-protected (1S) -1- (9-deazaguanine-9-yl) -1,4-dideoxy-1,4 by agitation with BOC anhydride as described in, Protective groups in organic synthesis, Wiley-Interscience, 1999. -Prepare imino-D-ribitol (compound 1.1). Thereafter, Greene, T .; Protecting the primary alcohol using a solvent TBS group such as CH ₂ Cl ₂ containing TBSC1 and imidazole as described in Protective groups in organic synthesis, Wiley-Interscience, 1999 to give compound 1.1. Can do. Compound 1.1 is then treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Upon defoaming, diethylphosphonomethyl triflate (prepared according to Tetrahedron Lett., 1986, 27, 1477) was added and the desired phosphonate diesters 2 and 3 after deprotection of the BOC group using trifluoroacetic acid (TFA) Is obtained. Compounds 2 and 3 can also be prepared via a more complex 2'OH protected analog of 1.1, followed by alkylation using diethylphosphonomethyltriflate to give compound 2 exclusively. Preparing compound 3 by introduction of different protecting groups at the 3′OH position, followed by deprotection of 2′OH and alkylation with diethylphosphonomethyltriflate at the 2 ′ center, followed by global deprotection. You can also.

Example 94: Preparation of exemplary compounds of the invention (IV. Parent molecule)

The synthetic scheme for a specific target I is outlined below:
(Scheme I)

Recommended procedure for O-alkylation: Mix phenol and Cs ₂ CO ₃ in DMF (about 1: 1.2) and stir well at 0 ° C. for 30 minutes. Add triflate (1.2 eq). The reaction should be complete within 1 hour.

  Examples for trifluoromethanesulfonyloxymethylphosphonate are shown separately.

  Further compounds: The following target II is prepared after the initial biological evaluation of target I.

  (Scheme 2)

References for camptothecin-7-aldehyde: Chem. Pharm. Bull. 1991, 39, 2574.

  References on the reaction of Witting ylide with camptothecin aldehyde: Med. Chem. 2000, 43, 3963.

Example 95: Preparation of exemplary compounds of the invention (V. Parent molecule)

The synthetic scheme for a specific target I is outlined below:

References for reductive amination of anthracyclines: J. Am. Med. Chem. 1998, 41, 965.

  An experiment on an aldehyde intermediate from allyl phosphonate is shown.

  Further compounds: The following targets II and III are prepared after the initial biological evaluation of target I.

References on N-acylation of anthracyclines: Med. Chem. 1980, 23, 1166.

Example 96 Preparation of Exemplary Compounds of the Invention (Parent Molecule)

The synthesis schemes for specific targets I and II are outlined below.

References for the synthesis of target I: Org. Pro. Res. Dev. (Shows web publications).

  Further compounds: The following targets III and IV are prepared after the initial biological evaluation of targets I and II.

(Mycophenolate)
Representative compounds of the present invention having the following formula can be prepared as described in Examples 201-204.

For example, as shown by compounds D, E, and G above, three regions of mycophenolate mofetil can be used for phosphonate prodrug attachment. Also, as shown in Compound F, the carboxylic acid can be replaced with phosphonic acid.

  Example 201 Preparation of Representative Compound of Formula 204

Representative compounds of the present invention can be prepared as illustrated above. The morpholinoethyl moiety can be used as a prodrug functional group to improve bioavailability and can be replaced with a phosphonate prodrug handle as described above. Mycophenolate mofetil is described in, for example, Sigma Chemical Company, St. Commercially available from Louis, Mo. Activation of the carboxylic acid 201.1 in the presence of free phenol and subsequent addition of an alcohol carrying a phosphonate moiety gives 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. Thionyl chloride is added followed by a catalytic amount of DMF. The reaction mixture was stirred at room temperature for 3 hours, after which volatile components were removed in vacuo. The phosphonate-alcohol is dissolved in dichloromethane and cooled to about 4 ° C. on an ice bath. Dissolve mycophenolic acid chloride 201.2 in dichloromethane and add to the cooled solution. After stirring for 90 minutes at 4 ° C., the reaction mixture is washed with water followed by aqueous sodium bicarbonate. The organic solution is dried under reduced pressure to give phosphonate 201.3.

  Example 202 Preparation of Representative Compound of Formula 207

Representative compounds of the present invention can be prepared as illustrated above. As illustrated above, the C-4 phenol position provides a reaction handle for additional analogs. Once the 202.1 carboxylic acid is blocked by morpholinoethyl, such as in compound 202.2, it can be alkylated under basic conditions. A base such as pyridine, potassium carbonate, or triethylamine is used. A free radical such as trifluoromethyl sulfonate, mesylate, bromide, or iodide is attached to the phosphonate prodrug subunit and reacted with compound 202.2 in the presence of a base. Compound 202.3 can be used either directly or in the salt form (compound 202.4). Of the many salts that can be prepared, there are specific embodiments of chloride and bisulfate. Certain compounds of the invention can be prepared as follows.

Compound 202.5 is prepared analogously to compound 201.2 (described in Example 201). Cool the morpholinoethanol in dichloromethane to 4 ° C. Dissolve mycophenolic acid chloride 202.5 in dichloromethane and add to the cooled solution. This solution is stirred for 90 minutes to give compound 202.2. The reaction mixture is washed with water and dried over sodium sulfate. Removal of the solvent gives isolated compound 202.2. The phenolic position of 202.2 is alkylated by suspension of the compound in pyridine. Triflate 202.6 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. Removal of the organic phase gives compound 202.7. 202.7 hydrochloride is also prepared. Compound 202.7 is dissolved in isopropanol and the solution is added to a mixture of hydrochloric acid and isopropanol. The hydrochloride 202.8 is recovered by filtration and dried in vacuo.
Example 203 Preparation of Representative Compound of Formula 205

Representative compounds of the present invention can be prepared as illustrated above. The carboxylate salt of mycophenolic acid is replaced with a phosphonic acid that also serves as a prodrug handle. To remove the carboxylic acid containing side chains, the acid chloride 202.5 (prepared in Example 202) is converted to the ester 203.1. Protection of the phenol with a silyl group followed by dihydroxylation and diol cleavage gives aldehyde 203.3 (Pankiewicz, et al., J. Med. Chem., 2002, 45, 703), (Patterson et al. al., U.S. 5,444,072) (Example 20). A wittig reaction using ylide 203.4 carrying an appropriately protected phosphonate provides the desired compound 203.5. Final deprotection gives compound 203.6. Certain compounds of the present invention can be prepared as follows.

Mycophenolic acid ester 203.8 is prepared by stirring acid chloride 203.7 with MeOH. Then, the phenol position of the mycophenolic acid ester is protected with a silyl group such as TBS to give compound 203.9. Once the phenolic position is protected, dihydroxylation using osmium tetroxide and subsequent cleavage of the periodate affords aldehyde 203.10. The aldehyde 203.10 and excess ylide 203.11 are 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. (Pankiewicz et al., J. Med. Chem., 2002, 45, 703). Final deprotection using HF-pyridine gives the final product 203.13.

  Example 204 Preparation of Representative Compounds of Formula 208

Representative compounds of the present invention can be prepared as illustrated above. As illustrated above, another point of attachment of the compound can be unmasked after demethylation of the mycophenolate 204.2. For this purpose, 4-OH is masked with a protecting group (P) such as a silyl group. Once 6-MeO is demethylated and alkylated, the 4-position protecting group is removed to give the final product 204.4. Initially, a morpholethanol group is introduced to complete the alkylation step. Different protecting groups can be introduced first and then removed. In such latter synthetic form, the last step is the formation of a morpholino ethyl ester prodrug. Certain compounds of the invention can be prepared as follows.

To obtain 204.6 using imidazole as base, phenol 204.5 is protected with a TBS group in CH ₂ Cl ₂ . Demethylation using a thiolate nucleophile gives compound 204.7. Various other methods in the literature are also available, such as described in Greene and Wuts' protective groups in organic synthesis. In order to obtain 204.8 using K ₂ CO ₃ or TEA, the alkylation of 6-OH using phosphonate triflate is allowed to proceed sufficiently. Final deprotection to remove the TBS group gives product 204.9.

  Example 251: Preparation of representative compounds of the invention

Representative compounds of the present invention can be prepared as illustrated above.

([4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid Diisopropyl ester)
7-hydroxy-6- (4-hydroxy-3-methyl-but-2-enyl) -5-methoxy-4-methyl-3H-isobenzofuran-1-one 1A (50 mg, 0.18 mmol, Pankiewicz et al. , J. Med. Heat at 5 ° C. for 5 hours. The reaction was quenched with 1N HCl. The mixture was poured into 5% aqueous lithium chloride solution, extracted with ethyl acetate and concentrated. The residue was purified by silica gel chromatography to give [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2. -Enyloxymethyl] -phosphonic acid diisopropyl ester 1B (25 mg, 32%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 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-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid and [4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid Monoisopropyl ester)
[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -diisopropylphosphonate To an acetonitrile solution of ester 1B (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 room temperature and stirred for 4 hours. The reaction was quenched with methanol at 0 ° C. and the resulting mixture was concentrated. The residue was purified by separation reverse phase HPLC and after removal of the solvent as an oil [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)- 2-Methyl-but-2-enyloxymethyl] -phosphonic acid 1C (17 mg, 83%); ¹ H NMR (300 MHz, CD ₃ OD) d1.81 (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) and as oil [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5 Yl) -2-methyl-but-2-enyloxime Cyl] -phosphonic acid monoisopropyl ester 1D (2 mg, 7%) was obtained. 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 invention can be prepared as illustrated below.

([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 tetramethylmethylene diphosphonate (102 mg, 0.44 mmol) in THF (2.5 mL) was added sodium bis (trimethylsilyl) amide (1.0 M, 0.44 mL) in THF. After stirring for 30 minutes, 4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enal 2A ( 30 mg, 0.11 mmol, Pankiewicz et al., J. Med. Chem., 45,703) in THF (2.5 mL) was added and stirring continued for an additional 15 minutes. The reaction was quenched 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 (50-100%) / hexane to give [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo- as an oil. 1,3-Dihydro-isobenzofuran-5-yl) -3-methyl-penta-1,3-dienyl] -phosphonic acid dimethyl ester 2B (30 mg, 71%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 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-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-1,3-dienyl] -dimethylphosphonate To an acetonitrile solution of Este 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) at 0 ° C. The mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched with methanol at 0 ° C. and the resulting mixture was concentrated. The residue was purified by separation reverse phase HPLC, the solvent was removed and [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl as a solid] ) -3-Methyl-penta-1,3-dienyl] -phosphonic acid 2C (13 mg, 65%) was obtained. ¹ H NMR (300 MHz, CD ₃ OD) d 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 invention can be prepared as illustrated below.

(6- (4-Bromo-3-methyl-but-2-enyl) -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-enyl) -5-methoxy-4-methyl-3H-isobenzofuran-1-one 1A (100 mg, 0.36 mmol) and tetrabromide Carbon (143 mg, 0.43 mmol) was added continuously and the mixture was shaken for 1 hour at room temperature. Additional carbon tetrabromide (143 mg, 0.43 mmol) was added and the mixture was shaken for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (0% to 60% ethyl acetate / hexane) to give 6- (4-bromo-3-methyl-but-2-enyl) -7-hydroxy-5-methoxy-4-methyl as an oil. -3H-isobenzofuran-1-one 3B (52 mg, 42%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 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-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -phosphonic acid diethyl ester )
n-Butyllithium (1.6 M hexane solution, 1 mL) was added to the same volume of THF at −20 ° C. A solution of diethyl methylphosphonate (220 mg, 1.45 mmol) in THF (1 mL) was then 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-enyl) -7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one 3B (50 mg, 0.15 mmol) in THF (1 mL) ) The solution was added and the mixture was warmed at 0 ° C. for 2 hours, after which 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 subjected to silica gel chromatography (40% -100% ethyl acetate / hexane) to give [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1] as an oil. , 3-Dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -phosphonic acid diethyl ester 3C (27 mg, containing starting diethyl methylphosphonate). ¹ H NMR (300 MHz, CDCl ₃ ) d 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, 1 H), 7.65 (s, 1 H) ppm.

([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] -phosphonic acid diethyl ester 3C A mixture of (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 separated reverse phase HPLC (acetonitrile and 0.1% aqueous CF ₃ COOH) to give [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) d 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-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -phosphonic acid)
{5- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-sobenzofuran-5-yl] -3-methyl-pent-3- Enil} -phosphonic acid diethyl ester (20 mg, 0.039 mmol) in DMF (0.5 mL) and DCM (0.5 mL) was added to TMSBr (50.5 mL, 0.39 mmol) and then 2,6-lutidine (45 .3 mL, 0.39 mmol) was added. The reaction was allowed to proceed for 1 hour, at which point the reaction was complete as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by reverse phase HPLC. The filtrate containing the desired product was concentrated and treated with 10% TFA / DCM for 5 minutes. After concentration, the residue was purified by separation reverse phase HPLC to yield 7 mg (50%) of [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran as a solid. -5-yl) -3-methyl-pent-3-enyl] -phosphonic acid was obtained. ¹ H NMR (300 MHz, CD ₃ OD) d 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) d 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 invention can be prepared as illustrated below.

(2- (4-Bromo-but-2-enyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4- Methyl-hex-4-enoic acid methyl ester)
To a cooled (−78 ^° C.) mycophenolic acid methyl ester 4A (138 mg, 0.41 mmol) solution in THF (2.5 mL), sodium bis (trimethylsilyl) amide (1.0 M, 0.98 mL) in THF 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 was continued for 10 minutes. The resulting mixture was warmed to −30 ° C. and this temperature was maintained for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate and a residue was obtained after evaporation of the solution, which was purified by silica gel chromatography eluting with ethyl acetate (0% to 40%) / hexane to give 2- (4-bromo-butene as an oil. -2-enyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl Ester 4B (150 mg, 78%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 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) -but-2-enyl] -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-enyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl -A solution of hex-4-enoic acid methyl ester 4B (140 mg, 0.30 mmol) and triethyl phosphite (600 mg, 3.6 mmol) in toluene (30 mL) was stirred under reflux for 20 hours. The mixture was concentrated and chromatographed on silica gel eluting with ethyl acetate (60% to 100%) / hexane to give 2- [4- (diethoxy-phosphoryl) -but-2-enyl] -6- (4 as an oil. -Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester 4C (70 mg, 43%) was obtained. It was. ¹ H NMR (300 MHz, CDCl ₃ ) d 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-enyl] -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-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) A solution of THF (6 mL) and water (1 mL) containing a mixture of -4-methyl-hex-4-enoic acid methyl ester 4C (33 mg, 0.063 mmol) and lithium hydroxide (44 mg) was stirred at room temperature for 6 hours. did. The organic solvent was removed and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate extract is concentrated to give 2- [4- (diethoxy-phosphoryl) -but-2-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1, as an oil. 3-Dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid 4D (30 mg, 100%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 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) -but-2-enyl] -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-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) A mixture of methanol (3 mL) and water (1 mL) containing a mixture of -4-methyl-hex-4-enoic acid methyl ester 4C (25 mg, 0.048 mmol) and lithium hydroxide (200 mg) was added at 70 ° C. Stir for hours. The organic phase was evaporated, acidified with 2N HCl and extracted with ethyl acetate / acetonitrile. The organic phase is concentrated and the residue is purified by reverse phase HPLC (acetonitrile and 0.1% aqueous CF ₃ COOH) to give 2- [4- (ethoxy-hydroxy-phosphoryl) -but-2-enyl]-as an oil. 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%) Got. ¹ H NMR (300 MHz, CD ₃ OD) d 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) -but-2-enyl] -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-enyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5 Yl) -4-methyl-hex-4-enoic acid methyl ester (490 mg, 1.05 mmol) in trimethyl phosphite (2.5 mL, 21.1 mmol) was heated at 120 ° C. for 1 h. The reaction was cooled to room temperature. The reaction mixture was worked up by removal of the solvent in vacuo and chromatography using EtOAc-hexanes to give 460 mg (88%) of product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 1.77 (s, 3H), 2.081-2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H, J = 22Hz), 2.54 (d, 1H, J = 22Hz), 2.55-2.63 (m, 1H), 3.36 (d, 2H, J = 7Hz), 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, 1 H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) d 30.1 ppm; MS (m / z) 497.2 [M + H] ⁺ , 519. 2 [M + Na] ⁺ .

(2- [4- (Dimethoxy-phosphoryl) -but-2-enyl] -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-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) 4-methyl - hex-4-enoic acid methyl ester (460mg, 0.927mmol) _H 2 O containing, MeOH, the THF 1: 1: 2 solution (8 mL) LiOH. Stir with H ₂ O (78 mg, 1.86 mmol) at ambient temperature for 12 hours. LiOH. A _second batch of H ₂ O (40 mg, 0.952 mmol) was added. The reaction mixture was stirred at room temperature for an additional 16 hours, after which time the reaction did not proceed further. The reaction was quenched by the addition of saturated aqueous NH ₄ Cl. The organic phase was removed under reduced pressure and the product was extracted from the aqueous phase acidified by oxidation of 5 drops of 2N HCl with EtOAc. The product was further purified by chromatography to give the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) d 1.79 (s, 3H), 2.08-2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J = 22 Hz), 2.60 (d, 1 H, J = 22 Hz), 2.57-2.64 (m, 1 H), 3.38 (d, 2 H, J = 7 Hz), 3.72 (d, 6 H) , 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 ) d 30.5 ppm; MS (m / z) 481.2 [M−H] ⁻ .

(2- [4- (2- [4- (Dimethoxy-phosphoryl) -but-2-enyl] -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-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) To a solution of -4-methyl-hex-4-enoic acid (25 mg, 0.052 mmol) in acetonitrile (2 mL) was added 2,6-lutidine (60 mL, 0.52 mmol) and TMSBr (67 mL, 0.52 mmol). . The reaction was allowed to proceed for 45 minutes, at which point the reaction was complete as judged by LCMS. The reaction mixture was concentrated under reduced pressure and quenched with aqueous NaOH (1 mL). 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 yield 14.2 mg (60%) as a solid I got a thing. ¹ H NMR (300 MHz, CD ₃ OD) d1.81 (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) d25 .4 ppm; MS (m / z) 453 [M−H] ⁻ .

(2- [4- (Dimethoxy-phosphoryl) -but-2-enyl] -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-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) A solution of -4-methyl-hex-4-enoic acid (160 mg, 0.332 mmol) and trimethylsilylethanol (160 mg, 1.36 mmol) in THF (8.00 mL) was stirred with triphenylphosphine (345 mg, 1.33 mmol). did. To this solution was added diethyl azocarboxylate (230 mL, 1.33 mmol) at 0 ° C. The mixture was warmed to room temperature and stirred for 16 hours. Additional triphenylphosphine (180 mg, 0.692 mmol), trimethylsilylethanol (160 mg, 1.36 mmol), and diethyl azocarboxylate (115 mL, 0.665 mmol) were added and the reaction mixture was stirred at room temperature for an additional day. The reaction was worked up by removal of the solvent under reduced pressure and purification of the residue by silica gel chromatography to give 192 mg (85%) of product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (app t, 2H, J = 8 Hz), 4.30 (app t, 2H, J = 8 Hz), 5.12 (s, 2H), 5.15-5 .25 (m, 1H), 5.36-5.63 (m, 2H) ppm; 31 P (121.4MHz, CDCl 3) d29.3ppm; MS (m / ^{) 705.3 [M + Na] +} .

(2- [4- (hydroxy-methoxy-phosphoryl) -but-2-enyl] -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-enyl] -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 (184 mg, 0.270 mmol) in tert-butylamine (2.8 mL, 27 mmol) For 24 hours. The solution was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography using MeOH / CH ₂ Cl ₂ (0-30%) to give 75 mg of product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (brt, 1H, J = 6 Hz) ), 5.33-5.56 (m, 2H) , 8.49 (br s, 1H) ppm; 31 P (121.4MHz, CDCl ) D22.1ppm; MS (m / z ) 667.4 [M + Na] +.

(2- {4-[(1-Ethoxycarbonyl-ethoxy) -methoxy-phosphoryl] -but-2-enyl} -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsila Nyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester)
2- [4- (Hydroxy-methoxy-phosphoryl) -but-2-enyl] -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 (67 mg, 0.10 mmol) and PyBOP (234 mg, 0.450 mmol) in DMF (1. 5 mL) solution was stirred with (S)-(−)-ethyl lactate (53 mg, 0.45 mmol) and DIEA (174 mL, 1.00 mmol) at ambient temperature, at which point the starting material consumption was complete. Admitted. The reaction was completed by the addition of saturated aqueous sodium chloride and ethyl acetate. The organic phase was separated and washed with 5% aqueous lithium chloride. The organic phase 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 ) d 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), 5.1 2 (s, 2H), 5.19 (brt, 1H, J = 6 Hz), 5.33-5.61 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) d28.9, 29 .9 ppm; MS (m / z) 791.4 [M + Na] ⁺ .

(2- {4-[(1-Ethoxycarbonyl-ethoxy) -methoxy-phosphoryl] -but-2-enyl} -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-enyl} -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 (14 mg, 0.018 mmol) in THF (1 mL) 1 MTBAF in THF (55 mL, 0.055 mmol) was stirred for 1 hour. The reaction mixture was concentrated, acidified with 1N HCl and extracted with EtOAc. The organic phase was washed with brine and dried. The product was purified by silica gel chromatography with EtOH-EtOAc (0-10%). Further purification was obtained by dissolving the product in CH ₂ Cl ₂ and passing the product through a 13 mm Acrodisc syringe filter equipped with a 0.45 mm nylon membrane to give 8 mg (77%) of product. _{^{1 H NMR (300MHz, CDCl 3}} ) d0.92 (t, 3H, J = 7Hz), 1.30 (d, 3H, J = 8Hz), 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 (brt, 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 (121.4MHz, CDCl 3) d29. , 30.1ppm; MS (m / z ) 569.2 [M + H] +, 591.3 [M + Na] +.

(2- {4-[(1-carboxy-ethoxy) -hydroxy-phosphoryl] -but-2-enyl} -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-enyl} -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl) -Ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanylethyl ester (12 mg, 0.016 mmol) in tert-butylamine (1 mL, 9 .6 mmol) solution was heated at 65 ° C. for 16 hours. The solution was cooled to room temperature and concentrated to give the crude product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 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, 2 H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) d 28.9 ppm; MS (m / z) 725.3 [M−H] ⁻ .

(2- {4-[(1-carboxy-ethoxy) -hydroxy-phosphoryl] -but-2-enyl} -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-enyl} -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 (AC-2101-59) and tetrabutylammonium fluoride A THF (1 M, 54 mL, 0.054 mmol) solution was stirred in THF (1 mL) at ambient temperature for 2 hours, at which point a THF (54 mL, 0.054 mmol) solution containing excess tetrabutylammonium fluoride was added. Added. The reaction was stirred for an additional 16 hours by which time the reaction was complete. The reaction mixture was concentrated under reduced pressure and reverse using a Phenomenex Synergi 5m Hydro RP 80A column (50 × 21.2 mm) with an eluent of H ₂ O, 0.1% TFA-CH ₃ CN, 0.1% TFA. The product was purified by phase HPLC to give the product (8.0 mg) as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (brs, 1H), 5. 20 (s, 2H), 5.21-5.30 (m, 1H), 5.33-5.63 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) d 27.7 ppm; MS ( m / z) 525.2 [M−H] ⁻ .

(2- {4-[(1-Ethoxycarbonyl-ethylamine) -methoxy-phosphoryl] -but-2-enyl} -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsila Nyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester)
2- [4- (Hydroxy-methoxy-phosphoryl) -but-2-enyl] -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 (20 mg, 0.030 mmol) and PyBOP (62.4 mg, 0.120 mmol) in DMF ( 1.0 mL) solution was stirred with L-alanine ethyl ester hydrochloride (18 mg, 0.12 mmol) and DIEA (26 mL, 0.15 mmol) for 1 hour at ambient temperature, at which point complete consumption of starting material was observed. It was. The reaction was completed 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 Acrodisc (13 mm syringe filter with 0.45 mm nylon membrane) and by reverse phase HPLC using a Phenomenex Synergi 5m Hydro RP 80A column (50 × 21.2 mm) eluting with water and acetonitrile. Purified. Fractions containing product were pooled and dried in vacuo to remove acetonitrile. The remaining 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 ) d 0.03 (s, 9H), 0.05 (s, 9H), 0.923 (appt, 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 = 8Hz), 5.12 (s , 2H), 5.18-5.28 (m, 1H), 5.33-5.67 (m, 2H) ppm; 31 P (121. _{MHz, CDCl 3) d30.4,31.2ppm; MS} (m / z) 790.4 [M + Na] +.

(2- {4-[(1-Ethoxycarbonyl-ethylamine) -methoxy-phosphoryl] -but-2-enyl} -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-enyl} -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 (7.2 mg, 9.38 mmol) in THF (1 mL) To the solution was added TBAF (40 mL, 1M THF solution) at room temperature. The reaction mixture was stirred for 20 minutes at which point the starting material was completely converted to the desired product as determined by LCMS. The reaction mixture was dried under reduced pressure and redissolved in DMF. The product was purified by RP HPLC using a Phenomenex Synergi 5m Hydro RP 80A column (50 × 21.2 mm) with the eluent H _{2 O-CH} 3 CN. The fractions containing the desired product were _{pooled, H 2 O-MeOH (1} : 1) was further purified by Dowex 50WX8-400 was packaged into 4.5 cm × 2 cm column to elute the sodium salt, 3.2 mg of the desired product was obtained. ¹ H NMR (300 MHz, CD ₃ OD) d 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 (121.4MHz, CD 3 OD) d33.8,34. 2 ppm; MS (m / z) 568.2 [M + H] ⁺ , 590.3 [M + Na] ⁺ .

(6- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2- [4- (hydroxy-methoxy-phosphoryl) -but-2 -Enyl] -4-methyl-hex-4-enoic acid)
2- [4- (Hydroxy-methoxy-phosphoryl) -but-2-enyl] -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 (11 mg, 0.016 mmol) in THF (1 mL) at room temperature with TBAF (50 mL, 1 M THF solution) was added. The solution was stirred for 16 hours and concentrated. The solution was dried in vacuo 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 Phenomenex Synergi 5m Hydrode using an eluent of H ₂ O, 0.1% TFA-CH ₃ CN, 0.1% TFA. Purified by RP HPLC using an RP 80A column (50 x 21.2 mm). 6. The product from the column was subjected to ion exchange chromatography (Sodium salt form of Dowex 50WX8-400) using a 2 × 4.5 cm column eluting with H ₂ O—MeOH (1: 1) as an oil. 5 mg of the desired product was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 ) d 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-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4- Enic acid methyl ester)
6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester (222 mg , 0.66 mmol), triphenylphosphine (260 mg, 0.996 mmol), and diethylazocarboxylate (173 mg, 0.996 mmol) in THF (3 mL) were added trimethylsilylethanol (142 mL, 0.996 mmol) in THF (3 mL). ) The solution was added. The resulting yellow solution was warmed to room temperature and stirred overnight. The reaction was concentrated to dryness and ether and hexane were added. Triphenylphosphine oxide was removed by filtration 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 ) d 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, 1H) ppm.

([6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde)
Smith, D.M. B. et al. , J .; Org. Chem. , 1996, 61, 6, 2236, 6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5. A solution of -yl] -4-methyl-hex-4-enoic acid methyl ester (618 mg, 1.42 mmol) in MeOH (10 mL), CH ₂ Cl ₂ (10 mL), and pyridine (50 mL, 0.618 mmol) Cool to -70 ° C using a dry ice / acetone bath. The reaction was bubbled through a stream of ozone with a gas dispersion tube until the reaction turned blue (15 minutes). The ozone line was replaced with a stream of nitrogen and continued to bubble for an additional 15 minutes until the blue color disappeared. To this solution at −70 ° C., thiourea (75.7 mg, 0.994 mmol) was added in one portion and the cooling bath was removed. The reaction was warmed to room temperature and stirred for 15 hours. The reaction was worked up by partitioning between filtration and subsequent CH ₂ Cl ₂ and water to remove solid thiourea S- dioxide. The organic phase was removed. The aqueous phase was washed once more with CH ₂ Cl ₂ and the organic extracts were combined. The organic phase was washed with 1N HCl, saturated NaHCO ₃ , and brine. The organic extract was dried in vacuo and the residue purified by silica gel chromatography to give 357 mg (75%) of product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) d -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-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] -acetaldehyde (70 mg, 0 in toluene (2 mL). .21 mmol) was heated with 2- (triphenylphosphanylidene) -propionaldehyde (72.9 mg, 0.23 mmol) at 100 ° C. overnight. A second portion of 2- (triphenylphosphanylidene) -propionaldehyde (33 mg, 0.11 mmol) was added and the reaction mixture was heated for an additional day. After concentration, the residue was purified by silica gel chromatography to give 54 mg (83%) of the desired product as a pale yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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-but-2-enyl) -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] -2-methyl-but-2-enal A solution of (103 mg, 0.27 mmol) in methanol (5 mL) 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 THF solution). The ice bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture was stirred for an additional 40 minutes, immediately after which completion of starting aldehyde consumption was observed by TLC. The reaction was worked up by the addition of 1N aqueous HCl (0.5 mL) and the product was extracted with CH ₂ Cl ₂ . The organic phase was washed with saturated aqueous sodium bicarbonate and brine. The organic phase was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give 100 mg (97%) product as a clear liquid. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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-one)
[6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde (97 mg, 0.29 mmol) in THF ( To the solution, an aliquot of 2M LiBH ₄ in THF (150 mL, 0.300 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, at which point TLC showed complete consumption of starting material. The reaction mixture was worked up by addition of 1N aqueous HCl and extraction with EtOAc. The organic phase was dried under reduced pressure and the residue was purified by silica gel chromatography to give the product. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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-dihydro-isobenzofuran-5-yl] -ethoxymethyl} -phosphonic acid diisopropyl ester)
A mixture of 6- (2-hydroxy-ethyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (79 mg, 0.23 mmol) was added to DMF. (2 mL) was heated with bromomethylphosphonic acid diisopropyl ester (120 mg, 0.46 mmol) in the presence of lithium t-butoxide (22 mg, 0.27 mmol) at 70 ° C. overnight. The reaction mixture is purified by reverse phase HPLC (acetonitrile and 0.1% CF ₃ COOH aqueous solution) to give the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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 invention can be prepared as illustrated below.

([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) -1,3-dihydro-isobenzofuran-5-yl] -ethoxymethyl} -phosphonic acid diisopropyl ester To a solution of (7.5 mg, 0.014 mmol) in acetonitrile (2 mL) and 2,6-lutidine (25 mL, 0.21 mmol) was added trimethylsilyl bromide (27 mL, 0.21 mmol) at room temperature. The reaction was allowed to proceed for 18 hours, at which time LCMS indicated the reaction was complete. The reaction was quenched by the addition of MeOH and concentrated. The residue was purified by reverse phase HPLC using a C18 column. The recovered product was suspended in a 10% TFA / CH ₂ Cl ₂ solution to ensure complete deprotection. The reaction mixture was lyophilized to give the desired product. ¹ H NMR (300 MHz, CD ₃ OD) d2.12 (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 invention can be prepared as illustrated below.

(6- (4-Bromo-3-methyl-but-2-enyl) -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-enyl) -5-methoxy-4-methyl-3H-isobenzofuran-1-one (100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) was added continuously and the mixture was shaken for 1 hour at room temperature. Additional carbon tetrabromide (143 mg, 0.43 mmol) was added and the mixture was shaken for an additional hour. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (0% to 60% ethyl acetate / hexane) to give 6- (4-bromo-3-methyl-but-2-enyl) -7-hydroxy-5-methoxy-4-methyl as an oil. -3H-isobenzofuran-1-one (52 mg, 42%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 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-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl] -phosphonic acid dimethyl ester 6 -(4-Bromo-3-methyl-but-2-enyl) -7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one (33 mg, 0.097 mmol) trimethyl phosphite ( (1.0 mL, 8.5 mmol) solution was heated at 100 ° C. for 1 h, immediately after which LCMS indicated completion of the reaction. The reaction was worked up by removal of 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 ) d 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, 6 H, J = 11 Hz), 3.72 (s, 3 H), 5.14 (s, 2 H), 5.33 (q, 1 H, J = 6 Hz), 7.65 (Br s, 1 H) ppm; MS (m / z) 371 [M + H] ⁺ .

Example 257: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

([4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl] -phosphonic acid)
[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl] -phosphonic acid dimethyl ester ( TMSBr (63 mL, 0.49 mmol) and 2,6-lutidine (85 mL, 0.73 mmol) were added to a solution of 18 mg, 0.049 mmol) in acetonitrile (2 mL) at 0 ° C. The reaction was warmed to room temperature and stirred for 2 hours, at which time LCMS indicated completion of the reaction. The reaction was cooled to 0 ° C. and quenched by the addition of MeOH. The reaction mixture was dried under reduced pressure, for 20 minutes _H 2 O-acetonitrile gradient (5-0%) The residue was purified by RP HPLC using a C18 column using the product of 12.2 mg (73%) Obtained. ¹ H NMR (300 MHz, CD ₃ OD) d 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, 3 H), 5.24 (s, 2 H), 5.38 (q, 1 H, J = 7 Hz), 6.87 (br s, 1 H) ppm; MS (m / z) 341 [M−H] ⁻ .

Example 258: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

([4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid Monophenyl ester and [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -Phosphonic acid diphenyl ester)
[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid ( 49 mg, 0.13 mmol) in DMF (0.4 mL) and phenol (62 mg, 0.65 mmol) in DMF containing dicyclohexylcarbodiimide (107 mg, 0.52 mmol) and DMAP (8 mg, 0.065 mmol) at 0 ° C. 0.6 mL) was added slowly. The reaction was warmed to room temperature and heated at 140 ° C. for 10 hours. After cooling to room temperature, the mixture was filtered and extracted with 1N aqueous NaOH. The aqueous phase was acidified with 1N HCl and extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by RP HPLC to yield 18.5 mg of [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) as a pale yellow solid. 2-methyl-but-2-enyloxymethyl] -phosphonic acid monophenyl ester (main product, Example 8) and 4.1 mg of [4- (4-hydroxy-6-methoxy-7] as a pale yellow solid -Methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid diphenyl ester (byproduct) was also obtained. Main products: ¹ H NMR (300 MHz, CD ₃ OD) d 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) d 17.3 ppm; MS (m / z) 449.0 [ M + H] ⁺ , 471.2 [M + Na] ⁺ . By-products: ¹ H NMR (300 MHz, CD ₃ OD) d1.82 (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) d 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 invention can be prepared as illustrated below.

(2-{[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -Phenoxy-phosphinoyloxy} -propionic acid ethyl ester)
[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid mono To a solution of phenyl ester (18.5 mg, 0.040 mmol) and (S)-(−)-ethyl lactate (47 mL, 0.400 mmol) in pyridine (0.5 mL) was added PyBOP (32 mg, 0.060 mmol). . The solution was stirred at room temperature for 1 hour, at which point additional PyBOP (21 mg, 0.040 mmol) was added. The solution was stirred for an additional 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) d 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, 1 H), 7.15-7.27 (m, 3 H), 7.33-7.41 (m, 2 H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) d 18.9, 20.3 ppm (diastereomer at phosphorus); MS (m / z) 549.2 [M + H] ⁺ , 571.3 [M + Na] ⁺ .

Example 260 Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

(2-{[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -Phenoxy-phosphinoylamino} -propionic acid ethyl ester)
[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid mono To a solution of phenyl ester (20 mg, 0.045 mmol) and L-alanine ethyl ester hydrochloride (68.5 mg, 0.45 mmol) in pyridine (1.0 mL) was added PyBOP (70 mg, 0.14 mmol). After stirring overnight, the mixture was concentrated 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 a colorless gel. As a result, 3.6 mg of product was obtained. ¹ H NMR (300 MHz, CD ₃ OD) d 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) d 24.1, 25.0 ppm (diastereo with phosphorus) MS) (m / z) 546.2 [M-H] ⁺ .

Example 261: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

([4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid Monomethyl ester)
[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -diphenylphosphonate To a solution of ester (53 mg, 0.1 mmol) in methanol (0.5 mL) was added 1N aqueous NaOH (300 mL). After overnight stirring, the mixture was concentrated 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 monophosphonate. Along with phenyl ester (7 mg) and phosphonic acid dimethyl ester (14.5 mg), 5 mg of product was obtained as a colorless gel. ¹ H NMR (300 MHz, CD ₃ OD) d 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, 1 H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CD ₃ OD) d 21.5 ppm; MS (m / z) 385.2 [M−H] ⁺ , 387.1 [M + H] ⁺ .

Example 262: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

((2- {4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl- But-2-enylamino} -ethyl) -phosphonic acid diethyl ester)
4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2-enal (84 mg, 0.22 mmol), (2-amino-ethyl) -phosphonic acid diethyl ester oxalate (91 mg, 0.33 mmol), and sodium triacetoxyborohydride (93 mg, 0.44 mmol) in DMF (1.5 mL) ) Acetic acid (60 mL, 1.0 mmol) was added to the solution at room temperature. The solution was stirred for 2 days at which time the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and EtOAc. The organic phase 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 product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 ) d 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-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enylamino] -ethyl } -Phosphonic acid)
(2- {4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but A solution of 2-enylamino} -ethyl) -phosphonic acid diethyl ester (30 mg, 0.055 mmol), TMSBr (72 mL, 0.55 mmol), and 2,6-lutidine (64 mL, 0.55 mmol) was added to CH ₂ Cl ₂ (1 mL) and DMF (0.5 mL) were stirred at ambient temperature for 1 hour. The reaction mixture 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 7.8 mg of product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) d 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 = 7Hz) ppm;} 31 P (121.4MHz, CD 3 OD) d20.2ppm; 19 F NMR (282.6MHz, CD 3 OD) d-74.0ppm; MS (m / z) 386.3 [M + H] ⁺ .

Example 263: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

([2- (Methanesulfonyl- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl]- 2-methyl-but-2-enyl} -amino) -ethyl] -phosphonic acid diethyl ester)
(2- {4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but -2-enylamino} -ethyl) -phosphonic acid diethyl ester (45 mg, 0.092 mmol) in CH ₂ Cl ₂ (0.5 mL) was added methanesulfonyl chloride (21 mL, 0.28 mmol) and pyridine (45 mL) at ambient temperature. (mL, 0.55 mmol) and stirred overnight. The reaction was stopped by the addition of 2 drops of water. The reaction mixture was concentrated and purified by RP HPLC using a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA to yield 36 mg of product (63% ) ¹ H NMR (300 MHz, CDCl ₃ ) d 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) d 27.5 ppm; MS (m / z) 642. 2 [M + Na] ⁺ .

((2-{[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl]- Methanesulfonyl-amino} -ethyl) -phosphonic acid)
[2- (Methanesulfonyl- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2 -Methyl-but-2-enyl} -amino) -ethyl] -phosphonic acid diethyl ester (18 mg, 0.029 mmol) in acetonitrile (0.5 mL) was added TMSBr (38 mL, 0.29 mmol) and 2,6- Stir with lutidine (34 mL, 0.29 mmol) at room temperature for 2 hours. The reaction was worked up by addition of EtOAc and 1N HCl. The organic phase was washed with brine and the solvent was removed under reduced pressure. The residue was suspended 10 minutes in 10% _{TFA-CH 2} Cl 2 solution, then dried, (73%) of 9.9mg as a white solid of the desired product. ¹ H NMR (300 MHz, DMSO-d6) d 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, 1 H) ppm; ³¹ P (121.4 MHz, DMSO-d6) d 21.4 ppm; MS (m / z) 464.1 [M + H] ⁺ .

Example 264: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

([2- (Acetyl- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2 -Methyl-but-2-enyl} -amino) -ethyl] -phosphonic acid diethyl ester)
(2- {4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but Acetic anhydride (0.5 mL) was added to a solution of 2-enylamino} -ethyl) -phosphonic acid diethyl ester (32 mg, 0.059 mmol) in acetic acid (0.5 mL). The solution was stirred at room temperature for 90 minutes, at which point the reaction was quenched by the addition of 2 drops of water. The solution was removed 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 as a clear gel. (81%) was obtained. The NMR data of this compound show two 70:30 rotamers. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (121.4MHz, CDCl 3) d27.5 and 28 MS (m / z) 584.1 [M + H] ⁺ , 606.2 [M + Na] ⁺ .

((2- {Acetyl- [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl ] -Amino} -ethyl) -phosphonic acid)
[2- (acetyl- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2- Methyl-but-2-enyl} -amino) -ethyl] -phosphonic acid diethyl ester (14 mg, 0.024 mmol) in acetonitrile (0.5 mL) was added to TMSBr (31 mL, 0.24 mmol) and 2,6-lutidine. (28 mL, 0.24 mmol) was added. The solution was stirred at room temperature for 1 hour. The reaction was quenched by the addition of methanol and 1N HCl. The product was extracted with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ 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 5.4 mg of product (53%) as a white solid Got. The NMR data for one compound shows two rotamers. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (brs, 2H), 5.17 (s, 2H), 5.31 (brs, 1H) ppm; ³¹ P (121 .4 MHz, CDCl ₃ ) d 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 invention can be prepared as illustrated below.

([2- (benzyl- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2 -Methyl-but-2-enyl} -amino) -ethyl] -phosphonic acid diethyl ester)
(2- {4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but A solution of 2-enylamino} -ethyl) -phosphonic acid diethyl ester (30 mg, 0.055 mmol), benzaldehyde (5.6 mL, 0.055 mmol), and sodium triacetoxyborohydride (23 mg, 0.11 mmol) , Acetic acid (15.7 mL, 0.28 mmol) in DMF (0.5 mL) and stirred overnight at room temperature. The reaction was quenched with 10% aqueous Na ₂ CO ₃ and the product was extracted with EtOAc. The organic phase 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 of product (43%) as a clear gel. Obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (brd, 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 (121.4MHz, CDCl 3) d 30.9ppm; MS ( m / z) 632.4 [M + H] ⁺ , 654.3 [M + Na] ⁺ .

((2- {benzyl- [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl ] -Amino} -ethyl) -phosphonic acid)
(2- {4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but 2-enylamino} -ethyl) -phosphonic acid diethyl ester (15 mg, 0.024 mmol) in acetonitrile (0.5 mL) was added TMSBr (31 mL, 0.24 mmol) and 2,6-lutidine (28 mL, 0 mL). .24 mmol). The solution was stirred at ambient temperature for 1 hour, at which point the reaction was quenched with methanol. The solvent was removed in vacuo and purified by RP HPLC using a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA to give 11 mg of product (93% ) ¹ H NMR (300 MHz, CD ₃ OD) d 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 ) d 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 invention can be prepared as illustrated below.

([2- (Formyl- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2 -Methyl-but-2-enyl} -amino) -ethyl] -phosphonic acid diethyl ester)
(2- {4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but To a solution of 2-enylamino} -ethyl) -phosphonic acid diethyl ester (74 mg, 0.14 mmol) in formic acid (1 mL) was added formic anhydride (1 mL) and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the crude product was used in the next step. The NMR data of this compound show two 70:30 rotamers. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 to 2.08 (m, 2H), 2.19 (s, 3H), 3.34 to 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 ( 121.4MHz, CDCl ₃₎ d27.5 and 28.1ppm; MS (m / z) 570.1 [M + H] +, 592.2 [M + Na ^+.

((2- {Formyl- [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl ] -Amino} -ethyl) -phosphonic acid)
Crude [2- (formyl- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2 -Methyl-but-2-enyl} -amino) -ethyl] -phosphonic acid diethyl ester (78 mg, 0.14 mmol) in acetonitrile (1 mL) was added TMSBr (177 mL, 1.4 mmol) and 2,6-lutidine ( 163 mL, 1.4 mmol) was added. The solution was stirred at room temperature for 1 hour, at which point the reaction was quenched by the addition of methanol and 1N aqueous HCl. The product was extracted with EtOAc and purified by RP HPLC using a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA to yield 29 mg of product as a white solid. Obtained. The NMR data of this compound show two 70:30 rotamers. ¹ H NMR (300 MHz, CD ₃ OD) d 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 Invention Representative compounds of the invention can be prepared as illustrated below.

(({4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but- 2-enylamino} -methyl) -phosphonic acid diethyl ester)
4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2-enal (500 mg, 1.33 mmol), (2-aminomethyl) phosphonic acid diethyl ester oxalate (376 mg, 1.46 mmol), sodium triacetoxyborohydride (563 mg, 2.66 mmol) in DMF (10 mL) at room temperature. Acetic acid (380 mL, 6.65 mmol) was added. The solution was stirred overnight at which time the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and EtOAc. The organic phase was separated and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 500 mg (71%) of product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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 ) d 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-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enylamino] -methyl}- Phosphonic acid)
({4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2 -Enylamino} -methyl) -phosphonic acid diethyl ester (20 mg, 0.038 mmol) in DMF (0.5 mL) was charged with TMSBr (49 mL, 0.38 mmol) and 2,6-lutidine (44 mL, 0.38 mmol). Added. The solution was stirred at room temperature for 1 hour, at which point the reaction was quenched by the addition of methanol. 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 product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD and CDCl ₃ ) d 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 ) d 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 invention can be prepared as illustrated below.

(2-({2- [4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enylamino ] -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-but-2-enal (188 mg, 0.5 mmol) solution of 2-[(2-aminoethyl) phenoxy-phosphinoyloxy] -propionic acid ethyl ester acetate (315.8 mg, 0.75 mmol) in CH ₂ Cl ₂ (3 mL). The solution and stirred at ambient temperature for 2 hours. Sodium triacetoxyborohydride (159 mg, 0.75 mmol) was added to the solution and the reaction was allowed to proceed for 1 hour. The reaction was quenched by the addition of saturated aqueous NaHCO ₃ and the product was extracted with EtOAc. The organic phase 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 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 product as a white solid. Got. The NMR data for this compound show two rotamers at 45:55 phosphorus. ¹ H NMR (300 MHz, CD ₃ OD) d 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, 2H) ) Ppm; ³¹ P (121.4 MHz, CD ₃ OD) d 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 invention can be prepared as illustrated below.

(2- [Hydroxy- (2- {4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2-enylamino} -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-but-2-enal (38 mg, 0.1 mmol) solution of 2-[(2-aminoethyl) -phenoxy-phosphinoyloxy] -propionic acid ethyl ester acetic acid (63 mg, 0.15 mmol) in CH ₂ Cl ₂ (1 mL) Stir for 2 hours at ambient temperature. Sodium triacetoxyborohydride (32 mg, 0.15 mmol) was added to the solution and the reaction was allowed to proceed for 1 hour. The reaction was quenched by the addition of saturated aqueous NaHCO ₃ and the product was extracted with EtOAc. The organic phase 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 15 mg of product (154- 2) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 0.04 (s, 9H), 1.15 to 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 ) d 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-dihydro-isobenzofuran-5-yl) -2-methyl-but-2 -Enylamino] -ethyl} -phosphinoyloxy) -propionic acid)
2- [Hydroxy- (2- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl]- 2-methyl-but-2-enylamino} -ethyl) -phosphinoyloxy] -propionic acid ethyl ester (15 mg, 0.026 mmol) in 10% TFA-CH ₂ Cl ₂ (1 mL) was added at ambient temperature to 10%. Stir for minutes. The reaction was completed by removing the solvent. The residue was dissolved in THF (0.5 mL) and water (0.4 mL) and 1N aqueous NaOH (0.1 mL) was added. The solution was stirred at room temperature for 20 minutes, at which point it was acidified with 1N aqueous HCl. Purify the solution obtained 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 product as a white solid. Obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (brs, 2H), 3.75 (s, 3H), 4. 71-4.88 (m, 1H), 5.16 (s, 2H), 5.58-5.71 (m, 1H), 7.88 (brs, 3H), 8.60 (brs, 1H), 8.78 (br s, 1 H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) d 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 invention can be prepared as illustrated below.

({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 diethyl ester)
To a solution of diethyl cyanomethylphosphonate (241 mg, 1.38 mmol) in THF (1 mL) was added sodium bis (trimethylsilyl) amide (1.0 M, 1.13 mL, 1.15 mmol) in THF. After stirring for 30 minutes, the solution was added to 6- (4-bromo-3-methyl-but-2-enyl) -7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one (100 mg, 0.23 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 1 hour, after which saturated aqueous ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate. The organic phase 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 ) d 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 ) d 18.18 ppm; MS (m / z) 560 [M + Na] ⁺ .

([1-Cyano-5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-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 diethyl ester (25 mg, 0.047 mmol) was dissolved in a 10% TFA / CH ₂ Cl ₂ (5 mL) solution and stirred at room temperature for 2 hours. The reaction mixture was dried in vacuo 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 ) d 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 ) d 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 invention can be prepared as illustrated below.

([1-cyano-5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl]- Phosphonic acid)
{1-cyano-5- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -3-methyl- To a solution of pent-3-enyl} -phosphonic acid diethyl ester (35 mg, 0.065 mmol) in acetonitrile (2 mL) was added TMSBr (180 mL, 1.38 mmol) and 2,6-lutidine (160 mL, 1.38 mmol). . The reaction solution was stirred at room temperature for 1 hour and then quenched with MeOH. The reaction mixture 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 15 mg (60%) of the desired Product was obtained. ¹ H NMR (300 MHz, CD ₃ OD) d 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) d 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 invention can be prepared as illustrated below.

({1-cyano-5- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -1,3 -Dimethyl-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- Sodium bis (trimethylsilyl) amide (1.0 M, 1.13 mL, 1.15 mmol) was added to a solution of pento-3-enyl} -phosphonic acid diethyl ester (45 mg, 0.084 mmol) in THF (0.5 mL). . After stirring for 20 minutes, iodomethane (52 mL, 0.84 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase 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. It was. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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 ) d 22.26 ppm; MS (m / z) 574 [M + Na] ⁺ .

([1-Cyano-5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -1,3-dimethyl-pent-3-enyl ] -Phosphonic acid)
{1-cyano-5- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -1,3- To a solution of dimethyl-pent-3-enyl} -phosphonic acid diethyl ester (18 mg, 0.04 mmol) in DMF (0.5 mL) and DCM (0.5 mL) was added TMSBr (51 mL, 0.4 mmol) and 2,6- Lutidine (46 mL, 0.4 mmol) was added. The reaction solution was stirred at room temperature overnight and then quenched with MeOH. The reaction mixture 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 4.5 mg (33%) Of the desired product. ¹ H NMR (300 MHz, CD ₃ OD) d 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) d 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 invention can be prepared as illustrated below.

(2-Ethyl-4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -but-2- Enal)
Of [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde (1.5 g, 4.46 mmol) The toluene (14 mL) solution was heated with 2- (triphenyl-phosphanylidene) -butyraldehyde (1.68 g, 5.35 mmol) at 100 ° C. overnight. A second portion of 2- (triphenyl-phosphanylidene) -butyraldehyde (495 mg, 1.49 mmol) was added and the reaction mixture was heated for an additional day. After concentration, the residue was purified by silica gel column chromatography to give 1.3 g (83%) of the desired product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 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-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one)
2-Ethyl-4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -but-2-enal A solution of (1.3 g, 3.30 mmol) in methanol (10 mL) and THF (10 mL) was cooled to 0 ° C. CeCl ₃ (8.25 mL, 0.4 M, MeOH: H ₂ O, 9: 1) solution was added followed by LiBH ₄ (1.66 mL, 3.30 mmol of 2M THF solution). The ice bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture was stirred for an additional 40 minutes, immediately after which completion of starting aldehyde consumption was observed by TLC. The reaction was worked up by addition of 1N aqueous HCl and extracted with EtOAc. The organic phase was washed with saturated sodium bicarbonate solution and brine. The organic phase is concentrated under reduced pressure and the residue is purified by silica gel chromatography to give 948 mg (73%) of product as a clear liquid. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one)
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 for 1 hour at room temperature. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel to give 233 mg (77%) of product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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-dihydro-isobenzofuran-5-yl) -but-2-enyl] -phosphonic acid)
6- (3-Bromomethyl-pent-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy-3H-isobenzofuran-1-one (230 mg, 0.5 mmol) A solution of trimethyl phosphate (1.5 mL, 12.75 mmol) was heated for 4 hours at 100 ° C. The reaction was completed by removal of excess trimethyl phosphite under reduced pressure, the residue was dissolved in acetonitrile (1 mL). TMSBr (646 mL, 5.0 mmol) and 2,6-lutidine (580 mL, 5.0 mmol) were added at 0 ° C. The reaction solution was warmed to room temperature and stirred for 4 hours. The reaction was quenched by the addition of MeOH The reaction mixture was dried in vacuo and a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA was used. The residue was purified by RP HPLC using an existing C18 column to give 77 mg (58%) of product ¹ H NMR (300 MHz, CD ₃ OD) d 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) d 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 invention can be prepared as illustrated below.

({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 diethyl ester)
To a THF (1 mL) solution of diethyl cyanomethylphosphonate (233 mg, 1.32 mmol) was added a THF solution of sodium bis (trimethylsilyl) amide (1.0 M, 1.21 mL, 1.21 mmol). After stirring for 30 minutes, the solution was treated with 6- (3-bromomethyl-pent-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy-3H-isobenzofuran-1-one. (100 mg, 0.22 mmol) in THF (1 mL) was added dropwise and the resulting mixture was stirred at room temperature overnight, followed by addition of saturated aqueous ammonium chloride solution, and the reaction mixture was extracted with ethyl acetate. The residue was purified by separation reverse phase HPLC to give 51 mg (42%) of the desired product ¹ H NMR (300 MHz, CDCl ₃ ) d 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, 3 ), 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 ) d 18.26 ppm; MS (m / z) 574 [M + Na] ⁺ .

([1-Cyano-3-ethyl-5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -pent-3-enyl]- 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 diethyl ester (19.5 mg, 0.035 mmol) was dissolved in 10% TFA / CH ₂ Cl ₂ solution (2 mL) and stirred at room temperature for 10 minutes. The reaction mixture was dried in vacuo 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 mL, 0.2 mmol) and 2,6-lutidine (23 mL, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight and then quenched with MeOH. The reaction mixture was dried in vacuo and the residue purified by RP HPLC using a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA to give 5.1 mg ( 65%) of the desired product was obtained. ¹ H NMR (300 MHz, CD ₃ OD) d 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, 1 H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) d 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 invention can be prepared as illustrated below.

({2-Ethyl-4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -but-2 -Enyloxymethyl} -phosphonic acid diisopropyl ester)
Bromomethylphosphonic acid diisopropyl ester (680 mg, 2.62 mmol) and 6- (3-hydroxymethyl-pent-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H- To a solution of isobenzofuran-1-one (688 mg, 1.75 mmol) in DMF (3 mL) was added lithium t-butoxide (1.0 M HF solution; 2.6 mL). The reaction was heated at 70 ° C. for 2 hours. After cooling to ambient temperature, additional bromomethylphosphonic acid diisopropyl ester (680 mg, 2.62 mmol) and lithium t-butoxide (1.0 M THF solution; 2.6 mL) were added. The reaction mixture was heated at 70 ° C. for an additional hour, cooled, poured into lithium chloride solution (5% aqueous solution) and extracted with ethyl acetate. The organic extract was dried and purified by silica gel chromatography eluting with hexane-ethyl acetate to give 347 mg (35%) of product as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 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, 2 H), 5.4 (t, 1 H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) d 20.26 ppm; Na] ⁺ .

([2-Ethyl-4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -but-2-enyloxymethyl] -phosphonic acid )
{2-Ethyl-4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -but-2- Enyloxymethyl} -phosphonic acid diisopropyl ester (347 mg, 0.61 mmol) in acetonitrile (5 mL) was added 2,6-lutidine (0.71 mL, 6.1 mmol) and bromotrimethylsilane (0.786 mL, 6.1 mmol). ) Was added. The mixture was stirred at room temperature for 3 hours, quenched with methanol (5 mL), concentrated and partitioned between ethyl acetate and 1N HCl (aq). The organic phase was concentrated to give free phosphonic acid as a 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 after lyophilization ( 10 mg). ¹ H NMR (300 MHz, CDCl ₃ ) d1.007 (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 ) d 22.8 ppm; MS (m / z) 385.2 [M−H] ⁺ , 387 .1 [M + H] ⁺ .

Example 276: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

(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) (synthesized according to JW Patterson, Tetrahedron, 1993, 49, 4789-4798) and pyridine (11. 4 g, 144.0 mmol) in dichloromethane (DCM) (20 mL) at 0 ° C. was added triflic anhydride (12.19 g, 43.2 mmol). The reaction was stirred at 0 ° C. for 2 hours, after which additional triflic acid (3 mL) was added. Stirring was continued for an additional hour at 0 ° C. The reaction mixture was poured into a mixture of DCM and HCl (1N). The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were dried with sodium sulfate. Filtration and evaporation of the solvent under reduced pressure gave the crude product, which was purified by silica gel chromatography to give 8.39 g of product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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 ): d = -74 ppm.

(6-hydroxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethyl ester)
To a solution of 6-allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethyl ester (8.39 g, 20.3 mmol) in toluene (20 mL) under a nitrogen atmosphere at room temperature was added tetrakistriphenylphosphine palladium (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 crude reaction mixture was partitioned between diethyl ether and HCl (0.1N). The organic phase was washed with brine and dried over sodium sulfate. Filtration and evaporation under reduced pressure of the solvent gave the crude material, which was 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 ): d = 2.20 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 7.01 (s, 1H) ppm; ¹⁹ F NMR (282 MHz, CDCl ₃ ): d = −74 ppm.

(6-hydroxy-3-methyl-4-vinyl-phthalic acid dimethyl ester)
To a solution of 6-hydroxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethyl ester (2.17 g, 5.85 mmol) in N-methylpyrrolidinone (15 mL) was added lithium chloride (743 mg, 17.5 mmol) and tritium. Phenylarsine (179 mg, 0.585 mmol) was added. Tributylvinyltin (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 a 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 continued for 1 hour. The aqueous phase was extracted with EtOAc and the organic extract was filtered through Celite. The combined organic phases were washed with water and dried over sodium sulfate. The solvent was filtered and evaporated under reduced pressure to give the crude material, which was purified by silica gel chromatography to give 1.27 g (87%) of product as an off-white solid. ¹ H NMR (300 MHz, CDCl ₃ ): d = 2.16 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 5.46 (dd, J = 11.1 , 1.2 Hz, 1 H), 5.72 (dd, J = 17.1, 0.9 Hz, 1 H), 6.86 (dd, J = 17.1, 11.1 Hz, 1 H), 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 a 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 an off-white solid. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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, 1H), 10.79 (s, 1H) ppm.

(16-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 to 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 a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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 to 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 a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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, 1 H) ppm.

(5 6-allyl-5-ethyl-7-hydroxy-4-methyl-3H-isobenzofuran-1-one)
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. Sodium hydroxide (0.798 g, 19.95 mmol) in water (10 mL) was added and the suspension was heated to 55 ° C. After 16 hours, the reaction was cooled to room temperature and washed with diethyl ether. The aqueous phase was acidified (1N HCl) and the suspension was extracted with EtOAc. The combined organic phases were dried with sodium sulfate. The solvent was filtered and evaporated under reduced pressure to give the desired bis acid as a white solid (0.846 g, 98%, M ⁺ = 263).

Bisacid was dissolved in acetic acid (6 mL) and HCl (concentrate, 1.5 mL). The reaction was heated to 80 ° C. Zinc powder (0.635 g, 9.72 mmol, respectively) was added in portions every hour for 7 hours. Stirring was continued at 80 ° C. for another 10 hours. 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. The solvent was filtered and evaporated under reduced pressure to give the crude product, which was purified by silica gel chromatography to give 0.375 g (50%) of product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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, 1 H), 7.66 (s, 1 H) ppm.

(5 6-allyl-5-ethyl-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one)
6-allyl-5-ethyl-7-hydroxy-4-methyl-3H-isobenzofuran-1-one (199 mg, 0.857 mmol), PPh ₃ (337 mg, 1.286 mmol), and 2-trimethylsilylethanol at 0 ° C. To a THF (3 mL) solution was 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 under reduced pressure and the crude material was dissolved in diethyl ether (3 mL). Hexane (1.5 mL) was added. Triphenylphosphine oxide was removed by filtration 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 ): d = 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-dihydro-isobenzofuran-5-yl] -acetaldehyde)
Smith, D.M. B. et al. , J .; Org. Chem. , 1996, 61, 6, 2236 according to the procedure of 6-allyl-5-ethyl-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (261 mg,. 788 mmol) in MeOH (5 mL), CH ₂ Cl ₂ (5 mL), and pyridine (50 μL) were cooled to −70 ° C. using a dry ice / acetone bath. The reaction was bubbled through a stream of ozone with a gas dispersion tube until the reaction turned blue (15 minutes). The ozone line was replaced with a stream of nitrogen and continued to bubble for an additional 15 minutes until the blue color disappeared. To this solution at −78 ° C., thiourea (59.9 mg, 0.778 mmol) was added in one portion and the cooling bath was removed. The reaction was warmed to room temperature and stirred for 15 hours. The reaction mixture was filtered and then partitioned between CH ₂ Cl ₂ and water. The aqueous phase was washed once more with CH ₂ Cl ₂ and the organic extracts were combined, washed with 1N aqueous HCl, saturated NaHCO ₃ , and brine, and dried over sodium sulfate. The solvent was filtered and evaporated under reduced pressure to give the crude product, which was purified by silica gel chromatography to give 181 mg (69%) of product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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-dihydro-isobenzofuran-5-yl] -2-methyl-but-2- Enal)
[6-Ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde (90 mg, 0.269 mmol) and 2- Toluene (3 mL) containing (triphenyl-phosphorylidene) -propionaldehyde (72.9 mg, 0.23 mmol) was heated to 100 ° C. After 15 hours, a second 2- (triphenyl-phosphanylidene) -propionaldehyde moiety (33 mg, 0.11 mmol) was added and the reaction mixture was heated for an additional 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 a pale yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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-but-2-enyl) -4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one)
4- [6-Ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2-enal (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 quenched with 1N HCl (0.5 mL). MeOH was removed under reduced pressure and the crude material was partitioned between DCM water. The aqueous phase was extracted with DCM and the combined organic phases were washed with aqueous sodium bicarbonate and dried over sodium sulfate. Filtration and evaporation of the solvent gave a crude oil, which was purified by silica gel chromatography to give 57.2 mg (73%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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-but-2-enyl) -5-ethyl-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one)
5-ethyl-6- (4-hydroxy-3-methyl-but-2-enyl) -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 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 58.0 mg (87%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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-dihydro-isobenzofuran-5-yl] -2-methyl-but-2 -Enyl} -phosphonic acid)
4- [6′-ethyl-7′-methyl-3′-oxo-4 ′-(2 ″ -trimethylsilanyl-ethoxy) -1 ′, 3′-dihydro-isobenzofuran-5′-yl]- A solution of 2-methyl-but-2-enyl bromide (58 mg, 0.132 mmol) in trimethyl phosphite (0.8 mL) was heated to 110 ° C. After 2 hours, the reaction was complete. The reaction was cooled to room temperature and excess trimethyl phosphite was removed under reduced pressure. The crude material was used in 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 was stirred at room temperature. After 15 minutes, lutidine (155.7 mg, 1.453 mmol) was added and stirring was continued at room temperature. After 2 hours, additional trimethylsilyl bromide (202.2 mg, 1.321 mmol) was added and stirring was continued at room temperature. After 4 hours, the reaction was quenched with MeOH (2 mL). The solvent was evaporated under reduced pressure and the crude material was purified by RP-HPLC (eluent: water / MeCN). Product-containing fractions were combined and lyophilized to give 2.3 mg (5.1%) of free phosphonic acid. ¹ H NMR (300 MHz, DMSO-d6): d = 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 PNMR (121 MHz, DMSO-d6): d = 22.19 ppm; MS = 341 [M ⁺⁺ 1].

Example 277: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

([2-Ethyl-4- [6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -but-2 -Enal)
[6-Ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde (90 mg, 0.269 mmol) and 2- Toluene containing (triphenyl-phosphorylidene) -butyraldehyde (98.4 mg, 0.296 mmol) was heated to 100 ° C. After 15 hours, a second portion of 2- (triphenyl-phosphanylidene) -butyraldehyde (98.4 mg, 0.296 mmol) was added and the reaction mixture was heated for an additional 33 hours. After concentration, the residue was purified by silica gel chromatography to give 50.3 mg (48%) of the desired product as a pale yellow oil.

(5-Ethyl-6- (3-hydroxymethyl-pent-2-enyl) -4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one)
2-Ethyl-4- [6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -but-2-enal (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. A solution of lithium borohydride in THF (2M, 0.065 mL) was added dropwise. After 10 minutes, the reaction was quenched with 1N HCl (0.5 mL). Methanol was removed under reduced pressure and the crude material was partitioned between DCM and water. The aqueous phase was extracted with DCM and the combined organic layers were washed with sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation under reduced pressure of the solvent gave a crude oil that was purified by silica gel chromatography to give 35.4 mg (70%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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-enyl) -5-ethyl-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one)
5-ethyl-6- (3-hydroxymethyl-pent-2-enyl) -4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (35.4 mg. 090 mmol) was dissolved in DCM (3.0 mL). Polymer supported 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 was removed by evaporation. The crude material was purified by silica gel chromatography to give 32.0 mg (78%) of the desired product. The material was used in the next step without further characterization.

([2-Ethyl-4- (6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -but-2-enyl] -phosphonic acid)
Of 6- (3-bromomethyl-pent-2-enyl) -5-ethyl-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (32 mg, 0.070 mmol) A trimethyl phosphite (0.8 mL) solution was heated to 110 ° C. After 2 hours, the reaction was complete. The reaction was cooled to room temperature and excess trimethyl phosphite was removed under reduced pressure. The crude material was used in the next step without further characterization.

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 was stirred at room temperature. After 2 hours, a second batch of trimethylsilyl bromide (108.0 mg, 0.706 mmol) was added. After 3 hours, the reaction was quenched with MeOH (2 mL). The solvent was evaporated under reduced pressure and the crude material was purified by RP-HPLC (eluent: water / MeCN). Product containing fractions were combined and lyophilized to give 15.7 mg (63%) of product. ¹ H NMR (300 MHz, DMSO-d6): d = 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-d6): d = 22.26 ppm; MS = 355 [M ⁺⁺ 1].

  Example 278: Preparation of a representative compound of the invention.

  Representative compounds of the present invention can be prepared as illustrated below.

((2- {4- [6-Ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl- But-2-enylamino} -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-enal (19.7 mg, 0.052 mmol) and aminoethylphosphonic acid diethyl ester oxalate (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 crude reaction mixture was purified by RP-HPLC (eluent: water / MeCN) to give 27.7 mg (97%) of the desired product after lyophilization. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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, 1 H) ppm; ³¹ P NMR (121 MHz, CDCl ₃ ): d = 27.39 ppm; MS = 540 [M ⁺ +1].

({2- [4- (6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enylamino] -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-enylamino} -ethyl) -phosphonic acid diethyl ester (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 was stirred at room temperature. After 20 hours, the reaction was quenched with MeOH (0.3 mL). The solvent was evaporated under reduced pressure and the crude product was purified by RP-HPLC (eluent: water / MeCN). Product containing fractions were combined and lyophilized to give 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 was continued at room temperature. After 20 minutes, the solvent was removed under reduced pressure and the crude material was purified by RP-HPLC (eluent: water / MeCN * 0.1% TFA). Product containing fractions were combined and lyophilized to give 7.6 mg (52%) of product as a TFA salt. ¹ H NMR (300 MHz, DMSO-d6): d = 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 (121MHz, DMSO-d6): d = 20.02ppm; 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-enylamino} -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-enal (26.6 mg, 0.068 mmol) and aminoethylphosphonic acid diethyl ester oxalate (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 hours, the crude reaction product was purified by RP-HPLC (eluent: water / MeCN) to give 24.9 mg (65%) of the desired product after lyophilization. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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) ³¹ P NMR (121 MHz, CDCl ₃ ): d = 27.71 ppm; MS = 554 [M ⁺⁺ 1].

({2- [2-Ethyl-4- (6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -but-2-enylamino] -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-enylamino} -ethyl) -phosphonic acid diethyl ester (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 was stirred at room temperature. After 20 hours, the reaction was quenched with MeOH (0.15 mL). The solvent was evaporated under reduced pressure and the crude material was purified by RP-HPLC (eluent: water / MeCN). Product containing fractions were combined and lyophilized to give 8.0 mg of free phosphonic acid [MS: 498M ^{+ +} 1].

This material was dissolved in DCM (0.5 mL). TFA (0.05 mL) was added and stirring was continued at room temperature. After 20 minutes, the solvent was removed under reduced pressure and the crude material was purified by RP-HPLC (eluent: water / MeCN * 0.1% TFA). Product containing fractions were combined and lyophilized to give 4.4 mg (54%) of product as the TFA salt. ¹ H NMR (300 MHz, DMSO-d6): d = 1.05 (m, 6H), 1.60 (m, 2H), 2.10 (s, 3H), 2.67 (q, J = 7. 5Hz, 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 (121MHz, DMSO} -d6): d = 16.93ppm; MS = 398 [M + +1].

Example 279: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

(2-({4- [6-Ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl- But-2-enyl} -phenoxy-phosphinoylamino) -propionic acid ethyl ester)
4- [6′-ethyl-7′-methyl-3′-oxo-4 ′-(2 ″ -trimethylsilanyl-ethoxy) -1 ′, 3′-dihydro-isobenzofuran-5′-yl]- 2-Methyl-but-2-ene-phosphonic acid (44.8 mg, 0.101 mmol), dicyclohexylcarbodiimide (52.6 mg, 0.254 mmol), and phenol (95.8 mg, 1.018 mmol) were added to pyridine (0 3 mL) and heated at 70 ° C. for 4 hours. The reaction mixture was cooled to room temperature and pyridine was removed under reduced pressure. The crude material was partitioned between DCM and HCl (0.1N). The aqueous phase was extracted with DCM and the combined organic phases were dried over sodium sulfate. Filtration and evaporation of the solvent under reduced pressure gave 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 (2N, 0.8 mL) was added in portions (0.2 mL). After all starting material was consumed, the organic phase was removed in vacuo and the crude material was partitioned between chloroform and aqueous HCl (1N). The aqueous phase was extracted with chloroform. The combined organic phases were dried with sodium sulfate. Filtration and evaporation of the solvent gave the crude product as a mixture of monophenyl ester and symmetrical anhydride.

The crude material from the previous step and ethyl (L) -alanine hydrochloride (78.1 mg, 0.509 mmol) were dissolved in DMF (0.4 mL). DMAP (1.2 mg, catalyst) was added followed by diisopropylethylamine (131.3 mg, 1.018 mmol). Stirring was continued at room temperature. After 20 minutes, the anhydride was completely changed. After 2 hours, PyBOP (101 mg, 0.202 mmol) was added and stirring was continued at room temperature. The reaction was filtered and the crude reaction solution was purified by RP-HPLC (eluent: water / MeCN). Product containing fractions were combined and lyophilized to give the product (15.7 mg, 25% over 3 steps) as a white powder. ¹ H NMR (300 MHz, CDCl ₃ ): d = 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) ³¹ P NMR (121 MHz, CDCl ₃ ): d = 27.04, 27.73 ppm; MS = 615 [M ⁺ +1]. .

(2-{[4- (6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl] -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-enyl} -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 natively. The crude material was purified by RP-HPLC (eluent: water / MeCN). Product containing fractions were combined and lyophilized to a white powder (5.5 mg, 87%). ¹ H NMR (300 MHz, CDCl ₃ ): d = 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 ): d = 27.11, 27.57 ppm; MS = 515 [M ⁺⁺ 1].

Example 280: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

(6- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4- Enoic acid)
6- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-ene A mixture of methanol (20 mL) and water (7 mL) containing a mixture of acid methyl ester (1.5 g, 3.45 mmol) and sodium hydroxide (552 mg) was stirred at room temperature for 1 hour. 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 ) d 0.02 (s, 9H), 1.15 to 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-dihydro-isobenzofuran-5-yl] -4-methyl-hexyl- 4-enoylamino} -methyl) -phosphonic acid diethyl ester)
6- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-ene To a solution of acid (50 mg, 0.12 mmol) in THF (1 mL) at 0 ° C. was added isobutyl chloroformate (17 mL, 0.13 mmol) and triethylamine (50 mL, 0.36 mmol). After stirring for 2 hours at 0 ° C., 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 separation reverse phase HPLC to give 54.8 mg (81%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) d 0.03 (s, 9H), 1.15 to 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, 1 H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) d 23.01 ppm; MS (m / z) 568 [M−H] ⁻ , 592 [M + Na] ⁺ .

({[6- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoylamino] -methyl}- Phosphonic acid)
({6- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4 -Enoylamino} -methyl) -phosphonic acid diethyl ester (40 mg, 0.07 mmol) in acetonitrile (1 mL) was added TMSBr (91 mL, 0.7 mmol) followed by 2,6-lutidine (81.5 mL, 0 mL). 0.7 mmol) was added. The reaction was allowed to proceed overnight, at which point the reaction was complete as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by separation 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) d 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) d 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 invention can be prepared as illustrated below.

((2- {6- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl- Hex-4-enoylamino} -ethyl) -phosphonic acid diethyl ester)
6- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-ene To a solution of acid (50 mg, 0.12 mmol) in THF (1 mL) at 0 ° C. was added isobutyl chloroformate (17 mL, 0.13 mmol) and triethylamine (50 mL, 0.36 mmol). After stirring for 2 hours at 0 ° C., diethyl (aminoethyl) phosphonate oxalate (62 mg, 0.26 mmol) was added and stirring was continued for 1 hour at room temperature. After removal of the solvent, the residue was purified by separation reverse phase HPLC to give 37 mg (54%) of the desired product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) d 0.03 (s, 9H), 1.15 to 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, 1 H), 6.30 (bs, 1 H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) d 29.91 ppm; MS (m / z) 584 [M + H] ⁺ .

({2- [6- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoylamino] -ethyl } -Phosphonic acid)
(2- {6- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex To a solution of -4-enoylamino} -ethyl) -phosphonic acid diethyl ester (36.6 mg, 0.063 mmol) in acetonitrile (1 mL) was added TMSBr (81 mL, 0.63 mmol) followed by 2,6-lutidine (73 mL). 0.63 mmol) was added. The reaction was allowed to proceed overnight, at which point the reaction was complete as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by separation 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) d 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) d 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 invention can be prepared as illustrated below.

({4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2 -Enyl} -phosphonic acid diphenyl ester)
[{4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2 -Enyl} -phosphonic acid (260 mg, 0.59 mmol) in DMF (6 mL) and phenol (555 mg, 5.9 mmol) in dicyclohexylcarbodiimide (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 room temperature, the mixture was partitioned between EtOAc / hexane (1: 1) and 5% aqueous LiCl. The organic phase was washed repeatedly with 5% aqueous LiCl and dried over Na ₂ SO ₄ . After removal of 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-dihydro-isobenzofuran-5-yl] -2-methyl-but-2 -Enyl} -phosphonic acid monophenyl ester)
{4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2- To a solution of enyl} -phosphonic acid diphenyl ester (75 mg, 0.126 mmol) in THF (5 mL) was added 1N NaOH (0.1 mL) solution. The mixture was stirred at room temperature for 16 hours. EtOAc was added and the resulting mixture was washed with 1H HCl. The organic phase was concentrated to dryness 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 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-dihydro-isobenzofuran-5-yl] -2-methyl- But-2-enyl} -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-but-2- Eny} -phosphonic acid monophenyl ester (25 mg, 0.048 mmol) and (S)-(−)-ethyl lactate (34 mg, 0.288 mmol) in pyridine (1 mL) with PyBOP (125 mg, 0.24 mmol). Added. The solution was stirred at room temperature for 16 hours 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-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl] -phenoxy -Phosphinoyloxy} -propionic acid ethyl ester)
2-({4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but To a solution of 2-enyl} -phenoxy-phosphinoyloxy) -propionic acid ethyl ester (24 mg, 0.039 mmol) in DCM (1 mL) was added TFA (0.5 mL) and the mixture was stirred at room temperature for 10 min. did. The reaction mixture was dried in vacuo 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 ) d1.18-1.34 (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 ) d 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 invention can be prepared as illustrated below.

(2-{[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl] -phenoxy -Phosphinoyloxy} -propionic acid)
2-{[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl] -phenoxy- To a solution of phosphinoyloxy} -propionic acid ethyl ester (10 mg, 0.019 mmol) in THF (3 mL) was added 1N NaOH (232 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was dried in vacuo 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) d1.41 (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, 1 H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) d 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 invention can be prepared as illustrated below.

(2-{[4- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyl] -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- Enil} -phosphonic acid monophenyl ester (1 g, ca. 1.9 mmol) was combined with pyBOP (2 g, 4 mmol) and DMAP (120 mg, 0.96 mmol). A solution of L-alanine ethyl ester hydrochloride (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 stirred at room temperature for 12 hours. 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 10% TFA / CH ₂ Cl ₂ (30 mL) with vigorous stirring at −40 ° C. The reaction was gradually warmed to 0 ° C. After 3 hours, the reaction was complete. Pyridine (4.5 mL) was added and the reaction mixture was concentrated. The product was purified by isolated TLC (5% MeOH / CH ₂ Cl ₂ ) and concentrated to give 210 mg (21%) of the desired product as a pale 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 invention can be prepared as illustrated below.

(2- (Dimethoxy-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)
To a solution of trimethylphosphonoacetate (63 mL, 0.39 mmol) in THF (1 mL) was added NaN (TMS) ₂ (0.39 mmol, 0.39 mL) at ambient temperature. After 30 minutes, 6- (4-Bromo-3-methyl-but-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one A solution of (69 mg, 0.156 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 2 hours, at which time precipitation was observed. The reaction mixture was worked up by addition of saturated aqueous ammonium chloride and extraction of the product with EtOAc. The organic extract was dried and the product purified by silica gel chromatography using 0-100% EtOAc-hexanes to give 40 mg of the desired product as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 ) d 25.1 ppm; MS (m / z) 565.2 [M + Na] ⁺ .

(6- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -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-dihydro-isobenzofuran-5-yl] -4 -Trimethylsilyl bromide (0.18 mL) was added to a solution of methyl-hex-4-enoic acid methyl ester (30 mg, 0.055 mmol) in acetonitrile (2 mL). After 10 minutes, 2,6-lutidine (0.16 mL) was added to the reaction at ambient temperature. The reaction was allowed to proceed for 16 hours and then concentrated to dryness. The residue was resuspended in DMF: H ₂ O (8: _{2, 1} mL) solution and RP HPLC using a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA. To give 18 mg of product as a white powder. ¹ H NMR (300 MHz, CD ₃ OD) d1.81 (s, 3H), 2.16 (s, 3H), 2.40-2.49 (m, 1H), 2.63 (dt, 1H, J = 6,17 Hz), 3.07 (ddd, 1 H, J = 4, 12, 23 Hz), 3.38 (3, 2 H, J = 7 Hz), 3.52 (s, 3 H), 3.77 (s , 3H), 5.25 (s, 2H), 5.28 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) d 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 invention can be prepared as illustrated below.

(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)
To a solution of [bis- (2,2,2-trifluoro-ethoxy) -phosphoryl] -acetic acid methyl ester (186 mL, 0.88 mmol) in anhydrous THF (2 mL) was added 1N NaN (TMS) ₂ in THF (0.88 mL). , 0.88 mmol) solution was added. The solution was stirred at room temperature for 30 minutes, immediately followed by 6- (4-bromo-3-methyl-but-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy-3H -A solution of isobenzofuran-1-one (98 mg, 0.22 mmol) in THF (1 mL) was added and the reaction mixture was stirred overnight at which time precipitation was observed, with addition of saturated aqueous ammonium chloride and EtOAc. The reaction mixture was finished by extraction of the product of 1. The organic extract was dried and produced by RP HPLC using a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA. purification things, as a colorless oil product was obtained ^{72mg (48%). 1 H} NMR (300MHz, CDCl 3) d0.05 (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- (Bis- (2,2,2-trifluoroethoxy) phosphoryl) -6- [6-methoxy-7-methyl-3-oxo-4- (2-hydroxy) -1,3-dihydro-iso Benzofuran-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 dissolved in 10% trifluoroacetic acid in dichloromethane (5 mL). 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 as a colorless oil. 45 mg (75%) of product was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d1.81 (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 ) d 25.8 ppm; MS (m / z) 601.2 [M + Na] ⁺ .

Example 287: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

(6- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2- [hydroxy- (2,2,2-trifluoro-ethoxy ) -Phosphoryl] -4-methyl-hex-4-enoic acid)
To a solution of [bis- (2,2,2-trifluoro-ethoxy) -phosphoryl] -acetic acid methyl ester (186 mL, 0.88 mmol) in anhydrous THF (0.5 mL), a 1N NaOH solution (aqueous solution; 0.06 mL) And N-methylpyrrolidinone (0.2 mL) were added. After 6.5 hours, another aliquot of 1N NaOH (0.06 mL) was added and the mixture was stirred overnight. After concentration, the residue was suspended in DMF (less than 1 mL), neutralized with a few drops of TFA, and a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA was used. Purification by RP HPLC gave 5.6 mg (72%) of product as a white powder after lyophilization. ¹ H NMR (300 MHz, CD ₃ OD) d1.83 (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 invention can be prepared as illustrated below.

(Mono- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] phosphite] -2- Methyl-but-2-enyl} ester)
Shadid, B.M. et al. , Tetrahedron, 1989, 45, 12, 3889, 6- (4-hydroxy-3-methyl-but-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl- To a solution of ethoxy) -3H-isobenzofuran-1-one (75 mg, 0.20 mmol) and DIEA (49 mL, 0.28 mmol) in dioxane (2 mL) was added 2-chloro-4H-1,3,2-benzodioxa. Phospholin-4-one (56.7 mg, 0.28 mmol) was added. After 10 minutes, another 2-chloro-4H-1,3,2-benzodioxaphospholin-4-one (40 mg, 0.20 mmol) and DIEA (35 mL, 0.20 mmol) were added. The reaction was allowed to proceed for an additional hour at room temperature, after which the reaction was stopped by the addition of H ₂ O. The solution was stirred for an additional 10 minutes and concentrated in vacuo to a small volume. The product was wet triturated with diethyl ether and coevaporated with acetonitrile (4 × 10 mL) to give the product. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (brs, 1H); ³¹ P (121.4 MHz, CDCl ₃ ) d 7.22; MS (m / z) 441 [M−H] ⁻ .

Example 289: Preparation of Representative Compounds of the Invention Representative compounds of the invention can be prepared as illustrated below.

(Mono- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl phosphate -But-2-enyl} ester)
Phosphorous acid mono- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl -But-2-enyl} ester (27 mg, 0.06 mmol) in dioxane (1 mL) was diluted with DIEA (21 mL, 0.12 mmol) and N, O-bis (trimethylsilyl) acetamide (29 mL, 0.12 mmol) at room temperature. For 3 hours. To the reaction solution was added 2,2′-dipyridyl disulfide (16 mg, 0.072 mmol) and the mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was diluted by the addition of H ₂ O and the solution was stirred for an additional 2 hours and 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 in vacuo 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) d 1.87 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.79 (s, 3H), 4.28 (d, 2 H, J = 6 Hz), 5.26 (s, 2 H), 5.50-5.61 (m, 1 H); ³¹ P (121.4 MHz, CD ₃ OD) d 0.50; MS (m / z) 357 [ M-H] -.

Example 290: Specific Embodiments of the Invention Some compounds of the invention are shown below.

Example 291: Preparation of Representative Compounds of the Invention Additional representative compounds of the invention and intermediates thereof can be prepared according to the methods shown below.

(Synthesis of phenacetaldehyde (phenacetaldehyde) in which R ₁ and R ₂ are mutated)
The parent compound (R ₁ = OMe; R ₂ = Me) is reachable by the following semi-synthesis from mycophenolic acid.

To a solution of mycophenolic acid (500 g, 1.56 mol) in MeOH (4 L) under a nitrogen atmosphere, sulfuric acid (10 mL) was added dropwise, and the suspension was stirred at room temperature. After 2 hours, the reaction became homogeneous and a precipitate formed shortly thereafter. The reaction was stirred at room temperature for 10 hours, at which time TLC showed complete reaction. The reaction was cooled to 10 ° C. in an ice bath and 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 ) d, 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).

To a solution of 0.degree. C. (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) was added 2-trimethylsilyl. A solution of ethanol (2.05 mL, 14.3 mmol) in THF (20 mL) was added. The resulting yellow solution was warmed to room temperature and stirred for 4 hours. The reaction was worked up by concentration drying of the solution and addition of ether and hexane. Triphenylphosphine oxide was removed by filtration 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 ) d 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, 1H).

A solution of (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 stream of ozone with a gas dispersion tube until the reaction turned blue (1.5 hours). The ozone line was replaced with a stream of nitrogen and continued to bubble for an additional 30 minutes until the blue color disappeared. To this solution at −70 ° C., thiourea (1.2 g, 15.4 mmol) was added in one portion and the cooling bath was removed. The reaction was warmed to room temperature and stirred for 15 hours. The reaction was worked up by partitioning between filtration and subsequent CH ₂ Cl ₂ and water to remove solid thiourea S- dioxide. The organic phase was removed. The aqueous phase was washed with CH ₂ Cl ₂ and the organic extracts were combined, washed with 1N HCl, saturated NaHCO ₃ , and brine, and dried in vacuo. The residue was purified by silica gel chromatography to give 7.3 g (99%) of product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) d -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 1} variant)

J. et al. Med. Chem. , 1996, 39, 4181-4196, is converted to the desired aldehyde using methods similar to those described above.

J. et al. Med. Chem. , 1996, 39, 4181-4196, is converted to the desired aldehyde using methods similar to those described above.

J. et al. Med. Chem. , 1996, 39, 4181-4196, is converted to the desired aldehyde using methods similar to those described above.

Dissolve the aldehyde in an organic solvent such as methanol and add sodium borohydride. After completion of the reaction, an aqueous HCl solution is added and the solvent is removed under reduced pressure. Further purification by chromatography.

  The obtained alcohol is dissolved in an organic solvent such as dichloromethane. Add pyridine and acetic anhydride and continue to stir at room temperature. After the reaction is complete, additional DCM is added and the solution is washed with aqueous HCl, aqueous sodium bicarbonate and dried over sodium sulfate. Filtration and evaporation under reduced pressure of the solvent gives the crude product. Further purification by chromatography.

  J. et al. Med. Chem. , 1996, 39, 4181-4196, the acetate is dissolved in DCM and bromide is added. After the reaction is complete, additional DCM is added and the solution is washed with sodium thiosulfate and brine. Dry the organic phase with sodium sulfate. Filtration and evaporation of the solvent gives the crude material. Further purification by chromatography.

  J. et al. Med. Chem. The product of the previous step, lithium chloride, triphenylarsine, tributylvinyltin, and tris (dibenzylideneacetone) dipalladium (O) -chloroform adduct are prepared according to the procedure of Heated at a high temperature of about 55 ° C. in an organic solvent such as methylpyrrolidinone. After completion of the reaction, the mixture was cooled to room temperature and poured into a mixture of ice, potassium fluoride, water, and ethyl acetate. Stirring continued for 1 hour. The suspension is filtered through Celite and extracted with ethyl acetate. The combined organic extracts are dried with sodium sulfate. The solvent is removed under reduced pressure and the crude material is further purified by chromatography.

  J. et al. Org. Chem. , 1984, 48, 4155-4156, the product of the above step is dissolved in an organic solvent such as DCM or THF. 1,1,1-Tris (acyloxy) -1,1-dihydro-1,2-benziodoxol-3- (1H) -one (Dess-Martin reagent) is added and the solution is stirred at room temperature. After completion of the reaction, diethyl ether was added, and then an aqueous sodium hydroxide solution was added. The phases are separated and the organic phase is washed with aqueous sodium hydroxide, water and dried over sodium sulfate. Filtration and evaporation of the solvent gives the crude product. Further purification by chromatography.

The starting material is dissolved in an organic solvent such as toluene. J. et al. Org. Chem. , 2003, 68, 452-459, P (isobutyl NCH ₂ CH ₂ ) ₃ N, palladium (II) acetate, sodium tert butoxide, and benzylamine were added and the mixture was heated to 80 ° C. After completion of the reaction, the mixture is cooled to room temperature and the solvent is removed under reduced pressure. The crude material is purified by chromatography. Any residual acetate is removed by brief treatment with a solution of sodium methoxide in methanol.

  The benzyl protected aniline is dissolved in an organic solvent such as DMF. A palladium carbon catalyst is added and the reaction mixture is placed under a hydrogen atmosphere. After the reaction is complete, the mixture is filtered through Celite. The solvent is removed under reduced pressure. Further purification by chromatography.

  J. et al. Org. The resulting primary aniline is dissolved in an organic solvent such as THF, acetonitrile, or DMF and treated with formaldehyde and sodium triacetoxyborohydride as described in Chem, 1996, 61, 3849-3862. The reaction is quenched with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. The crude material is treated with an organic solvent such as dimethylformamide containing di-t-butyl bicarbonate and aqueous sodium hydroxide. The resulting carbamate is purified by chromatography.

  J. et al. Org. Chem. The primary alcohol product is dissolved in an organic solvent such as DCM or THF according to the procedure of 1984, 48, 4155-4156. 1,1,1-Tris (acyloxy) -1,1-dihydro-1,2-benziodoxol-3- (1H) -one (Dess-Martin reagent) is added and the solution is stirred at room temperature. After completion of the reaction, diethyl ether is added, and then an aqueous sodium hydroxide solution is added. The phases are separated and the organic phase is washed with aqueous sodium hydroxide, water and dried over sodium sulfate. Filtration and evaporation of the solvent gives the crude product. Further purification by chromatography.

Recl. Trav. Chem. The starting material is dissolved in an organic solvent such as DCM or THF according to the procedure of Pay-Bas, 1982, 101, 460 and treated with a mixture of formic acid and pivalic acid anhydride. After completion of the reaction, the solvent and all volatiles are removed in vacuo and the crude material is further purified by chromatography.

  Dissolve the product in an organic solvent such as DCM or THF. J. et al. Org. Chem. , 1984, 48, 4155-4156, 1,1,1-tris (acyloxy) -1,1-dihydro-1,2-benziodoxol-3- (1H) -one (Dess-Martin Reagent) and the solution is stirred at room temperature. After completion of the reaction, diethyl ether is added, and then an aqueous sodium hydroxide solution is added. The phases are separated and the organic phase is washed with aqueous sodium hydroxide, water and dried over sodium sulfate. Filtration and evaporation of the solvent gives the crude product. Further purification by chromatography.

_{(R 2} variants)

J. et al. Med. Chem. , 1996, 39, 4181-4196, the starting material is dissolved in an organic solvent such as DMF and treated 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 phases are dried with sodium sulfate. The solvent is filtered and evaporated to 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 the solution with ozone until the blue color persists. Remove excess ozone with a stream of nitrogen. The reaction mixture is warmed to room temperature and thiourea is added. Continue stirring at room temperature. The reaction mixture is filtered and partitioned between DCM and water. The aqueous phase is extracted with DCM and the combined organic phases are washed with HCl (1N), saturated aqueous sodium bicarbonate, and brine. The solution is dried with sodium sulfate. Filtration and evaporation of the solvent gives the crude aldehyde. Further purification 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 the solution with ozone until the blue color persists. Remove excess ozone with a stream of nitrogen. The reaction mixture is warmed to room temperature and thiourea is added. Continue stirring at room temperature. The reaction mixture is filtered and partitioned between DCM and water. The aqueous phase is extracted with DCM and the combined organic phases are washed with HCl (1N), saturated aqueous sodium bicarbonate, and brine. The solution is dried with sodium sulfate. Filtration and evaporation of the solvent gives the crude aldehyde. Further purification 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 solution is degassed. J. et al. Chem. Soc. Perkin Trans. The reaction mixture is heated to 120 ° C. according to the procedure of 1,1994, 1339-1346. After completion of the reaction, the mixture is cooled to room temperature and the solvent is removed under reduced pressure. The product is further purified by chromatography.

  (Synthesis of linkers for olefins and phosphonates)

Toluene (50 mL) containing phenacetaldehyde (5.3 g, 15.8 mmol) was heated at 100 ° C. overnight with 2- (triphenyl-phosphanylidene) -propionaldehyde (6.8 g, 20.5 mmol). After concentration, the residue was purified by silica gel chromatography to give 4.24 g (72%) of an unsaturated aldehyde as a pale yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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).

According to a reported procedure such as Tetrahedron, 1995, 51, 2099, trimethylsilylethyl protected aldehyde is treated with diethyl phosphite in the presence of a base such as triethylamine in a solvent such as acetonitrile, Hydroxyphosphonate is obtained. Hydroxyphosphonate O-alkylation and removal of the protecting group by treatment with either trifluoroacetic acid or tetrabutylammonium fluoride provides the desired phosphonate analog.

  Alternatively, the aldehyde is mixed with diethyl (2-aminoethyl) phosphonate and treated with a reducing agent such as sodium triacetoxyborohydride to give the aminophosphonate analog.

4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2-enal A solution of (103 mg, 0.27 mmol) in methanol (5 mL) 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 THF solution). The ice bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture was stirred for an additional 40 minutes, immediately after which completion of starting aldehyde consumption was observed by TLC. The reaction was worked up by the addition of 1N aqueous HCl (0.5 mL) and extracted with CH ₂ Cl ₂ . The organic phase was washed with saturated sodium bicarbonate solution and brine. The organic phase is concentrated under reduced pressure and the residue is purified by silica gel chromatography to give 100 mg (97%) of product as a clear liquid. ¹ H NMR (300 MHz, CDCl ₃ ) d0.00 (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).

Polymer supported triphenylphosphine is immersed in DCM for 1 hour. Allyl alcohol and carbon tetrabromide are added continuously. When the reaction is complete, the mixture is filtered and the filtrate is concentrated. If necessary, the bromide is purified by chromatography.

According to the procedure described in WO9522538 and the like, allyl bromide is converted into an alkali metal salt of ethyldiethoxyphosphoryl acetate (ethyldiethoxyphosphoryl acetate and sodium hexamethyldisilazide sodium in an inert organic solvent such as dimethylformamide). Treatment with (sodium hexyldisilazide) or reaction with sodium hydride) gives ethoxycarbonylphosphonate. The carboxylic ester group is converted to a carboxylic amide group and a hydroxymethyl group according to methods conventionally used for amide formation and ester reduction. For example, a carboxylic acid ester is saponified with an aqueous lithium hydroxide solution. The acid is activated with ethyl chloroformate and reduced with sodium borohydride to give the hydroxyl phosphonate analog after removal of the protecting group. The acid is converted to its acyl chloride and reacted with ethylamide to give the amide analog.

The arylacetaldehyde is coupled with 2- (diethoxyphosphoryl) -but-3-enoic acid ethyl ester according to the procedure reported in Synthesis, 1999, 282, etc. to give 2-vinyl substituted esters. Tetrahedron Lett. The 2-vinyl group is converted to a 2-cyclopropyl group under the cyclopropanation conditions described in 1998, 39, 8621 and the like. The ester can be converted to an alcohol and optionally further subjected to conditions such as the following to obtain various phosphonate-containing mycophenolic acid analogs.

The allylic alcohol is treated with bromomethylphosphonic acid diisopropyl ester in a solvent such as dimethylformamide in the presence of a base such as lithium t-butoxide. The phenol protecting group is then removed by treatment with trifluoroacetic acid.

Alternatively, J. Org. Org. Chem. Phenacetaldehyde can be converted to an allylphosphonium salt according to the procedure reported in 1987, 52, 849, etc. The phosphonium salt is then treated with a commercially available 3,3,3-trifluoro-2-oxo-propionic acid ethyl ester and a base such as sodium hydride to give the 2-trifluoromethyl substituted ester. The ester can be converted to an alcohol and optionally further subjected to the previously described reaction to obtain mycophenolic acid analogs with various chains containing phosphonate groups.

(Introduction of _{R 4} variants)

J. et al. Med. Chem. , 1996, 39, 4181-4196, and enone (synthesis outlined in Tetrahedron, 1985, 41, 4881-4889) and diene (Chem. Pharm. Bull., 1989, 37, 2948-2951) with toluene. In an organic solvent, and the mixture is 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 under reduced pressure. The crude reaction product is further purified by chromatography.

  J. et al. Med. Chem. , 1996, 39, 4181-4196, the product of Step 1 is dissolved in an organic solvent such as DCM and m-chloroperbenzoic acid is added. After completion of the reaction, the solution is poured into an aqueous sodium bisulfite solution. Wash the organic phase with saturated aqueous sodium bicarbonate and dry over sodium sulfate. Filtration and evaporation of the solvent gives the crude product.

  J. et al. Med. Chem. , 1996, 39, 4181-4196, the crude product is dissolved in an organic solvent such as toluene and treated with dichlorodicyanoquinone (DDQ). After completion of the reaction, the solvent is removed under reduced pressure and the crude material is further purified by chromatography.

  J. et al. Med. Chem. , 1996, 39, 46-55, the product is dissolved in an organic solvent such as DCM and treated with boron trichloride at reflux temperature. After the reaction is complete, the solution is washed with aqueous HCl. The solution is dried with sodium sulfate. Removal of the solvent gives the crude reaction product. Further purification by chromatography.

  The product from the previous step and triphenylphosphine are dissolved in an organic solvent such as tetrahydrofuran (THF). Diisopropyl azodicarboxylate (DIAD) is added dropwise at 0 ° C. Continue to stir. Add 2-trimethylsilylethanol in THF and continue to stir. After completion of the reaction, the solvent is removed under reduced pressure. The crude reaction solid is extracted with a mixture of organic solvents such as hexane and diethyl ether. Combine the washings and remove the solvent under reduced pressure. The desired product is further purified by chromatography and separated from unwanted regioisomers.

J. et al. Med. Chem. , 1996, 39, 4181-4196, the starting material is 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 phases are dried with sodium sulfate. Filtration and evaporation of the solvent gives the crude product. Further purification by chromatography.

J. et al. Am. Chem. Soc. 1966, 88, 5855-5866, the starting material is dissolved in an organic solvent such as benzene and reacted with dimethyl sulfoxide (DMSO), dicyclohexylcarbodiimide (DCC), and orthophosphonic acid. After the reaction is complete, the suspension is filtered and the organic phase is washed with aqueous sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation of the solvent gives the crude material. Further purification by chromatography.

  Chem. Rev. , 1962, 62, 347-404, the product of Step 1 is dissolved in an organic solvent such as DCM or THF and treated with Raney nickel. When all starting material is consumed, the reaction is filtered and the solvent removed in vacuo. Further purification by chromatography.

J. et al. Med. Chem. , 1996, 39, 4181-4196, the starting material is dissolved in an organic solvent such as DCM and bromide is added. After the reaction is complete, additional DCM is added and the solvent is washed with aqueous sodium thiosulfate. The organic phase is dried with sodium sulfate. Filtration and evaporation of the solvent gives the crude material. Further purification by silica gel chromatography.

  J. et al. Med. Chem. , 1996, 39, 4181-4196, starting materials, lithium chloride, triphenylarsine, tributylvinyltin, and tris (dibenzylideneacetone) dipalladium (O) -chloroform adduct, such as N-methylpyrrolidinone. In an organic solvent at a high temperature of about 55 ° C. After completion of the reaction, the mixture was cooled to room temperature and poured into a mixture of ice, potassium fluoride, water, and ethyl acetate. Stirring continued for 1 hour. The suspension is filtered through Celite and extracted with ethyl acetate. The combined organic extracts are dried with sodium sulfate. The solvent is removed under reduced pressure and the crude material is further purified by chromatography.

  J. et al. Med. Chem. , 1996, 39, 4181-4196, dissolve the product of step 2 in a mixture of organic solvents such as benzene and ethyl acetate. J. et al. Med. Chem. , 1996, 39, 4181-4196, tris (triphenylphosphine) rhodium (I) chloride is added and the reaction is placed under a hydrogen atmosphere. The solvent is removed under reduced pressure and the crude reaction is filtered through silica gel. Further purification by chromatography.

The starting material is dissolved in an organic solvent such as DMF. J. et al. Med. Chem. , 1996, 39, 4181-4196, add potassium carbonate and allyl bromide and continue to stir at room temperature. After all starting material is consumed, aqueous HCl and diethyl ether are added, the organic phase is recovered and the solvent is removed in vacuo.

  The crude material is dissolved in N, N diethylaniline and the reaction mixture is heated to a high temperature of about 180 ° C. After completion of the reaction, the mixture is cooled to room temperature and poured into a mixture of aqueous HCl (2N) and ethyl acetate. The organic phase is washed with aqueous HCl (2N) and dried over sodium sulfate. Filtration and removal of the solvent gives the crude product. Further purification 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 the solution with ozone until the blue color persists. Remove excess ozone with a stream of nitrogen. The reaction mixture is warmed to room temperature and thiourea is added. Continue stirring at room temperature. The reaction mixture is filtered and partitioned between DCM and water. The aqueous phase is extracted with DCM and the combined organic phases are washed with HCl (1N), saturated aqueous sodium bicarbonate, and brine. The solution is dried with sodium sulfate. Filtration and evaporation of the solvent gives the crude aldehyde. Further purification by chromatography.

Chem. Rev. , 1989, 89, 863-927, the aldehyde is dissolved in an organic solvent such as THF, and triphenylphosphonium sec. Propyl bromide and potassium tert. React with butoxide. After completion of the reaction, the solvent is removed under reduced pressure and the crude material is purified by chromatography.
Introduction of linker into phosphonate

The phenols shown herein can optionally be alkylated with optimal reagents. Optionally, the phosphonate moiety is part of such a reagent. Alternatively, this is introduced by various means in subsequent steps, three of which are exemplified above. For example, an alkyl halide is heated with triethyl phosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., “Synthesis of Carbon-phosphorus Bonds,” CRC press, 1988). Alternatively, etoposide can be reacted with an anion of a dialkyl phosphinate. In a further example, the phosphonate reagent can be an electrophile (eg, condensing an acetylide anion with phosphorus oxychloride and quenching the intermediate dichlorophosphonate with ethanol to produce the desired diethyl ester of the phosphonic acid. Obtainable).

Example 316: Preparation of Additional Representative Mycophenolic Acid Compounds of the Invention Certain compounds of the invention can be prepared as follows.

([4- (6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid )
This product was prepared using methods similar to those described herein (eg, Examples 251 and 276). MS (negative mode): 369.3 [M ⁺ -1].

Example 317: Preparation of Additional Representative Mycophenolic Acid Compounds of the Invention Certain compounds of the 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-enyloxymethyl] -Phenoxy-phosphinoylamino} -propionic acid ethyl ester)
The desired product was prepared starting from Example 316 using methods similar to those described herein (eg, Example 261). MS (positive ^{mode): 546.3 [M + +1]} & 568.3 [M + + Na].

Example 318: Preparation of Additional Representative Mycophenolic Acid Compounds of the Invention Certain compounds of the invention can be prepared as follows.

(2-({2- [4- (6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enylamino ] -Ethyl} -phenoxy-phosphinoylamino) -propionic acid ethyl ester)
A method similar to that described herein (eg, Examples 268 and 316) is used, and the reductive amination step uses 2-[(2-amino-ethyl) -phenoxy-phosphinoylamino]- The product was prepared using propionic acid ethyl ester.
MS (positive ^{mode): 559.4 [M + +1]} & 581.3 [M + + Na].

Example 319: Preparation of Additional Representative Mycophenolic Acid Compounds of the Invention Certain compounds of the invention can be prepared as follows.

(2-((1-Ethoxycarbonyl-ethylamino)-{2- [4- (6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enylamino] -ethyl} -phosphinoylamino) -propionic acid ethyl ester)
2-[(2-Aminoethyl)-(1-ethoxycarbonyl-ethylamino) -phosphinoyl in a reductive amination step by a method analogous to that described herein (eg, Example 318). The product was prepared using amino] -propionic acid ethyl ester. 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 illustrated above and below.

Compound 330.3 (250 mg, 0.65 mmol) was dissolved in 10 mL absolute ethanol (15 mL) under an argon atmosphere. After the addition of NaOH (29 mg, 0.72 mmol), the reaction mixture was stirred at room temperature overnight. TLC (CHCl ₃ / MeOH, 9: 1) showed the completion of the reaction. The reaction mixture was concentrated to a solid and dissolved in ethyl acetate (20 mL). The solution was washed with deionized water (2 × 10 mL) and dried over Na ₂ SO ₄ . Concentration gave a solid that was purified by silica gel column chromatography (CHCl ₃ / MeOH, 4: 1) to give compound 330.4 (188 mg, 75%) pure as a solid. ESI-MS m / z 383 [M + H] ^< +>. ¹ H NMR (300 MHz, DMSO-d ₆ ): d 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% purity (Sphereclone 5 μL, H ₂ O: MeCN, 10-90% MeCN 20 min linear gradient, 1.0 mL / min).
Intermediate compound 330.3 was 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 an argon atmosphere and cooled to 0 ° C. Diethylphosphonomethyl-O-triflate (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 hours. TLC (cyclohexane / EtOAc, 1: 1) showed the reaction was complete. Deionized water (15 mL) was added and the mixture was extracted with EtOAC (2 × 50 mL). The organic phase was washed with 1N HCl (20 mL) followed by water (2 × 20 mL), dried over Na ₂ SO ₄ and concentrated to a semi-solid. Purification by silica gel column chromatography (cyclohexane / EtOAc, 1: 1) gave compound 330.1 (3.86 g, 97%) pure as an oil.
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 absolute ethanol (15 mL) and 6N HCl (2 mL) under an argon atmosphere. After the addition of SnCl ₂ .2H ₂ O (5.26 g, 27.72 mmol), the reaction mixture was stirred at room temperature overnight. TLC (CHCl ₃ / MeOH, 9: 1) showed the completion of the reaction. The mixture was concentrated to a semi-solid and dissolved in ethyl acetate (30 mL). The ethyl acetate phase was washed with deionized water (10 mL) and saturated NaHCO ₃ (10 mL) and dried over Na ₂ SO ₄ . Concentration gave a solid that was used without further 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 dry THF (15 mL) under an argon atmosphere. After the addition of 5-methylisoxazole-4-carboxylic acid (381 mg, 3.00 mmol) and diisopropylcarbodiimide (511 μL, 3.30 mmol), the reaction mixture was stirred at room temperature for 6 hours. TLC (CHCl ₃ / MeOH, 9: 1) showed the completion of the reaction. The reaction mixture was filtered and the filtrate was concentrated to give a solid that was dissolved in ethyl acetate (25 mL). The solution was washed with deionized water (2 × 10 mL) and dried over Na ₂ SO ₄ . Concentration gave a solid that was purified by silica gel column chromatography (CHCl ₃ / MeOH, 95: 5) to give pure compound 330.3 (680 mg, 55%) as a pale yellow solid. ESI-MS m / z 383 [M + H] ^< +>. ¹ H NMR (300 MHz, CDCl ₃ ): d 7.11 (1H, s, ArH), 7.06 (2H, s, ArH), 4.29-4.20 (4H, m, OCH ₂ ), 4 _{.14 (2H, d, J =} 10.4Hz, OCH 2), 2.76 (3H, s, CH 3), 2.14 (3H, s, CH 3), 1.37 (6H, t, J = 7.0Hz, _CH 3). ³¹ P NMR (121.7 MHz, DMSO-d ₆ / external H ₃ PO ₄ ) δ ppm 19.7-20.0 (m); HPLC: purity 98% (Sphereclone 5 μL, H ₂ O: MeCN, 10 90% MeCN 20 min linear gradient, 1.0 mL / min).

  Example 331 Synthesis of Representative Prednisone Compounds of the Invention

Representative compounds of the present invention can be prepared as illustrated above. Derivatization of the C-21 hydroxyl group by alkylation of prednisone 331.1 with the appropriate phosphonate provides compound 331.2 of the invention. Certain compounds of the invention can be prepared as follows.

After sodium hydride extraction of the first hydroxy proton in 331.1, diethyl phosphonate triflate is added to give ether 331.4.

  Example 332 Synthesis of Representative Prednisone Compounds of the Invention

Representative compound 332.3 of the present invention can be prepared as illustrated above. Protection of prednisone 332.1 at the first site of low inhibition results in alcohol 332.5, and alkylation of the exposed hydroxyl group with the appropriate phosphonate provides 332.6. Removal of the protecting group completes the construction of analog 332.3. Certain compounds can be prepared as follows.

One protection of prednisone 332.1 as its TBS gives ether 332.7. After alkylation with diethyl phosphonate 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 .

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (67.0 mg, 177 μmol) in DMF (3.0 mL) was added diethylcyanophosphonate. (34.8 μL, 230 μmol) and diisopropylethylamine (Hunig base, DIEA, 30.4 μL, 177 μmol) were added. The solution was stirred at ambient temperature for 4 hours, at which time diethyl (aminomethyl) -phosphonate oxalate (45.4 mg, 177 μmol) was added. The solution was stirred for an additional 4 hours, at which point the starting material was completely consumed. The reaction was worked up by removal of the solvent under reduced pressure and purification of the residue by silica gel chromatography using MeOH—CH ₂ Cl ₂ (10-30%). The product recovered from this chromatography step was sufficiently pure to proceed with the next reaction. A small amount of product (20 mg) was re-purified by RP HPLC on a _C18 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 ) d 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 ) d 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-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -methyl) -phosphonic Acid Silica Gel Chromatography Subsequent crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid diethyl ester (60 mg, 126 mmol) in dry DMF (0 .90 mL) solution was 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 hours, after which the reaction mixture was cooled to room temperature. The solvent volume was reduced to about 700 μL under reduced pressure and diluted with H ₂ O (100 μL). The solution was purified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 26.8 mg (51%) of the desired compound as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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, 1H), 8.56 (s, 1H); MS (m / z) 419.2 [M + H] ⁺ .

Example 502 Synthesis of Exemplary Compounds of the Invention Preparation of (2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid diethyl ester To 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) was added diethylcyanophosphonate. (31.8 mL, 210 mmol) and DIEA (27.8 mL, 161 mmol) were added. The solution was stirred at ambient temperature for 4 hours, at which time diethyl (aminomethyl) -phosphonate oxalate (43.8 mg, 161 μmol) was added. The solution was stirred for an additional 3 hours, by which time the starting material was completely consumed. The reaction was worked up by removal of the solvent under reduced pressure and purification of the residue by silica gel chromatography using MeOH—CH ₂ Cl ₂ (10-30%). The product recovered from this chromatography step was sufficiently pure to proceed with the next reaction. A small amount of product (32 mg) was repurified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 19 mg (70%) of pure product. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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 (app 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, 1H). ³¹ P (121.4 MHz, DMSO-d ₆ ) d 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-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid Atmospheric Temperature Of crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl-phosphonic acid diethyl ester (61 mg, 125 mmol) after silica gel column chromatography To the DMF (1.00 mL) solution was added TMSBr (129.0 μL, 999.2 mmol), and the solution was heated at 70 ° C. for 5.5 hours, at which point LCMS analysis demonstrated 90% completion of the reaction. The reaction mixture was cooled to room temperature and stirred for an additional 12 hours, solvent was removed under reduced pressure and DMF / H ₂ O (800 mL, 1 mL). 1) and the reaction was completed by dissolution in 1N aqueous NaOH (15 mL) The product was purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give a yellow solid 29 mg (53%) of the desired compound was obtained as ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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, 1 H), 8.56 (s, 1 H) ³¹ P (121.4 MHz, DMSO-d ₆ ) d23. 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] -benzylamino} -propyl) -phosphonic acid diethyl ester To 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) was added diethylcyanophosphonate. (31.8 mL, 210 mmol) and DIEA (27.8 mL, 161 mmol) were added. The solution was stirred at ambient temperature for 3 hours, at which time diethyl (aminopropyl) phosphonate oxalate (34.9 mg, 122.6 mmol) was added. The solution was stirred for an additional 2 hours at which point the starting material was completely consumed. The reaction was worked up by removal of the solvent under reduced pressure and purification of the residue by silica gel chromatography using MeOH—CH ₂ Cl ₂ (10-30%). The product recovered from this chromatography step (65.5 mg) was pure enough to proceed to the next reaction. A small amount (32.8 mg) was repurified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 23.2 mg (75%) pure product. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 1.20 (t, 6H, J = 7.2 Hz), 1.64-1.75 (m, 4H), 3.22 (s, 3H), 3 .41 (m, 2H), 3.98 (app 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, 1 H), 8.70 (s, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 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-pteridin-6-ylmethyl) -methyl-amino] -benzylamino} -propyl) -phosphonic acid Atmospheric Temperature (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzylamino} -propyl) -phosphonic acid diethyl ester (32.2 mg, 66 .2 mmol) in dry DMF (0.50 mL) was added TMSBr (68.0 μL, 529.6 mmol). The reaction was heated at 70 ° C. for 1.0 hour, at which time LCMS analysis proved complete. The reaction mixture was cooled to room temperature and water (60 μL) and methanol (60 μL) were added. The crude reaction mixture was purified by RP HPLC on a _C18 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 ) d 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 (brs, 1H), 8.69. (S, 1H). ³¹ P (121.4 MHz, DMSO-d ₆ ) d 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 Preparation of ethyl ester [diastereomeric mixture with phosphorus] 4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (60.0 mg, 158. To a solution of 3 mmol) in DMF (2.5 mL) was added diethyl cyanophosphonate (31.2 mL, 205.7 mmol) and DIEA (81.8 mL, 474.9 mmol). The solution was stirred at ambient temperature for 3.5 hours, at which time (S) -2-[(2-aminoethyl) phenoxyphosphinoyloxy] -propionic acid ethyl ester monoacetate (57.1 mg, 158.3 mmol). A mixture of diastereomers with phosphorus) in DMF (200 mL) was added. The solution was stirred for an additional 1.5 hours, immediately after completion of starting material consumption was observed. The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography using MeOH—CH ₂ Cl ₂ (10-30%). A small amount of product (24.8 mg) was re-purified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 15.8 mg (65%) pure product. It was. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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 (brs, 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 ) d26. 6,27.4. MS (m / z) 609.2 [M + H] &lt; ⁺ &gt;.

Example 507 Synthesis of Exemplary Compounds of the Invention 2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] benzoylamino} -ethyl) phenoxyphosphinoyloxy] -propion Preparation of acid [diastereomeric mixture with phosphorus] 2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] benzoylamino} ethyl) phenoxy-phosphinoyloxy] propion To a solution of acid ethyl ester (mixture of diastereomers with phosphorus; 40.0 mg, 65.7 mmol) in DMF (0.4 mL), acetonitrile (0.2 mL), and water (0.2 mL) in aqueous sodium hydroxide solution (1N, 131.4 μL) was added. 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 _C18 column using H ₂ O / acetonitrile (2-95%) to yield 23.7 mg (71.3%) pure product. Got. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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, 1 H), 8.63 (s, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 25.1. MS (m / z) 505.2 [M + H] &lt; ⁺ &gt;.

Example 508 Synthesis of Exemplary Compounds of the Invention 2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] -benzoylamino} ethyl) -phenoxyphosphinoyloxy] propion Preparation of acid ethyl ester [phosphorus diastereomerically pure] 4-[(2,4-Diaminopteridin-6-ylmethyl) -methyl-amino] benzoic acid hemihydrochloride dihydrate (101.9 mg, 268. To a solution of 9 mmol) in DMF (3.3 mL), diethyl cyanophosphonate (53.0 mL, 349.5 mmol) and DIEA (138.0 mL, 806.7 mmol) were added. The solution was stirred at ambient temperature for 2.5 hours, at which time (S) -2-[(2-aminoethyl) phenoxyphosphinoyloxy] -propionic acid ethyl ester monoacetate (phosphorus diastereomerically). Pure; 268.9 mmol) in DMF (500 mL) was added. The solution was stirred for an additional 30 minutes immediately after completion of starting material consumption was observed. The solvent was removed under reduced pressure 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 _C18 column using H ₂ O / acetonitrile (2-95%) to give 28.7 mg (75.1%) pure product. Got. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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, 1 H), 8.71 (s, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 26.6. MS (m / z) 609.2 [M + H] &lt; ⁺ &gt;.

Example 509 Synthesis of Exemplary Compounds of the Invention 2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] -benzoylamino} -ethyl) -phenoxyphosphinoylamino] Preparation of propionic acid ethyl ester (mixture of diastereomers with phosphorus) 4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (39.6 mg, To a solution of 104.0 mmol) in DMF (1.2 mL) was added diethyl cyanophosphonate (20.6 mL, 136.1 mmol) and DIEA (36.0 mL, 209.4 mmol). The solution is stirred at ambient temperature for 3 hours, at which time (S) -2-[(2-aminoethyl) phenoxyphosphinoylamino] propionic acid ethyl ester monoacetate (mixture of diastereomers with phosphorus; 104. 0 mmol) of DMF (200 mL) was added. The solution was stirred for 30 minutes, at which point completion of starting material consumption was observed. The reaction aliquot (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 mg) was re-purified by RP HPLC on a _C18 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 ) d1.11 (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 (brs, 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 ) d 29.5, 30.1 . MS (m / z) 608.2 [M + H] &lt; ⁺ &gt;.

Example 510 Synthesis of Exemplary Compounds of the Invention 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6- (diethoxy-phosphoryl) -hexanoic acid Preparation 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) solution , Diethyl cyanophosphonate (30.8 mL, 199.4 mmol) and DIEA (85.8 mL, 498.6 mmol) were added. The solution was stirred at ambient temperature for 3.5 hours, at which time (L) -2-amino-6-diethylphosphonatohexanoic acid (44.3 mg, 166.2 mmol) was added. The solution was stirred for an additional 48 hours. The reaction was worked up by removal of the solvent under reduced pressure and purification of the residue by silica gel chromatography using MeOH—CH ₂ Cl ₂ (10-30%). The product recovered from this chromatography step (87 mg) was sufficiently pure to proceed to the next reaction. An aliquot of the product (51.0 mg) was re-purified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 24.7 mg (44%) of pure product. It was. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 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 (brs, 1H), 6.81 (d, 2H, J = 9 Hz), 7.73 (d, 2 H, 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) d31.8; 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 Silica gel column at ambient temperature Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino})-2 ′ (L)-(6 ′-(phosphonic acid diethyl ester) after chromatography ) Hexanoic acid) (20 mg, 34.6 mmol) in dry DMF (0.60 mL) was added TMSBr (18.0 μL, 139.2 μmol). The solution was then heated at 70 ° C. for 18 hours, after which the reaction mixture was cooled to room temperature. The solution was removed under reduced pressure and dissolved in DMF (400 mL) and water (60 mL). The solution was purified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (2-95%) to give 8.9 mg (49%) of product as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) d1.45 (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, 1 H), 8.55 (s, 1 H); MS (m / z) 519.2 [M + H] ⁺ .

Example 512 Synthesis of Exemplary Compounds of the Invention Synthesis of (L) -2-Cbz-amino-hexanoic acid-6-phosphonic acid (L) -2-amino-6- (diethoxyphosphonyl) hexane at ambient temperature To a suspension of acid (106 mg, 396.8 mmol) in dry DMF (2.00 mL) was added TMSBr (307.0 μL, 2,381.0 mmol). The solution was then heated at 70 ° C. for 2 hours, after which the reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The crude material was dissolved in water (0.25 mL) and NaOH (1-N, 2.50 mL). Benzyl chloroformate (79.3 mL, 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 phase was acidified to pH 1 with aqueous HCl. The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried with sodium sulfate. Filtration and evaporation of the solvent gave the crude product, which was pure enough for further conversion. ¹ H NMR (300 MHz, DMSO-d ₆ ) d1.42-1.65 (m, 8H), 3.90 (m, 1H), 5.02 (s, 2H), 7.32 (s, 5H) ), 7.55 (m, 1 H), 7.94 (s, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 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 (L) -2-Cbz-amino-hexanoic acid— To a solution of 6-phosphonic acid (137.3 mg, 397.9 mmol) in 2-TMS ethanol (2.5 mL) was added acetyl chloride (50 mL). Stirring was continued at room temperature. Full conversion was observed after 22 hours. The solvent was removed under reduced pressure. The crude material was sufficiently pure for the next step.

  Half of the crude material (198.9 mmol) is 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 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 mL, 389.0 mmol) in methylene chloride (1.0 mL) was added. Stirring was continued at room temperature. After 4 hours, the solvent was removed under reduced pressure.

  The crude material was dissolved in tetrahydrofuran (THF) (3.0 mL) and aqueous sodium hydroxide (1N, 0.885 mL) was added. Stirring was continued at room temperature. After 14 hours, the solvent was removed under reduced pressure to give crude phosphonate monophenyl ester (63.8 mg). This material was dissolved in 2-TMS ethanol (1.0 mL) and acetyl chloride (20 mL) was added. Stirring was continued at room temperature. After 22 hours, complete conversion to the carboxylic acid ester was observed. The solvent was removed under reduced pressure. The material was sufficiently pure for the next step.

  Half of the crude material (75 mmol) was dissolved in ethanol (1.5 mL). Pd / C (5%, 20 mg) was added and the reaction was placed under a hydrogen gas atmosphere. After 1.5 hours, Celite was added and the crude reaction mixture was filtered through Celite. The solvent was evaporated under reduced pressure and the crude material was 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)- Preparation of hexanoic acid TMS ethanol ester 4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (22.7 mg, 60.0 mmol) in DMF (0 To the solution was added diethyl cyanophosphonate (12.4 mL, 78.0 mmol) and DIEA (31.0 mL, 180.0 mmol). The solution was stirred for 1 hour at ambient temperature, at which time (L) -2-amino-6-monophenoxyphosphonatohexanoic acid 2′TMS ethyl ester (70.5 mmol) dissolved in DMF (0.2 mL) was added. did. The solution was stirred for an additional 3.5 hours. The crude reaction mixture was purified by RP HPLC on a _C18 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 ) d0.0 (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, 1 H, J = 7.8 Hz), 8.71 (s, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 26.2; MS (m / z) 695.2 [M] ⁺ .

Example 515 Synthesis of Exemplary Compounds of the Invention 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 ′-(monophenylmono (S) Preparation of ethyl lactate-phosphonate) -hexanoic acid TMS ethanol ester 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 ′-(monophenyl-phosphonate ) -Hexanoic acid TMS ethanol ester (14.5 mg, 20.8 μmol) in DMF (0.70 mL), PyBOP (32.4 mg, 62.4 μmol), DIEA (21.4 mg, 166.4 μmol), and ( S) Ethyl lactate (19.6 mg, 166.4 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was purified by RP HPLC on a _C18 column using H ₂ O / acetonitrile (5-95%) to give 13.5 mg (about 4: 1) diastereomeric mixture with phosphoric acid ( 81%) of pure product was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 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 (brs, 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, 1 H); ³¹ P (121.4 MHz, DMSO-d ₆ ) d 30.5, 29.2; MS (m / z) 795.2 [M] ⁺ .

  Example 516 Synthesis of Exemplary Compounds of the Invention

The compounds of the invention can generally be prepared as illustrated above. For example, specific 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 time of defoaming, an excess amount of E-1,4-dibromobutene is added. After quenching with aqueous ammonium chloride and extraction of the product with an organic solvent such as ethyl acetate, the monoalkylated product is isolated by chromatography. The bromide thus obtained is heated with triethyl phosphite in a solvent such as toluene (or see other Arbuzov reaction conditions: Engel, R., Synthesis of carbon-phospho bond, CRC press, 1988). The desired phosphonic acid diethyl ester is obtained.

  Example 517 Synthesis of Exemplary Compounds of the Invention

The compounds of the present invention can generally be prepared as illustrated above (see also Ind. J. Chem., Sect B, 1990, 10, 954). Certain intermediates useful in the above 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 time of defoaming, an excess amount of E-1,4-dibromobutene is added. After quenching with aqueous ammonium chloride and extraction of the product with an organic solvent such as ethyl acetate, the monoalkylated product is isolated by chromatography. The bromide thus obtained is heated with triethyl phosphite in a solvent such as toluene (or see other Arbuzov reaction conditions: Engel, R., Synthesis of carbon-phospho bond, CRC press, 1988). The desired phosphonic acid diethyl ester is obtained.

Example 518 Synthesis of Exemplary Compounds of the Invention (Scheme 518-1)

With a suitable oxidizing agent, the primary alcohol shown at 518.3 (5 ′ hydroxyl group) can be converted to a carboxylic acid or its corresponding ester. In the case of an ester, a further deprotection step provides the carboxylic acid 518-1.4. Various oxidation procedures are described in the literature and can be used herein. These include, but are not limited to, the following methods: (i) Dissolution of pyridinium dichromate in Ac ₂ O, t-BuOH, and dichloromethane yields the t-butyl ester followed by trifluoroacetic acid. The ester is converted to the corresponding carboxylic acid by deprotection using reagents such as (Classon, et al, Acta Chem. Scand. Ser. B; 39; 1985; 501-504. Cristalli, et al; J. Med. Chem .; 31; 1988; 1179-1183); (ii) iodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy, the free radical (TEMPO) acetonitrile. The carboxylic acid is obtained by dissolution in (Epp, et J. Org. Chem. 64; 1999; 293-295. Jung et al ;, J. Org. Chem .; 66; 2001; 2624-2635); (iii) sodium periodate, ruthenium chloride Dissolution of (III) in chloroform provides the carboxylic acid (Kim, et al, J Med. Chem. 37; 1994; 4020-4030. Hamma, et al; J. Med. Chem .; 35; 1992; (Iv) dissolution of chromium trioxide in acetic acid yields the carboxylic acid (Olsson et al; J. Med. Chem .; 29; 1986; 1683-1689. Gallo). -Rodriguez et al; J. Med. Chem .; 37; 36-646); (v) dissolution of potassium permanganate in potassium hydroxide provides the carboxylic acid (Ha, et al; J. Med. Chem .; 29; 1986; 1683-1689). Franchetti, et al., J. Med. Chem .; 41; 1998; 1708-1715) (vi) S. et al. Carboxylic acid is obtained by nucleoside oxidase derived from maltofilia (see Mahmodian, et al; Tetrahedron; 54; 1998; 8171-8182).

  The preparation of 518-1.5 from 518-1.4 using lead (IV) tetraacetate has been described by Teng et al; Org. Chem. 59; 1994; 278-280 and Schultz, et al; Org. Chem. 48; 1983; 3408-3412. When lead (IV) tetraacetate is used with lithium chloride (see Kochi, et al; J. Am. Chem. Soc .; 87; 1965; 2052), the corresponding chloride is obtained (1.5. LG = Cl). The same product can be obtained by combining lead (IV) tetraacetate with N-chlorosuccinimide (1.5, LG = Cl) (Wang, et al; Tet. Asym .; 1; 1990; 527 and Wilson et al; Tet. Asym .; 1; 1990; 525). Alternatively, the leaving group (LG) of acetate can be converted to other leaving groups such as bromide by treatment with trimethylsilyl bromide to give 518-1.5 (Spencer, et al; J. Org. Chem). 64; 1999; 3987-3955).

Coupling of 518-1.5 (LG = OAc) with various nucleophiles is described by Teng et al; Synlett; 1996; 346-348 and US 6,087,482 (paragraph 54, line 64 to 55). (Paragraph 20)). Specifically, the coupling of 518-1.5 with diethyl hydroxymethylphosphonate in the presence of trimethylsilyl trifluoromethanesulfonate (TMS-OTf) is described. It can be expected that other compounds having the general structure of HO-linker-POR ^P1 R ^P2 can be used as long as the functional groups in these compounds are compatible with the coupling reaction conditions. There are numerous examples in the published literature describing the coupling of 518-1.5 (LG = halogen) with various alcohols. Silver (I) salt (see Kim et al; J. Org. Chem .; 56; 1991; 2642-2647, Toikka et al; J. Chem. Soc. Perkins Trans. 1; 13; 1999; 1877-1884. ), Mercury (II) salts (see Veneman et al; Recl. Trav. Chim. Pays-Bas; 106; 1987; 129-131), boron trifluoride diethyl ether compounds (Kunz et al; Hel. Chim Acta; 68; 1985; 283-287), tin (II) chloride (O'Leary et al; J. Org. Chem .; 59; 1994; 6629-6636), alkoxide (see Shortnacy-Fowler et al; Nucl a number of reagents such as osides Nucleotides; 20; 2001; see 1583-1598), and iodine (see Kartha et al; J. Chem. Soc. Perkins Trans. 1; 2001; 770-772). Can be used to promote the reaction. These methods can be selectively used in combination with different methods in the formation of 518-1.5 using various free radicals (LG) to give 518-1.6.

Introduction of protecting groups and removal of protecting groups from compounds are techniques commonly practiced in organic synthesis. A number of sources of this technique, the published literature ^{(e.g., Greene and Wuts, Protecting Groups in} Organic Synthesis, 3 rd Ed., John Wiley & Sons, Inc., 1999) available from. The main purpose is to transiently convert the functional group so that it can survive a series of subsequent reaction procedures. The original functional group can then be repaired by a deprotection procedure envisioned in advance. Thus, the transformations of 518-1.1 to 518-1.2, 518-1.2 to 518-1.3, and 518-1.6 to 518-A can be performed with functional groups already present in the compound structure. It is intended that the main component of the conversion (conversion from 518-1.3 to 518-1.6) will occur while preserving.

The 5 ′ hydroxyl group of ribavirin (518-2) can be selectively protected with a suitable protecting group. Treatment of product 518-3 with benzyl chloride (an appropriate base) in the presence of a catalytic amount of 4-dimethylaminopyridine to convert the 2 ′ and 3 ′ hydroxyl groups to their corresponding benzoyl esters 518-4. it can. 518-5 can be obtained by selectively protecting the 5 ′ hydroxyl group. Following the procedure described for the similar compound in FIG. 2 of US Pat. No. 6,087,482, 518-4 can be converted to 518-7 in a three step sequence. Treatment of 518-7 with a coupling agent such as trimethylsilyl trifluoromethanesulfonate in the presence of an alcohol containing the appropriate phosphonate group can give 518-8. Finally, treatment with 518-8 aqueous sodium hydroxide can deprotect the 2 'and 3' hydroxyl groups to give 518-1. It is important to point out that R ^P1 and R ^{P2 in} 518-8 and 518-1 need not be identical.

  Various compounds of general structure 518-1.1 can be prepared using procedures described in the literature or purchased from commercial suppliers. The following is a good source of information on the preparation techniques for various compounds of general structure 518-1.1: Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994 and Vorbrugen and Ruhdez, Hando ns John Wiley & Sons, Inc. , 2001. Some exemplary procedures, starting materials, and their suppliers include:

Compound 518-2.1 in scheme 518-2 is prepared using the described method (WO01 / 90121, table on page 115). The 5 ′ hydroxyl group in 518-2.1 is protected as t-butyldimethylsilyl (TBDMS) ether. The 2 ′ and 3 ′ hydroxyl groups can be protected as benzoyl (Bz) esters to give 518-2.2. The 5 ′ hydroxyl group can then be deprotected to give 518-2.3. Oxidation using iodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy (free radical (TEMPO)) converts the primary alcohol to the corresponding acid 518-2.4 To do. Further oxidation of 518-2.4 using lead tetraacetate gives 518-2.5. Coupling of 518-2.5 with diethyl hydroxymethylphosphonate (available from Sigma-Aldrich, Cat. No. 39, 262-6), which occurs by TMS-OTf, can give 518-2.6. Treatment of 518-2.6 with TMS-Br converts the phosphodiester to the corresponding phosphonic acid 518-2.7. Deprotection of the 2 ′ 3 ′ hydroxyl group gives 518-2.8 as an example of the general structure 518-A, where Base is adenine and 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 R ^P1 and R ^P2 are both hydroxyl groups).

  (Scheme 518-2)

The phosphonic acids in 518-2.7 and 518-2.8 are used as examples for illustrative purposes. Other phosphonate forms can be utilized via phosphonic acid or other forms (such as the corresponding diesters). For more details, see (Phosphonate Interconversion).

  A number of compounds of general structure 518-1.1 having a sugar moiety in their L conformation are either commercially available or can be prepared by procedures described in published literature. The reverse D-conformation enantiomer of the previously discussed L-nucleoside analog is derived from a precursor that is the reverse enantiomer of 518-3.1, 518-3.2, and 518-3.3. Can be prepared. Scheme 518-3 describes the preparation of the reverse enantiomer of 518-3.1, 518-3.2, and 518-3.3.

  (Scheme 518-3)

Using the reaction sequence outlined in Scheme 518-3, the commercially available starting material 518-4.1 can be converted to 518-4.4, the reverse enantiomer of 518-3.1. The diol should be selectively introduced into the opposite side of the tert-butyldimethylsilyl (TBDMS) ether of the hydroxymethyl group by an osmium tetroxide catalyzed hydroxylation reaction. The diol in intermediate 518-4.3 can be protected as TBDMS ether. Reduction of the lactone with diisobutylaluminum hydride at low temperature yields 518-4.6, which can be converted to 518-4.6 by acetylation. Deprotection of 518-4.6 should yield L-ribose (518-4.7). All hydroxyl groups in 518-4.7 can be converted to the corresponding benzoyl esters by an acylation reaction. A standard coupling reaction using various nucleobases should yield 518-4.10, the reverse enantiomer of 518-3.3.

  (Scheme 518-4)

The synthesis of 3-cyano-1- (2,3,5-tri-O-acetyl-bD-ribofuranosyl) -1,2,4-triazole (518-2) is described in US 2002/0156030 A1, page 6, paragraph 0078 to paragraph 0079. Using the starting materials and using the chemical transformation series outlined in Schemes 518-4 and 518-5, respectively, the carboxamide compound 518-1 (Scheme 518-4) or the formamidine compound 518-1 (Scheme 518- 5) can be synthesized.

  (Scheme 518-5)

Using appropriate protection and deprotection procedures (see Greene and Wuts, (1999) Protective Groups in Organic Synthesis), the 5 'hydroxyl group is protected while the 2' and 3 'hydroxyl groups are not protected 518 -3 can be prepared (Schemes 518-4 and 518-5). After protection, a protective group such as a benzoyl group can be introduced into the 2 ′ and 3 ′ hydroxyl groups as in 158-4 by the deprotection procedure, leaving the 5 ′ hydroxyl groups unprotected. Oxidation can convert the primary alcohol in 518-4 to the corresponding carboxylic acid or ester thereof. Optional deprotection of the ester gives the acid 518-5 as the product. Further oxidation using an oxidizing agent such as lead tetraacetate can convert 518-5 to the free radical or acetate 518-6. Treatment of 518-6 with an alcohol containing a phosphonate group in the presence of a suitable coupling agent such as trimethylsilyl trifluoromethanesulfonate gives 518-8 as the product. Finally, treatment of 518-8 using the procedure described in US 2002/0156030 A1, page 6, paragraph 0081 should give 518-1 as the product. It is important to point out that R ^P1 and R ^{P2 in} 518-7, 518-8, and 518-1 need not be the same.

  (Scheme 518-6)

A solution of tert-butyl hydroperoxide (t-BuOOH) in benzene (68%, 3 eq) is prepared at room temperature with allylic alcohol 518-1 (synthesized as described in Tet. Letters (1997) 38: 2355-58) and VO (acac) ₂ is added dropwise to a benzene (final concentration 0.1 M) solution (Scheme 518-6). After stirring for 1 hour at room temperature, saturated 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, the crude product 518-2 is purified by column chromatography on silica.

Epoxide 518-2 and p-anisylchlorodiphenylmethane (1.5 eq) are dissolved in anhydrous pyridine (0.17M) and stirred at 25 ° C. for 2 days. The solvent is removed in vacuo and the residue is dissolved in EtOAc. The organics are washed with water, saturated aqueous NaHCO ₃ solution, and brine and dried over sodium sulfate. After removal of the solvent, the crude product 518-3 is purified by column chromatography on silica.

To a solution of methyltriphenylphosphonium bromide bromide (2 eq) in anhydrous THF at −78 ° C. is added n-butyllithium (2.2 eq). The solution is warmed to room temperature and stirred for 20 minutes. After re-cooling to −78 ° C., this solution is added to THF (final concentration 0.06M) with fully protected epoxide 518-3. The reaction mixture is warmed to room temperature and stirred for 12 hours, at which point H ₂ O is added and extracted with diethyl ether. The combined organics are dried with sodium sulfate. After removal of the solvent, the crude product 518-4 is purified by column chromatography on silica.

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 min. To do. 518-4 DMF solution is then added and the reaction mixture is stirred at 120 ° C. for 12 hours, at which point the solvent is 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, the crude product 518-5 is purified by column chromatography on silica.

  Compound 518-5 was dissolved in dichloromethane and 1,1,1-tris (acetyloxy) -1,1-dihydro-1,2-benziodoxol-3- (1H) -one (Aldrich, Dess-Martin) Periodinane, 4 eq) is added to a solution of dichloromethane (final concentration 0.06 M). The reaction mixture is stirred at room temperature for 4 days, at which time it is diluted with EtOAc and poured into saturated aqueous sodium bicarbonate solution of sodium thiosulfate. The organic phase is separated and dried over sodium sulfate. After removal of the solvent, the crude product 518-6 is purified by column chromatography on silica.

A solution of ketone 518-6 in anhydrous THF is added to a solution of methylmagnesium bromide (4 equivalents) in anhydrous THF (0.1 M) at -78 ° C. The reaction mixture is stirred at −60 ° C. for 12 hours, at which point the reaction is quenched with saturated aqueous NH ₄ Cl. The mixture is filtered through celite and washed with EtOAc. The combined organics are washed with saturated aqueous NH ₄ Cl, water and dried over sodium sulfate. After removal of the solvent, the crude product is purified by column chromatography on silica.

  A solution of alcohol 518-7 in anhydrous THF (0.06M) is treated with a solution of tetrabutylammonium fluoride (1.5 eq) in THF at room temperature. The reaction mixture is stirred for 3 hours, at which time the solvent is evaporated. The crude desilylated diol 518-8 is purified by column chromatography on silica.

Magnesium tert-butoxide (1 eq) is added to a solution of diol 518-8 and benzenesulfonic acid diisopropoxyphosphorylmethyl ester (1.2 eq) in anhydrous DMF (0.1 M). The reaction mixture is heated at 80 ° C. for 12 hours. After cooling to room temperature, 1N citric acid is added and extracted with EtOAc. The organics are neutralized with saturated aqueous NaHCO ₃ solution, washed with saturated NaCl and dried over sodium sulfate. After removal of the solvent, the crude product 518-9 is purified by column chromatography on silica.

  Compound 518-9 is dissolved in 80% acetic acid and stirred at room temperature for 12 hours. After removal of the solvent, the crude product 518-10 is purified by column chromatography on silica.

Phosphonate ester 518-10 and 2,6-lutidine (8 eq) was dissolved in _CH 3 CN, and treated with trimethylsilyl iodide (8 eq). After stirring for 3 hours at room temperature, triethylamine (8 equivalents) is added followed by methanol. After removal of the solvent, the crude product 518-11 is purified by column chromatography on silica.

  Phosphonic diacid 518-11 is dissolved in 1,4-dioxane, treated with 4N NaOH, and heated at 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 column chromatography on silica to give 518-12.

Compound 518-13 (Paquette et al J. Org. Chem. (1997) 62: 1730-1736) contains p-methoxybenzyl bromide (1.5 eq), sodium hydride (1.4 eq) at room temperature. Treat with dry DMF (Scheme 518-7). The reaction is monitored by TLC for the disappearance of 518-13. The reaction is stopped by the addition of saturated aqueous ammonium chloride solution. Extraction with diethyl ether gives the crude product, which can be purified by silica gel chromatography to give 518-14.

A THF solution of 518-14 is added dropwise to a THF solution of n-BuLi (1.2 eq) cooled to −78 ° C. under a nitrogen atmosphere. The solution is stirred at −78 ° C. for 1 hour. Excess HMPA (1.4 eq) is added. After 10 minutes, MeI (5 eq) in THF is added. After another 5 hours at −78 ° C., 20% NaH ₂ PO ₄ aqueous solution is added and the mixture is allowed to warm to room temperature. Extraction with diethyl ether gives the crude product, which is purified by silica gel chromatography to give 518-15.

  Dichlorodicyanoquinone (DDQ) is added to a solution 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 purified by silica gel chromatography to give 518-16.

  To a dioxane solution of 518-16, triphenylphosphine (2 eq), 2-amino-6-chloropurine (2 eq) are added at room temperature. Diisopropyl azodicarboxylate (2 eq, DIAD) is added dropwise by syringe. The mixture is stirred at room temperature for a further 3 hours. The reaction is stopped by adding water. Extraction with ethyl acetate gives the crude product, which is purified by silica gel chromatography to give 518-17.

  Alternatively, Crimmins, M., et al., Such as palladium coupling to cyclopentyl acetate. T.A. (1998) Tetrahedron 54: 9229-9272 can be used to add nucleobases.

  To a THF solution of compound 518-17 is added 1M tetrabutylammonium fluoride solution (1.2 eq, TBAF) at room temperature. After several more hours, a saturated aqueous ammonium chloride solution is added. Extraction with ethyl acetate gives the crude product, which is purified by silica gel chromatography to give 518-18.

Compound 518-18, diethyl bromomethylphosphonate (1.5 eq), and lithium t-butoxide (1.5 eq) are added sequentially to DMF. The mixture is stirred at 80 ° C. for several hours. After the mixture is cooled to room temperature, 1M KH ₂ PO ₄ solution is added. Extraction with ethyl acetate gives the crude product, which is purified by silica gel chromatography to give 518-19.

  To a solution of 518-19 in acetone, N-methylphosphine N-oxide (2 eq) and osmium tetroxide (0.2 eq) are added. The mixture is stirred at room temperature for 16 hours. Add 1M aqueous sodium sulfite solution. After stirring for an additional hour at room temperature, the mixture is evaporated to remove most of the acetone. The aqueous residue is frozen and lyophilized to give the crude product, which is 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 onto ice. The mixture is then frozen and lyophilized to give a residue that is purified by reverse phase HPLC to give 518-21.

  518-21 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 518-22.

  Known procedures can be used to convert compound 518-22 to the corresponding diphosphophosphonate 518-23 and prodrug.

  (Scheme 518-8)

3-Cyclopenten-1-ol 518-24 (108 uL, 1.2 mmol, 1.2 eq) is dissolved in 5 mL of dry THF (Scheme 518-8). Cool the solution to 0 ° C. 1.35M n-BuLi solution (0.89 mL, 1.2 mmol, 1.2 eq) is added via syringe. After 10 minutes, diisopropylphosphonomethyl p-toluenesulfonate (350 mg, 1.0 mmol, 1.0 equiv) is added. The mixture is stirred in a 45 ° C. bath for 3.5 hours. The reaction is stopped with a pH 7 phosphate buffer. Extraction with diethyl ether gives the crude product, which is purified by silica gel chromatography (elution with 45% ethyl acetate in hexane) to give 178 mg of 518-25 (68%).

To a solution of 518-25 (168 mg, 0.69 mmol, 1 eq) in 12 mL acetone is added 8 mL water containing 273 mg NaHCO ₃ . The mixture is then cooled to 0 ° C. 4 mL of water containing oxone (519 mg, 0.85 mmol, 1.3 eq) is added in portions over 5 minutes. The mixture is stirred vigorously for 2.5 hours. The mixture is then evaporated under reduced pressure to remove most of the acetone. The aqueous residue is extracted with ethyl acetate to give the crude product, which is purified by silica gel chromatography to give 518-26 as a clear oil.

To a 0.25 mL DMF solution of 518-26 (21 mg, 0.076 mmol, 1.0 eq), cytosine (13 mg, 1.5 eq), cesium carbonate (6 mg, 0.25 eq), and magnesium t-butoxide were added. Added. The mixture is heated at 140 ° C. for several hours. After cooling to room temperature, the reaction mixture is purified by reverse phase HPLC to give 12.5 mg of 518-27 (42%). ¹ H NMR (CDCl 3): d 9.60 (br s, 1 H), 8.96 (br s, 1 H), 7.87 (d, 1 H), 6.21 (d, 1 H), 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 described in WO 03/105770 can be applied to add a nucleobase containing a nucleophilic amine to the cyclopentyl epoxide.

  The conversion from 518-27 to 518-28 is described in Scheme 518-2 above. Using the procedures described herein, conversion of 518-28 to the corresponding diphosphophosphonate 518-29 and a phosphorus prodrug (eg, 518-30) can be performed.

  Cyclopentyl intermediate 518-31 can be prepared by procedures analogous to US5202064 and US5340816 (Scheme 518-4). Diol 518-31 is converted to cyclopentenone 518-32 and treated with IBr in the presence of the appropriate phosphonate alcohol to give 518-33. Inversion of iodide 518-33 provides cyclopentanone intermediate 518-34. Nysted methyleneation (US38665848; Aldrichim. Acta (1993) 26:14) gives exocyclic methylene 518-35, which can be deprotected to give 518-36.

  Cyclopentanone 518-34 may be a versatile intermediate for forming other compounds of the invention by reduction to cyclopentyl 518-37 or Wittig or Grubb olefination with alkenyl 518-38.

  (Scheme 518-9)

Scheme 518-10 converts intermediate 518-39 to guanosylcyclopentenone 518-40 (J. Am. Chem. Soc. (1972) 94: 3213) followed by treatment with IBr and diethylphosphomethanol. Iodide 518-41 is obtained (J. Org. Chem. (1991) 56: 2642). Nucleophilic substitution with AgOAc gives acetate 518-42. 518-43 was obtained after methyleneation using the Nysted procedure (US 3865848; Aldrichim. Acta 1993, 26, 14), the acetate group was removed by addition of sodium methoxide, and the resulting alcohol was inverted by Mitsunobo protocol. Deprotection of the second acetate yields 518-44. Desilylation of 518-44 with tetrabutylammonium fluoride (TBAF) provides 518-45.

  (Scheme 518-10)

Specific embodiments

Example 519 Synthesis of Exemplary Compounds of the Invention

Synthesis of 519-1: To an 8 mL anhydrous pyridine solution of 3′-deoxyuridine (995 mg, 4.36 mmol), t-butyldiphenylsilyl chloride (TBDPS-Cl, 1.38 g, 5.01 mmol) and 4-dimethylaminopyridine (DMAP, 27 mg, 0.22 mmol) was added. The mixture was stirred at 23 ° C. for 14 hours and then cooled to 0 ° C. in an ice-water bath. To this mixture was added benzoyl chloride (735 mg, 0.61 mL, 5.2 mmol). The mixture was warmed to 23 ° C. and stirred for an additional 2 hours. The mixture was concentrated in vacuo to give a paste that was partitioned between water and ethyl acetate. The aqueous phase is extracted once with ethyl acetate. The combined ethyl acetate phases were washed sequentially with 1M aqueous citric acid solution, saturated sodium bicarbonate, and brine. This was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product as a yellow oil. Purification by silica gel chromatography (15-65% ethyl acetate in hexane) gave a colorless oil. Yield 1.35 g (54%). ¹ H NMR (DMSO-d6): d 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, 13 H), 5.99 (s, 1 H), 5.58 (m, 1 H), 7.34 (d, J = 8.2 Hz, 1 H), 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: To a 5 mL anhydrous N, N-dimethylformamide solution of 519-1 (1.31 g, 2.3 mmol), benzyl chloromethyl ether (0.54 g, 3.45 mmol), N, N— Diisopropylethylamine (446 mg, 0.60 mL, 3.45 mmol) was added. The mixture was stirred at 23 ° C. for 4 hours. Water was added. The mixture was extracted with ethyl acetate. The organic phase was washed successively with 1M aqueous citric acid solution, saturated sodium bicarbonate, and brine. This was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product as a yellow oil which was 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. 1M TBAF solution (4.6 mL, 4.6 mmol) was added via syringe. The mixture was warmed to 23 ° C. and stirred for an additional 2 hours. An additional 2.3 mL of 1M TBAF was added. The mixture was further stirred at 23 ° C. for 2 hours. To the solution was added a saturated aqueous ammonium chloride solution. The mixture was evaporated under reduced pressure to remove most of the THF. The aqueous phase was extracted with ethyl acetate. The aqueous phase was washed with brine. This was then dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product as a yellow oil. Purification by silica gel chromatography (30-80% ethyl acetate in hexane) gave a white solid. Yield of 520-2: 805 mg (77% over 2 steps). ¹ H NMR (DMSO-d6): d 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: To a 1: 1 mixture solution of 520-2 (800 mg, 1.77 mmol) in 3.5 mL acetonitrile / water was added iodobenzene diacetate (1.25 g, 3.89 mmol) and TEMPO (55 mg, 0.35 mmol) was added. The mixture was stirred at 23 ° C. for 14 hours. The mixture was then frozen in a −78 ° C. bath and lyophilized to give a solid residue. The 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): d 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) was added to 7 mL anhydrous DMF deoxygenated solution of 521-3 (730 mg, 1.57 mmol) and pyridine (0.51 mL, 6.26 mmol). Added. The mixture was stirred for 14 hours at 23 ° C. protected from light. The mixture is diluted with 15 mL ethyl acetate and 10 mL water. The mixture was filtered through a Celite pad and separated. The aqueous phase was extracted with another 10 mL ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give the crude product as an oil. The crude product 522-4 was purified by silica gel chromatography (10-50% ethyl acetate in hexane). Two diastereomeric products were obtained as white foam. Yield: 400 mg (53%). ¹ H NMR (DMSO-d6): d 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 6 mL anhydrous dichloromethane solution of 522-4 (300 mg, 0.63 mmol) was added diethyl hydroxymethylphosphonate (0.37 mL, 2.5 mmol) followed by trimethylsilyl trifluoromethanesulfonate (0.34 mL). , 1.88 mmol) was 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 phase was washed with 1M aqueous citric acid solution, saturated sodium bicarbonate, and brine. It was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (75-95% ethyl acetate in hexane) to give two products (523-5a and 523-5b) which are diastereomers of each other as shown above. Yield of 523-5a: 53 mg (14%). Yield of 523-5b: 129 mg (35%).

Analytical data of 5a: ¹ H NMR (acetonitrile-d3): d 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 stereochemical properties of 523-5a were confirmed by further two-dimensional NMR experiments.

Analysis data of 523-5b: ¹ H NMR (acetonitrile-d3): d8.08 (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: To a 3 mL acetonitrile solution of 523-5a (110 mg, 0.19 mmol) was added 2,6-lutidine (0.43 mL, 3.74 mmol) followed by iodotrimethylsilane (0.53 mL, 3 .74 mmol) was added. After stirring for 30 minutes at 23 ° C., the mixture was heated to 40 ° C. and stirred at this temperature for a further 4 hours. The reaction mixture was cooled to 23 ° C. (0.52 mL, 3.74 mmol) was added followed by water (10 mL). The aqueous mixture was extracted twice with 5 mL diethyl ether. The resulting aqueous solution was frozen in a −78 ° C. bath and lyophilized to give a yellow solid. The crude product was purified by reverse phase HPLC to give 524-6 as a pale yellow solid. Yield 26 mg (34%). MS (m / z) 411.3 (M-H &lt;^-&gt;).

  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) were added in 0.3 mL. Dissolved in anhydrous dimethylformamide (DMF). The mixture was stirred at 23 ° C. for 4 hours. MeOH (0.020 mL) was added and the mixture was stirred for an additional 30 minutes. A 0.63 mL anhydrous DMF solution of tributylammonium pyrophosphate (159 mg, 0.29 mmol) was added. The resulting mixture was stirred at 23 ° C. for 14 hours. The mixture was evaporated under reduced pressure 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% trimethylammonium bicarbonate aqueous solution) 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 1M aqueous sodium hydroxide 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 with an ion exchange column (DEAE-cellulose resin, 0-50% triethylammonium bicarbonate aqueous solution) to obtain diphosphophosphonate 525-7, a triethylammonium salt of the above structure, as a white solid. Got. Yield 10 mg (45% over 2 steps). ¹ H NMR (D ₂ O): d 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): d 7.46 (d, 1P), −9.45 (d, 1P), −23.11 (t, 1P) ppm. MS (m / z) 467.0 (M-H &lt;^-&gt;).

  Example 526 Synthesis of Exemplary Compounds of the Invention

Synthesis of 526-8: To a 0.4 mL aqueous solution of 524-6 (16 mg, 0.039 mmol) was added NaOH (7.8 mg, 0.19 mmol). 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 (eluting with 100% water) to give 4.6 mg of 526-8 (38% yield) as a white solid. ¹ H NMR (D ₂ O): d 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): d12.60 (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 equivalents) at room temperature with allylic alcohol 526-1 (synthesized as described in Tet. Let., 38: 2355 (1997)) and VO (acac) ₂ is added dropwise to a benzene (final concentration 0.1 M) solution (Scheme 518-6). After stirring for 1 hour at room temperature, saturated 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, the crude product 526-2 is purified by column chromatography on silica.

Epoxide 526-2 and p-anisylchlorodiphenylmethane (1.5 eq) are dissolved in anhydrous pyridine (0.17M) and stirred at 25 ° C. for 2 days. The solvent is removed in vacuo and the residue is dissolved in EtOAc. The organics are washed with water, saturated aqueous NaHCO ₃ solution, and brine and dried over sodium sulfate. After removal of the solvent, the crude product 526-3 is purified by column chromatography on silica.

To a solution of methyltriphenylphosphonium bromide bromide (2 eq) in anhydrous THF at −78 ° C. is added n-butyllithium (2.2 eq). The solution is warmed to room temperature and stirred for 20 minutes. After recooling to −78 ° C., this solution is added to THF (final concentration 0.06 M) containing all the protected epoxide 518-3. The reaction mixture is warmed to room temperature and stirred for 12 hours, at which point H ₂ O is added and extracted with diethyl ether. The combined organics are dried with sodium sulfate. After removal of the solvent, the crude product 526-4 is purified by column chromatography on silica.

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 min. To do. 526-4 DMF solution is then added and the reaction mixture is stirred at 120 ° C. for 12 hours, at which time the solvent is 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, the crude product 526-5 is purified by column chromatography on silica.

  Compound 526-5 was dissolved in dichloromethane and 1,1,1-tris (acetyloxy) -1,1-dihydro-1,2-benziodoxol-3- (1H) -one (Aldrich, Dess-Martin) Periodinane, 4 eq) is added to a solution of dichloromethane (final concentration 0.06 M). The reaction mixture is stirred at room temperature for 4 days, at which time it is diluted with EtOAc and poured into saturated aqueous sodium bicarbonate solution of sodium thiosulfate. The organic phase is separated and dried over sodium sulfate. After removal of the solvent, the crude product 6 is purified by column chromatography on silica.

A solution of ketone 526-6 in anhydrous THF is added at −78 ° C. to a solution of methylmagnesium bromide (4 equivalents) in anhydrous THF (0.1 M). The reaction mixture is stirred at −60 ° C. for 12 hours, at which point the reaction is quenched with saturated aqueous NH ₄ Cl. The mixture is filtered through celite and washed with EtOAc. The combined organics are washed with saturated aqueous NH ₄ Cl, water and dried over sodium sulfate. After removal of the solvent, the crude product 526-7 is purified by column chromatography on silica.

  A solution of alcohol 7 in anhydrous THF (0.06M) is treated with a solution of tetrabutylammonium fluoride (1.5 eq) in THF at room temperature. The reaction mixture is stirred for 3 hours, at which time the solvent is evaporated. The crude desilylated diol 526-8 is purified by column chromatography on silica.

Magnesium tert-butoxide (1 eq) is added to a solution of diol 526-8 and benzenesulfonic acid diisopropoxyphosphorylmethyl ester (1.2 eq) in anhydrous DMF (0.1 M). The reaction mixture is heated at 80 ° C. for 12 hours. After cooling to room temperature, 1N citric acid is added and extracted with EtOAc. The organics are neutralized with saturated aqueous NaHCO ₃ solution, washed with saturated NaCl and dried over sodium sulfate. After removal of the solvent, the crude product 526-9 is purified by column chromatography on silica.

  Compound 526-9 is dissolved in 80% acetic acid and stirred at room temperature for 12 hours. After removal of the solvent, the crude product 526-10 is purified by column chromatography on silica.

Phosphonate ester 526-10 and 2,6-lutidine (8 eq) are dissolved in CH ₃ CN and treated with trimethylsilyl iodide (8 eq). After stirring for 3 hours at room temperature, triethylamine (8 equivalents) is added followed by methanol. After removal of the solvent, the crude product 526-11 is purified by column chromatography on silica.

Phosphonic diacid 526-11 is dissolved in 1,4-dioxane, treated with 4N NaOH and heated at 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 column chromatography on silica to give 526-12.

  (Scheme 526-2)

Compound 526-13 (Paquette et al J. Org. Chem. (1997) 62: 1730-1736) contains p-methoxybenzyl bromide (1.5 eq), sodium hydride (1.4 eq) at room temperature. Treat with dry DMF (Scheme 526-2). The reaction is monitored by TLC for the disappearance of 526-13. The reaction is stopped by the addition of saturated aqueous ammonium chloride solution. Extraction with diethyl ether gives the crude product, which can be purified by silica gel chromatography to give 526-14.

A THF solution of 526-14 is added dropwise to a THF solution of n-BuLi (1.2 eq) cooled to −78 ° C. under a nitrogen atmosphere. The solution is stirred at −78 ° C. for 1 hour. Excess HMPA (1.4 eq) is added. After 10 minutes, MeI (5 eq) in THF is added. After another 5 hours at −78 ° C., 20% NaH ₂ PO ₄ aqueous solution is added and the mixture is allowed to warm to room temperature. Extraction with diethyl ether gives the crude product, which is purified by silica gel chromatography to give 526-15.

  Dichlorodicyanoquinone (DDQ) is added to a solution of compound 526-15 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 purified by silica gel chromatography to give 526-16.

  To a dioxane solution of 526-16, triphenylphosphine (2 equivalents), 2-amino-6-chloropurine (2 equivalents) are added at room temperature. Diisopropyl azodicarboxylate (2 eq, DIAD) is added dropwise by syringe. The mixture is stirred at room temperature for a further 3 hours. The reaction is stopped by adding water. Extraction with ethyl acetate gives the crude product, which is purified by silica gel chromatography to give 526-17.

  To a THF solution of compound 526-17 is added 1M tetrabutylammonium fluoride solution (1.2 eq, TBAF) at room temperature. After several more hours, a saturated aqueous ammonium chloride solution is added. Extraction with ethyl acetate gives the crude product, which is purified by silica gel chromatography to give 526-18.

Compound 526-18, diethyl bromomethylphosphonate (1.5 eq), and lithium t-butoxide (1.5 eq) are added sequentially to DMF. The mixture is stirred at 80 ° C. for several hours. After the mixture is cooled to room temperature, 1M KH ₂ PO ₄ solution is added. Extraction with ethyl acetate gives the crude product, which is purified by silica gel chromatography to give 526-19.

  To an acetone solution of 526-19, N-methylphosphine N-oxide (2 eq) and osmium tetroxide (0.2 eq) are added. The mixture is stirred at room temperature for 16 hours. Add 1M aqueous sodium sulfite solution. After stirring for an additional hour at room temperature, the mixture is evaporated to remove most of the acetone. The aqueous residue is frozen and lyophilized to give the crude product, which is purified by reverse phase HPLC to give 526-20.

  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 onto ice. The mixture is then frozen and lyophilized to give a residue that is 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 4 N HCl and purified by reverse phase HPLC to give 526-22.

  Compound 526-22 can be converted to the corresponding diphosphophosphonate 526-23 and prodrug using known procedures.

  (Scheme 526-3)

3-Cyclopenten-1-ol 526-24 (108 uL, 1.2 mmol, 1.2 eq) is dissolved in 5 mL of dry THF. Cool the solution to 0 ° C. 1.35M n-BuLi solution (0.89 mL, 1.2 mmol, 1.2 eq) is added via syringe. After 10 minutes, diisopropylphosphonomethyl p-toluenesulfonate (350 mg, 1.0 mmol, 1.0 equiv) is added. The mixture is stirred in a 45 ° C. bath for 3.5 hours. The reaction is stopped with a pH 7 phosphate buffer. Extraction with diethyl ether gives the crude product, which is purified by silica gel chromatography (elution with 45% ethyl acetate in hexane) to give 178 mg of 526-25 (68%).

To a solution of 526-25 (168 mg, 0.69 mmol, 1 eq) in 12 mL of acetone is added 8 mL of water containing 273 mg of NaHCO ₃ . The mixture is then cooled to 0 ° C. 4 mL of water containing oxone (519 mg, 0.85 mmol, 1.3 eq) is added in portions over 5 minutes. The mixture is stirred vigorously for 2.5 hours. The mixture is then evaporated under reduced pressure to remove most of the acetone. The aqueous residue is extracted with ethyl acetate to give the crude product, which is purified by silica gel chromatography to give 526-26 as a clear oil.

To a 0.25 mL DMF solution of 526-26 (21 mg, 0.076 mmol, 1.0 eq), cytosine (13 mg, 1.5 eq), cesium carbonate (6 mg, 0.25 eq), and magnesium t-butoxide were added. Added. The mixture is heated at 140 ° C. for several hours. After cooling to room temperature, the reaction mixture is purified by reverse phase HPLC to give 12.5 mg of 526-27 (42%). ¹ H NMR (CDCl 3): d 9.60 (br s, 1 H), 8.96 (br s, 1 H), 7.87 (d, 1 H), 6.21 (d, 1 H), 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.

  The conversion from 526-27 to 526-28 is described in Scheme 526-2 above. Using the procedures described herein, conversion of 526-28 to the corresponding diphosphophosphonate 526-29 and phosphoprodrug (eg, 526-30) can be performed.

  Cyclopentyl intermediate 526-31 can be prepared by procedures analogous to US52020624 and US5340816 (Scheme 526-4). Diol 526-31 is converted to cyclopentenone 526-32 and treated with IBr in the presence of the appropriate phosphonate alcohol to give 526-33. The iodide 526-33 is inverted to give the cyclopentanone intermediate 526-34. Nysted methyleneation (US38665848; Aldrichim. Acta (1993) 26:14) gives exocyclic methylene 526-35, which can be deprotected to give 526-36.

  Cyclopentanone 526-34 can be a versatile intermediate to form other compounds of the invention by reduction to cyclopentyl 526-37 or Wittig or Grubb olefination with alkenyl 526-38.

  (Scheme 526-4)

Scheme 526-5 converts intermediate 526-39 to guanosylcyclopentenone 526-40 (J. Am. Chem. Soc. (1972) 94: 3213) followed by treatment with IBr and diethylphosphomethanol. Iodide 526-41 is obtained (J. Org. Chem. (1991) 56: 2642). Nucleophilic substitution with AgOAc gives acetate 526-42. 526-43 was obtained after methyleneation using Nysted's procedure (US38665848; Aldrichim. Acta 1993, 26, 14), the acetate group was removed by addition of sodium methoxide, and the resulting alcohol was inverted by Mitsunobo protocol. Deprotection of the second acetate gives 526-44. Desilylation of 526-44 with tetrabutylammonium fluoride (TBAF) provides 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 were placed in a 500 mL round bottom flask. Acetone (220 mL) was added. To this slurry stirred at room temperature, 3.6 mL of 96% sulfuric acid was added. The mixture was stirred for an additional 24 hours at room temperature under a nitrogen atmosphere. Filter the mixture to remove solids. The solid was washed with 50 mL acetone. To the combined filtrate was added 25.3 mL of concentrated ammonium hydroxide. The precipitate was removed by filtration. The filtrate was evaporated under reduced pressure to give an oil, which was coevaporated with absolute ethanol to give a yellow oil. The crude product was stirred vigorously with 160 mL of 0.06 M aqueous HCl at room temperature for 2.5 hours. The reaction mixture was homogeneous at the end of the reaction. Solid NaHCO ₃ (3.26 g) was added in portions. After completion of gas evolution, the mixture was filtered. The filtrate was frozen and lyophilized overnight to give a syrup that was dissolved in ethyl acetate and dried over anhydrous Na ₂ SO ₄ to give the desired diol as a yellow oil. Proton NMR showed that the product was over 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 equiv) and 2-iodobenzoyl chloride (7.01 g, 26.3 mmol) were added to anhydrous dichloromethane (25 mL). The solution was cooled with an ice-water bath. Triethylamine (3.85 mL, 27.6 mmol, 1.05 eq) was added dropwise with a syringe. The mixture was stirred at 0 ° C. for 30 minutes and slowly warmed to room temperature over 1 hour. Water was added to the reaction mixture. The mixture was washed with 1M aqueous HCl. The aqueous wash was extracted with 20 mL dichloromethane. The combined organic extracts were washed with a mixture of 20 mL brine and 5 mL saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by silica gel chromatography (elution with 0-50% EtOAc in hexanes) to give the desired monoester 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): calcd 420.01 (M + H ⁺ ), 443.00 (M + Na ⁺ ), found 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 equiv) was dissolved in 35 mL anhydrous dichloromethane. Dess-Martin periodinane (9.6 g, 22.6 mmol, 1.25 equiv) was added. The mixture was stirred at room temperature for 14 hours. 1M sodium sulfite solution (7.5 mL) was added. The resulting mixture was stirred at room temperature for an additional 2 hours. Saturated NaHCO ₃ solution was added in portions to adjust the pH of the aqueous phase to 6. The two phases were separated. The aqueous phase was extracted twice with 15 mL dichloromethane. The combined organic extracts were washed with brine and dried over anhydrous Na ₂ SO ₄ for 4 hours with good stirring. This was filtered and dried over excess anhydrous MgSO ₄ with good stirring. The mixture was filtered and concentrated in vacuo to give the product as a clear oil, 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): calcd _{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 obtained in the previous step (6.15 g, 14.7 mmol, 1.0 eq) was dissolved in 29 mL of THF. The solution was cooled in an ice water bath. A solution of 3.0M methylmagnesium bromide in diethyl ether (5.39 mL, 16.2 mmol, 1.1 eq) was added dropwise with a syringe. The mixture was stirred at 0 ° C. for 2 hours. To the reaction mixture was added aqueous citric acid (1 M, 10 mL). The resulting mixture was evaporated under reduced pressure to remove most of the THF. The aqueous residue was extracted twice with 10 mL EtOAc. The organic extract was washed with saturated NaHCO ₃ and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the product as a white solid. 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): calc. 457.01 (M + Na ⁺ ), found 457.27 (M + Na ⁺ ).

  Example 531 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 531-5: To a 20 mL anhydrous pyridine solution of 530-4 (6.1 g, 14.1 mmol), triethylamine (3.13 mL, 22.5 mmol) and DMAP (0.343 g, 2.8 mmol) were added. Then benzyl 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 under reduced pressure to remove most of the pyridine. The residue was acidified with 1M aqueous citric acid solution. The resulting mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (0-35% ethyl acetate in hexanes) to give 7.0 g (92%) of 5. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ 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): calc. 561.04 (M + Na ⁺ ), found 561.06 (M + Na ⁺ ).

  Example 532 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 532-6: Acetic anhydride (7.7 mL) was added to a 26 mL glacial acetic acid solution of 531-5 (7.0 g, 13 mmol). The solution was cooled in an ice water bath. Concentrated sulfuric acid (1.9 mL) was added dropwise with a syringe over 10 minutes. The cooling bath was removed and the solution was warmed to room temperature and stirred at that temperature for an additional 20 minutes. The reaction mixture was poured into a mixture of 75 mL diethyl ether and 75 g ice. The phases were separated and the aqueous phase was extracted with 75 mL diethyl ether. The combined ether extracts were stirred with 250 mL water. Solid NaHCO3 was added in portions until gas evolution ceased. The phases were separated. The aqueous phase 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. Two diastereomers (probably anomers) of the same molecular weight were present in the composition mixture. 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 dichloromethane. The solution was cooled in an ice water bath. A solution of SnCl ₄ in dichloromethane (1.0 M, 29 mL, 29 mmol) was added via syringe. The cooling bath was removed and the mixture was warmed to room temperature and stirred for an additional hour. The mixture was again cooled to 0 ° C. Triethylamine (15 mL) was added via syringe. The resulting solution was poured into a mixture of 75 g ice and 75 mL EtOAc. The mixture was filtered through Celite. The solid was washed thoroughly with EtOAc. The combined filtrate was washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (25-75% EtOAc in hexanes). As a result, 7 was obtained as a pale yellow foam. Yield: 6.0 g (75%). ¹ H NMR (DMSO-d ₆ , 300 MHz): δ 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 ^< + ^> ), Found 713.08 (M + Na ^< + ^> ).

  Example 534 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 534-8: To a 30 mL dichloromethane solution of 533-7 (4.7 g, 6.8 mmol) was added 27.2 mL 1.0 M KH ₂ PO ₄ aqueous solution. 0.8M NaOCl aqueous solution was added. The mixture was stirred at room temperature for 1 hour. Methanol (10 mL) was added. Solid K2CO3 was added in portions until the pH of the aqueous phase reached 9-10. The mixture was stirred at room temperature for an additional hour. 1M aq Na ₂ SO ₃ (10 mL) was added and the mixture was stirred at room temperature for an additional 30 minutes. The two phases were separated. The aqueous phase was further extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 534-8 as a yellow foam, which was used directly in the next step without further purification. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ 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 ): δ 20.63 (s, 1P) ppm. MS (m / z): calcd 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, 6.8 mL acetonitrile, and 6.8 mL water obtained above, iodobenzene diacetate (4.97 g, 15 mmol) and TEMPO (0.213 g, 1. 36 mmol) was added. The mixture was stirred vigorously at room temperature for 6 hours. This was then frozen and lyophilized to give an orange solid which was dissolved in dichloromethane and purified by silica gel chromatography (0-10% MeOH in CH2Cl2) to give 534-9 as a pale yellow solid. It was. Yield: 2.8 g (87% over 2 steps). ¹ H NMR (DMSO-d ₆ , 300 MHz): δ 13.39 (br s, 1H), 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 ): δ 20.79 (s, 1 P) ppm. MS (m / z): Calculated 473.12 (M−H ⁻ ), found 472.95 (M−H ⁻ ).

  Example 536 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 536-10: To a 2.0 mL anhydrous DMF solution of 535-9 (474 mg, 1.0 mmol) was added pyridine (238 mg, 3.0 mmol) and lead tetraacetate (1.33 g, 3.0 mmol). . The mixture was stirred at room temperature for 7 hours while protected from light. It was then poured into a mixture of 10 g ice and 10 mL diethyl ether. The mixture was filtered to remove the precipitate. The biphasic filtrate was separated. The aqueous phase was extracted twice with ether. The combined ether extracts were washed with 1M citric acid and saturated NaHCO ₃ , and brine. After drying over anhydrous MgSO 4, the ether solution was concentrated under reduced pressure to give 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 ^< + ^> ), Found 511.11 (M + Na ^< + ^> ).

  Example 537 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 537-11: To a 2.0 mL anhydrous acetonitrile solution of 536-10 (211 mg, 0.43 mmol), 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 room temperature for 3 hours. An additional 443 mg of O, O-bis (trimethylsilyl) uracil was added and the mixture was stirred at room temperature for an additional 4 hours. 2,6-lutidine (371 mg, 3.46 mmol) was added dropwise with a syringe, and then TMS-I (259 mg, 1.3 mmol) was added dropwise. The mixture was stirred at room temperature for an additional hour and poured onto 10 g ice. The mixture was exsanguinated and filtered through a Celite pad. The filtrate was frozen and lyophilized to give a yellow solid that was dissolved in water and purified by reverse phase HPLC to give 537-11 as a white solid. Yield: 20 mg (10%). MS (m / z): calc. 483.08 (M−H ⁻ ), found 483.34 (M−H ⁻ ).

  Example 538 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 538-12: NaOH (4.3 mg, 0.11 mmol) was added to a 0.3 mL aqueous solution of 537-11 (17 mg, 0.035 mmol). 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): δ 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): δ 14.60 (s, 1 P) ppm. MS (m / z): Calculated value 337.04 (M−H ⁻ ), found value 337.38 (M−H ⁻ ).

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: To a stirred solution of 527-1 (50 mg, 0.11 mmol) in 1 mL acetonitrile under nitrogen was added 2,4,6-triisopropylbenzenesulfonyl chloride (65 mg, 0.21 mmol), DMAP ( 26 mg, 0.21 mmol), and triethylamine (22 mg, 0.21 mmol) were added. The mixture was stirred at room temperature for 4 hours. Aqueous ammonia (29%, 1 mL) was added. The mixture was stirred at room temperature for 2 hours. After extraction with EtOAc, purification by silica gel chromatography gave 540-2 as a white solid. MS (m / z): calc. 468.15 (M + H ⁺ ), found 468.0 (M + H ⁺ ).

  Example 541 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 541-3: 2,6-Lutidine (118 mg, 1.10 mmol) and TMS-I (165 mg, 0.84 mmol) were added to the 540-2 acetonitrile solution obtained above. The mixture was stirred at room temperature for 2 hours. Triethylamine was added followed by water. The mixture was then frozen and lyophilized to give a solid residue. The crude product was purified by reverse phase HPLC to give 541-3 as a white solid. Yield: 44 mg (97% over 2 steps). MS (m / z): Calculated 410.1 (M−H ⁻ ), Found 410.2 (M−H ⁻ ).

  Example 542 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 542-4: NaOH (20 mg, 0.5 mmol) was added to a 0.5 mL aqueous solution of 541-3 (40 mg, 0.097 mmol). The solution was stirred at room temperature for 30 minutes. Reverse phase HPLC purification gave 542-4 as a white solid. Yield: 28 mg (94%). ¹ H NMR (D ₂ O, 300 MHz) δ 7.79 (d, J = 7.6 Hz, 1H), 5.95 (d, J = 7.6 Hz, 1H), 5.88 (d, J = 2) .8 Hz, 1 H), 5.40 (m, 1 H), 4.42 (m, 1 H), 3.78 (dd, J = 12.8, 9.8 Hz, 1 H), 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) δ 14.66 ppm. MS (m / z): Calculated value 306.05 (M−H ⁻ ), found value 305.8 (M−H ⁻ ).

  Example 543 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 543-5: To a 0.25 mL DMF solution of diacid 542-4 (9 mg, 0.029 mmol) was added tributylamine (5.4 mg, 0.03 mmol) followed by carbonyldiimidazole (48 mg, 0.3 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, at which point MeOH (0.010 mL) was added and stirred for an additional 30 minutes. A solution of tributylammonium pyrophosphate (161 mg, 0.3 mmol) in DMF (0.64 mL) was added and the reaction mixture was stirred for 14 hours. After the solvent was evaporated under reduced pressure, 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) α7.78 (d, J = 7.6 Hz, 1H), 6.02 (d, J = 7.6 Hz, 1H), 5.88 (d, J = 2) .9 Hz, 1 H), 5.42 (m, 1 H), 4.41 (m, 1 H), 4.05-3.62 (m, 2 H), 3.05 (q, J = 7.4 Hz, triethyl Ammonium), 2.23-1.95 (m, 2H), 1.13 (t, J = 7.4 Hz, triethylammonium) ppm. _{^{31 P NMR (D 2 O,}} 300 MHz) δ7.58 (d), - 8.34 (d), - 22.71 (t) ppm. MS (m / z): Calculated 465.98 (M−H ⁻ ), found 466.16 (M−H ⁻ ).

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: To a stirred pyridine solution of 1-O-methyl-2′-deoxy-D-ribose (23.9 g, 161.41 mmol) under nitrogen was added t-butyldiphenylsilyl chloride (48 mL, 186 mmol). ) Was added dropwise. Upon completion of the addition, N, N-dimethyl-4-aminopyridine was added as a solid. The reaction was stirred at room temperature for 12 hours and monitored by TLC. Upon completion of the reaction by TLC, pyridine was removed under reduced pressure. The oily residue was suspended in ethyl acetate (150 mL) and a white solid was formed. The mixture was filtered and the solid was washed with 50 mL of additional ethyl acetate. The solid was then discarded. 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 phase was collected and dried over MgSO ₄ (anhydrous). Evaporation and purification by column chromatography gave the desired mixture of diastereomers 545-2. Yield: 31.15 g (500%). ¹ H NMR (CD ₃ CN, 300 MHz): δ 1.08 m, 9H); 1.85 m 1H; 2.27 m 2H; 3.3 s 3H; 3.7 m 2H; 3.90 m 1H; 4 .27 m 1H; 5.06 m 1H, 7.45 m 6H; 7.76 m 4H. 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 anhydrous THF (50 mL) under nitrogen at room temperature. To this stirred solution, a mixture of benzoic acid (3.162 g, 25.9 mmol) and diisopropyl azodicarboxylate dissolved in anhydrous THF (30 mL) was added dropwise. After the addition was complete, the reaction was stirred at room temperature for 12 hours. After completion of the reaction by TLC, the solvent was removed under reduced pressure. The residue was suspended in diethyl ether (60 mL). Hexane (120 mL) was added and the formed solid was filtered and discarded. The solvent was removed by rotary evaporation and the product 546-3 was purified by column chromatography (2% -15% EtOAc in hexane). Yield: 3.074 g (48.4%). ¹ H NMR (CD ₃ CN, 300 MHz): δ 0.98 m 9H; 2.07 m 1H; 2.42 m 2H; 3.35 s 3H; 3.85 m 1H; 3.99 m 1H; 5.10 m 1H; 7.30 m 1H; 7.47 m 5H; 7.65 m 6H; 7.80 m 1H; 7.95 m 1H; 8.22 m 1H 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 hydroxymethylphosphonic acid diethyl ester (7.76 mL, 52.65 mmol) were dissolved in 200 mL acetone. Toluene was removed by rotary evaporation under reduced pressure at 70 ° C. to reduce the reaction volume to about 25 mL. The reaction was cooled to room temperature and p-toluenesulfonic acid monohydrate (0.490 g, 2.58 mmol) was added as a solid with toluene (200 mL). Toluene was removed by rotary evaporation under reduced pressure at 70 ° C., and the reaction volume was again reduced to about 25 mL. Additional aliquots of toluene were added and removal by evaporation was repeated each time. The reaction was monitored by TLC and upon completion the residue was suspended in ethyl acetate ethyl acetate (100 mL). The organic phase was washed with sodium bicarbonate (saturated), brine and dried over MgSO ₄ (anhydrous). The desired phosphonate 547-4 was purified by column chromatography (10% to 90% EtOAc in hexane). Yield: 2.89 g (33%). ¹ H NMR (DMSO-d ₆ , 300 MHz): δ 0.92 s 9H; 1.25 t 6H; 2.35 t 2H; 3.84 m 4H; 4.05 m 4H; 4.32 q 1H; 37 t 1H; 5.62 q 1H; 7.26 t 2H; 7.30-7.55 m 8H; 7.60 d 2H; 7.65 t 1H; 7.82 d 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 room temperature for 12 hours. The reaction was monitored by TLC and upon completion methanol was removed under a stream of nitrogen. 6 mL of 1N acetic acid (aq) was added and the aqueous phase was extracted with ethyl acetate (2 × 125 mL). The organic phases were combined and dried over Na ₂ SO ₄ (anhydrous). The final product 548-5 was purified by column chromatography (50% -100% EtOAc in hexane). Yield: 1.59 g (90%). ¹ H NMR (DMSO-d ₆ , 300 MHz): δ 1.21 t 6H; 2.35 t 2H; 3.62-3.82 m 4H; 4.05 m 4H; 4.12 q 1H; 5.30 t 1H; 5.49 q 1H; 7.47 t 2H; 7.65 t 1H; 7.90 d 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 along with a catalytic amount of TEMPO (0.115 g, 0.74 mmol). The fish were stirred at room temperature for 12 hours and monitored by TLC. Upon completion of the reaction, it was frozen and lyophilized. Carboxylic acid 549-6 was purified by column chromatography (0-10% methanol in dichloromethane). Yield: 0.750 g (51%). ¹ H NMR (CD ₃ CN, 300 MHz): δ 1.30 t 6H; 2.45 t 2H; 3.84 m 1H; 4.00-4.20 m 5H; 4.82 d 1H; 5.50 t 1H 5.82 q 1H; 7.54 t 2H; 7.65 t 1H; 7.96 d 2H.

  Example 550 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 550-7: To a solution of acid 549-6 (88 mg, 0.22 mmol) in DMF (3.1 mL, 0.07 M) was added anhydrous pyridine (0.027 mL, 0.33 mmol), followed by Lead acetate (146 mg, 0.33 mmol) was added. After 14 hours at room temperature, Et ₂ O / H ₂ O (1: 1, 3 mL) was added. The organics were separated and washed with 1M aqueous citric acid, saturated NaHCO ₃ , saturated aqueous NaCl, and dried over sodium sulfate. After removal of the solvent, the 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: Can. J. et al. Chem. Dichloroethane (1.1 mL, 0.1 M) containing N-acetoxy-diphenylcarbamoylguanine (43 mg, 0.11 mmol) synthesized as described in 65: 1436 (1987) was converted to N, O-bis (trimethylsilyl) acetamide. (0.054 mL, 0.22 mmol). The reaction mixture was heated at 80 ° C. for 20 minutes, after which the solvent was removed under reduced pressure. The crude silylated protected guanine was combined with dichloroethane (1.1 mL, 0.1 M) containing phosphonate 550-7 (50 mg, 0.12 mmol), to which TMSOTf (28 μL, 0.153 mmol) was added. The reaction mixture was heated at 60 ° C. for 5 hours and then quenched with saturated aqueous NaHCO ₃ solution. The solution was 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 column chromatography on silica (2% MeOH / CH ₂ Cl ₂ ) to give the phosphonate diester 551-8 (18 mg, 22%). ¹ H NMR (CDCl ₃ , 300 MHz) δ 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) δ 20.07 (s) ppm. MS (m / z): calc. 744.2 (M + H ⁺ ), found 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 in MeOH (2 mL, 2.0 N) for 9 hours at room temperature. After removal of the solvent under reduced pressure, the crude product was purified by column chromatography on silica (10% MeOH / CH ₂ Cl ₂ ) to give 552-9. ¹ H NMR (CD ₃ OD, 300 MHz) δ 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) δ 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: Anhydrous acetonitrile (0.15 mL, 0.1 M) containing phosphonate guanosine derivative 552-9 (5.8 mg, 0.02 mmol) was added to 2,6-lutidine (0.014 mL, 0 M). .12 mmol) was added followed by iodotrimethylsilane (0.016 mL, 0.12 mmol). After stirring for 15 minutes, triethylamine (0.12 mmol) and methanol (0.020 mL) were added and the solvent was removed under reduced pressure. The crude product was purified by reverse phase column chromatography on C18 (0-10% MeOH / H ₂ O-1% AcOH) to give divalent phosphonic acid 553-10. ¹ H NMR (D ₂ O, 300 MHz) δ 7.91 (s, 1H), 5.86 (d, 1H), 5.41 (m, 1H), 3.42-3.65 (m, 2H) , 2.25-2.36 (m, 2H) ppm. ³¹ P NMR (D ₂ O, 300 MHz) δ 15.16 ppm. MS (m / z): Calculated value 346.1 (M−H ⁻ ), found value 346.3 (M−H ⁻ ).

  Example 554 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 554-11: Tributylamine (0.0086 mL, 0.036 mmol) was added to DMF (144 μL, 0.05 M) containing divalent phosphonic acid 553-10 (2.5 mg, 7.2 μmol). Then carbonyldiimidazole (12 mg, 0.072 mmol) was added. The reaction was stirred at room temperature for 12 hours, at which point MeOH (0.005 mL) was added and stirred for an additional 30 minutes. DMF (0.16 mL) containing tributylammonium pyrophosphate (0.040 mg, 72 mmol) was added and the reaction mixture was stirred for 1 hour. After evaporation of the solvent under reduced pressure, 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) δ 7.94 (s, 1H), 5.85 (d, 1H), 4.47 (m, 1H), 3.71-3.78 (m, 2H) 2.27-2.39 (m, 2H) ppm. ³¹ P NMR (D ₂ O, 300 MHz) δ 8.09 (d), 7.71 (s), 22.04 (t) ppm. MS (m / z): Calculated 505.99 (M−H ⁻ ), Found 506.2 (M−H ⁻ ).

Example 555 Synthesis of Exemplary Compounds of the Invention Schemes 555-5 to 555-9 below describe a general method for preparing [3.1.0] bicyclohexane scaffolds of compounds of Formulas 555-I and 555-II. To do. The exemplary structures, intermediates, substituents, protecting groups, reagents, and synthetic pathways selected for illustration herein are only meant to illustrate general preparation methods and are intended to limit the invention and The method is never intended to be prioritized.

[3.1.0] bicyclohexane scaffolds can be synthesized by intramolecular cyclopropanation of the carbene produced by decomposition of the diazo 1,3-ketoester (Moon et al (2000) Organic Letters 2 (24): 3793-3796). The required 1,3-ketoester 555-5.1 can be prepared from acetoacetate anion addition to ene-aldehyde (eg acrolein) (Scheme 555-5a). For example, ethyl acetoacetate was treated with 2 equivalents of diisopropylamidolithium at −78 ° C. followed by 1 equivalent of acrolein to give 1,3-keto ester 555-5.1 (Yoshimura et al (2002) Jour. Org.Chem.67: 5938-5945). The hydroxyl group can be protected with phenyldimethylsilyl chloride to give 555-5.2 (PG is phenyldimethylsilyl (PhMe ₂ Si—)). Other trialkylsilyl protecting groups may be useful. Diazotization with p-toluenesulfonyl azide gives 555-5.3. Treatment of 555-5.4 with a carbenoid insertion catalyst (eg, CuSO ₄ or Rh (OAc) ₂ ) provides 555-5.3 as a mixture of diastereomers.

(Scheme 555-5a)
The ester of 555-5.4 can be hydrolyzed to hydroxymethyl 555-5.5 or directly saponified to the carboxylic acid 555-5.6 (Scheme 555-5b). With a suitable oxidizing agent, the primary alcohol 555-5.5 can be converted to the carboxylic acid 555-5.6 or its corresponding ester. In the case of an ester, a further deprotection step provides the carboxylic acid 555-5.6. Various oxidation procedures are described in the literature and can be used herein. These include, but are not limited to, the following methods: (i) Dissolution of pyridinium dichromate in Ac ₂ O, t-BuOH, and dichloromethane yields the t-butyl ester followed by trifluoroacetic acid. The ester is converted to the corresponding carboxylic acid by deprotection using reagents such as (Classon, et al, Acta Chem. Scand. Ser. B; 39; 1985; 501-504. Cristalli, et al; J. Med. Chem .; 31; 1988; 1179-1183); (ii) iodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy, the free radical (TEMPO) acetonitrile. The carboxylic acid is obtained by dissolution in (Epp, et l; J. Org.Chem.64; 1999; 293-295.Jung et al; J.Org.Chem.; 66; 2001; 2624-2635;) (iii) sodium periodate, ruthenium chloride Dissolution of (III) in chloroform provides the carboxylic acid (Kim, et al, J Med. Chem. 37; 1994; 4020-4030. Hamma, et al; J. Med. Chem .; 35; 1992; (Iv) dissolution of chromium trioxide in acetic acid gives the carboxylic acid (Olsson et al; J. Med. Chem .; 29; 1986; 1683-1689. Gallo-Rodriguez). et al; J. Med. Chem .; 37; (V) dissolution of potassium permanganate in potassium hydroxide provides the carboxylic acid (Ha, et al; J. Med. Chem .; 29; 1986; 1683-1689. Franchetti, et al; J. Med. Chem .; 41; 1998; 1708-1715) (vi) S. Carboxylic acid is obtained by nucleoside oxidase derived from maltofilia (see Mahmodian, et al; Tetrahedron; 54; 1998; 8171-8182).

  Carboxylic acid 555-5.6 can be converted to acetate 555-5.7 by decarboxylation using lead (IV) tetraacetate (Teng et al; (1994) J. Org. Chem .; 59: 278-280; Schultz, et al; J. Org. Chem .; 48; 1983; 3408-3412). When lead (IV) tetraacetate is used with lithium chloride (see Kochi, et al; J. Am. Chem. Soc .; 87; 1965; 2052), the corresponding chloride 555-5.8 is obtained. It is done. 555-5.8 can also be purified by combination of lead (IV) tetraacetate with N-chlorosuccinimide (Wang, et al; Tet. Asym .; 1; 1990; 527 and Wilson et al; Tet. Asym. 1; 1990; 525). Alternatively, acetate can be converted to other leaving groups such as bromide by treatment with trimethylsilyl bromide (Spencer, et al; J. Org. Chem .; 64; 1999; 3987-3395).

(Scheme 555-5b)
Intermediates 555-5.7 and 555-5.8 are described in Teng et al; Synlett; 1996; 346-348 and US 6,087,482 (paragraph 54, line 64 to line 55, line 20). Can react with various nucleophiles. Specifically, 555-5.7 can be reacted with diethyl hydroxymethylphosphonate in the presence of trimethylsilyl trifluoromethanesulfonate (TMS-OTf) to give 555-5.9 (Scheme 555-5c) . It can be expected that other compounds having the general structure of HO-linker-POR ^P1 R ^P2 can be used as long as the functional groups in these compounds are compatible with the coupling reaction conditions. There are numerous examples in the published literature describing the coupling of 1 'acetylfuranosyl compounds with various alcohols. Silver (I) salt (see Kim et al (1991) J. Org. Chem. 56: 2642-2647, Toikka et al (1999) J. Chem. Soc. Perkins Trans. 1; 13: 1877-1884). ), Mercury (II) salts (see Veeneman et al (1987) Recl. Trav. Chim. Pays-Bas; 106: 129-131), boron trifluoride diethyl ether compounds (Kunz et al (1985) Hel. Chim Acta; 68: 283-287), tin (II) chloride (see O'Leary et al (1994) J. Org. Chem. 59: 6629-6636), alkoxides (Shortacy- Fowler et al (2001) N a number of reagents such as cleosides &Nucleotides; see 20: 1583-1598) and iodine (see Kartha et al (2001) J. Chem. Soc. Perkins Trans. 1 770-772). Reaction can be promoted. These methods can be selectively used in combination with different methods in the formation of intermediates from 555-5.6 using various free radicals (LG).

(Scheme 555-5c)
Introduction of a protecting group (denoted PG herein) into a compound and removal of the protecting group from the compound are techniques commonly practiced in organic synthesis. A number of sources of this technique, the published literature ^{(e.g., Greene and Wuts, Protecting Groups in} Organic Synthesis, 3 rd Ed., John Wiley & Sons, Inc., 1999) available from. The main purpose is to transiently convert the functional group and mask its reactivity so that it can go through a series of subsequent reaction procedures. The original functional group can then be repaired by a deprotection procedure envisioned in advance. Thus, the transformation in Scheme 555- (5a-c) is intended to build a [3.1.0] scaffold with the appropriate potential functionality or reaction components.

A ribofuranose analog 555-6.1 (Z ¹ is, for example, a hydroxyl group or a protected hydroxyl group, respectively) can be synthesized from a keto group of a certain intermediate (eg, 555-5.4) (Scheme 555- 6). The hydroxyl group can be protected as a benzoyl (Bz) ester to give 555-6.2. The bridgehead carboxylic acid ester can then be orthogonally hydrolyzed to give 555-6.3 or reduced to hydroxymethyl 555-6.4. For example, oxidation of 555-6.4 using iodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy (free radical (TEMPO)) corresponds to the primary alcohol. Convert to acid 555-6.3. Further oxidation of 555-6.3 using lead tetraacetate can give 555-6.5. Coupling 555-6.5 with diethyl hydroxymethylphosphonate (available from Sigma-Aldrich, Cat. No. 39, 262-6) by TMS-OTf can give 555-6.6. Treatment of 555-6.6 with TMS-Br converts the phosphodiester to the corresponding phosphonic acid 555-6.7. Deprotection of the 2 ′ and 3 ′ hydroxyl groups (eg, NH _{3 in} methanol) yields 555-6.8.

(Scheme 555-6)
As an illustrative example, 555- (6.6-6.8) containing phosphonic acid is used. Other phosphonate forms can be utilized via phosphonic acid, and other forms such as the corresponding diesters can also be utilized. See Schemes 555-A and 555- (1-4) for examples of interchange of phosphonate moieties.

  Compounds such as 555-6.6 can be further synthesized by selective deprotection of PG and introduction of a nucleobase moiety (B). For example, PG is a trialkylsilyl (eg, triethylsilyl, t-butyldimethylsilyl, or phenyldimethylsilyl) and 555-6.6 with a trifluoride reagent (eg, THF containing tetrabutylammonium fluoride). PG can be selectively removed by the treatment. The resulting hydroxyl group can be converted to a free radical (LG) such as chloro or acetate 555-7.1 under Vorbruggen type reaction conditions or establish a carbon-hydrogen bond with a nucleobase or a protected nucleobase reagent To react, hydroxyl 555-7.2 can be reacted in situ (eg, Mitsunobu conditions) to give 555-7.3 (Scheme 555-7). Suitable nucleobases or protected nucleobase reagents (B) include thymidine, cytosine, adenine, guanine, and silylated forms thereof. The resulting covalent bond can be 9-purinyl or 1-pyrimidinyl. Other regioisomers can be obtained and pure 555-7.3 compounds can be obtained using conventional separation means. The 2 'and 3' protecting groups (Bz = benzoyl) from intermediate 555-7.3 using aqueous base can be removed to give 555-7.4. Removal of the ethyl group at 555-7.4 using a dealkylating reagent such as trimethylsilyl bromide gave phosphonic acid 555-7.5, which is the other shown in Schemes 555-A and 1-4. Further synthesis can be done according to the reaction on the phosphonate moiety, including diphosphophosphonate and phosphophosphonate compounds.

(Scheme 555-7)
Scheme 555-8 shows an example of a pathway for 2'-b-methyl, 2'-3 'hydroxybicycloadenine compounds. The 3 ′ and 5 ′ hydroxyl groups (Kim, et al (2002) J. Med. Chem. 45: 208-218) of the [3.1.0] bicyclo analog of adenosine 555-8.1 were selectively silylated. 555-8.2 can be obtained. The 2 'hydroxyl group can be oxidized under Dess-Martin periodinane conditions to give 555-8.3. The 2 'keto of 555-8.3 can be methylated with Wittig reagent and desilylated to give 555-8.4. Epoxidation of 555-8.4 gives 555-8.5. Hydride attack on the methylene carbon of epoxide 555-8.5 yields 555-8.6 with a 2 ', 3'-a-dihydroxy, 2'-b-methyl motif. This synthetic route is versatile for the preparation of various 2 ′, 3′-a-dihydroxy, 2′-b-methyl [3.1.0] bicyclo compounds (B = any protected or unprotected nucleobase). can do.

(Scheme 555-8)
The 5 ′ hydroxymethyl group of 2 ′, 3′-a-dihydroxy, 2′-b-methyl [3.1.0] bicyclo compounds (eg, 555-8.6) is selected as shown in Scheme 555-9, etc. Can be synthesized by chemical reaction. The 5 ′ carbon can be removed by oxidative decarboxylation and the phosphonate moiety can be attached via an oxygen atom directly attached to the [3.1.0] backbone. The 5 ′ hydroxyl group of 555-8.6 is selectively protected as 5 ′ tert-butyldiphenylsilyl ether (TBDPS), and then the 2 ′ and 3 ′ hydroxyl groups are protected as methoxymethyl ether to yield 555-9.1. can get. Removal of the 5 ′ TBDPSi group using tetrabutylammonium fluoride (TBAF) and oxidation of the resulting hydroxymethyl with periodinane reagents PhI (OAc) ₂ and TEMPO to give the carboxylic acid 555-9.2 Can do. Oxidative decarboxylation of 555-9.2 using lead tetraacetate and treatment with lithium hydroxide provides 555-9.3. Alkylation of the hydroxyl group at 555-9.3 with bromomethyldiethyl phosphonate provides 555-9.4. Removal of the ethyl group and 2 ′, 3 ′ methoxymethyl (MOM) protecting group of the phosphonate using iodotrimethylsilane provides 555-9.5. For example, carbonyldiimidazole (CDI) can be used to activate the 555-9.5 phosphonic acid group and react with the anion of pyrophosphate to give diphosphophosphonate 555-9.6. Other phosphonic acid transformations can be performed as described in Schemes 555-A and 555 (1-4).

(Scheme 555-9)
Intermediate 555-8.2 can be used for multiple purposes in the preparation of 2'hydroxy [3.1.0] bicyclo compounds (Scheme 555-10). Protection of the 2 'hydroxyl group with para-methoxybenzyl bromide and silyl removal with TBAF gives 555-10.1. 555-10.2 is obtained by protecting the 5 ′ hydroxyl group with a TBDPSi group. Phenylchlorothionoformate is used to form the 3 'thioester of 555-10.2, which is then reduced with tributyltin hydride with AIBN to give 555-10.3. Desilylation with TBAF and oxidation with BAIB and TEMPO yields the carboxylic acid 555-10.4.

(Scheme 555-10)
Oxidative decarboxylation of 555-10.4 with lead tetraacetate followed by treatment with lithium hydroxide provides the hydroxyl 555-11.1 (Scheme 555-11). Alkylation of hydroxyl 555-11.1 with bromomethyldiethyl phosphonate gives 555-11.2. Cleavage of the ethyl group from diethylphosphonate with iodotrimethylsilane and deprotection of the 555-11.2 para-methoxybenzyl group with cerium ammonium nitrate yields 555-11.3. Activation of the phosphonate with CDI and addition of pyrophosphonate gives the 2'-hydroxydiphosphonate [3.1.0] compound 555-11.4.

(Scheme 555-11)
Example 556 Synthesis of Exemplary Compounds of the Invention The following scheme describes a general method for preparing 2′fluoro, 2′-3 ′ didehydronucleoside scaffolds of compounds of the invention.

  Methods for introducing fluorine at the 2 'position of ribonucleosides and nucleoside analogs are described in US5824793; US5859233; et al Journal of Medicinal Chemistry (2003), 46 (3), 389-398; Moon, H. et al. et al Journal of the Chemical Society, Perkin Transactions 1 (2002), (15), 1800-1804; Lee, Kyeong; Choi, Y. et al. et al Journal of Medicinal Chemistry (2002), 45 (6), 1313-1320; Lee, Kyeong; Choi, Yongseok; et al Nucleosides & Nucleotides (1999), 18 (4 & 5), 537-540; Lee, K. et al. et al Journal of Medicinal Chemistry (1999), 42 (7), 1320-1328; Choi, Y. et al. et al Tetrahedron Letters (1998), 39 (25), 4437-4440; Chen, Shu-Hui et al Bioorganic & Medicinal Chemistry Letters (1998), 8 (13), 1589-1594; Siddiquat et al. 1998), 39 (13), 1657-1660; Nakayama, Toshiaki et al Nucleic Acids Symposium Series (1991), 25 (Symp. Nucleic Acids Chem., 18th, 1991Jun Jur, 1991), 191-2g; of Medicin l Chemistry (1991), 34 (5), 1640-6; Sterzykki, Roman Z et al Journal of Medicinal Chemistry (1990), 33 (8), 2150-7; Martin, Joseph A ur al he h 90 ), 33 (8), 2137-45; Watanabe, Kyoichi et al. Journal of Medicinal Chemistry (1990), 33 (8), 2145-50; Zemlika et al. 3213-3218.

  Scheme 556 (AF) shows the synthetic route used to prepare the exemplary embodiments shown herein.

(Scheme 556-A)
Adenosine 556-A. The (−) enantiomer of 1 was tritylated in the pyridine with the excess of trityl chloride (Tr, triphenylmethyl Ph ₃ C—) with dimethylaminopyridine in the pyridine and the N-6 and 5 ′ hydroxyl groups of the adenine exocyclic amine. 556-A. 2 was obtained and treated with triflic anhydride in dichloromethane and DMAP to give 556-A. 3 is obtained (Scheme 556-A). The 2 ′ triflate group was replaced with fluoride using tetrabutylammonium fluoride in THF at room temperature to obtain 556-A. 4 is obtained.

Example 600
For purposes of illustration but not for the purpose of limiting the invention, embodiments of the invention are shown in tabular form below (Table 100). These embodiments are represented by the general formula “MBF” below.

Each embodiment of MBF is shown as a substitution nucleus (Sc). Sc is described herein in Formulas 1-336 (where A ⁰ is the covalent point of attachment of Sc to Lg) and Tables 1.1-1.5 below. For the embodiments described in Table 100, Sc is a numbered nucleus, and each substitution is indicated in turn by letters or numbers. Tables 1.1-1.5 are the nuclear schedules used in forming the embodiment of Table 100. Each nucleus (Sc) is indicated by a number from Table 1.1 to 1.5, and this designation is recognized at the beginning of each embodiment name. Similarly, Tables 10.1 to 10.19 and 20.1 to 20.36 list selective linking group (Lg) and prodrug (Pd ¹ and Pd ² ) substitutions, indicated by letters or numbers, respectively. Accordingly, compounds of formula MBF include compounds having Sc groups based on formulas 1-336 herein and the compounds of Table 100 below. In all cases, the compound of formula MBF has an Lg group and pd ¹ and pd ² are shown in the table below.

Thus, each named embodiment of Table 100 is represented by a number indicating a nucleus from Tables 1.1-1.5 followed by a letter indicating a linking group (Lg) from Tables 10.1-10.109, and Two prodrug groups (Pd ¹ and Pd ² ) from Tables 20.1-20.36 are shown with two numbers. In graphical tabular form, each embodiment of Table 100 is shown as a number having the following syntax:

Sc. Lg. Pd ¹ . Pd ²
Each Sc group with a tilde (“ ^˜ ”) is shown. Tilda is a covalent bond point between Sc and Lg. It is to be understood that Q ¹ and Q ² of the linking group (Lg) do not represent groups and atoms, but simply represent bonds. Q ¹ is the covalent bond site to the nucleus (Sc) and Q ² is the covalent bond point to the phosphorus atom of formula MBF. Each prodrug group (Pd ¹ and Pd ² ) is covalently bonded to the phosphorus atom of MBF with a tilde symbol (“˜”). Some embodiments of Tables 10.1 to 10.19 and 20.1 to 20.36 are divided into letters and numbers (10.1 to 10.19) or numbers and letters (Tables 20.1 to 20.36). Can be shown in combination. For example, BJ1 and BJ2 are the notations in Table 10. In any case, the notations in Tables 10.1 to 10.19 always begin with letters, and the notations in Tables 20.1 to 20.36 always begin with numbers. When the nucleus (Sc) is shown in square brackets ("[]") and the covalent bond is shown outside the bracket, the covalent bond point between Sc and Lg can be at any substitutable site of SC. Selection of attachment points is described herein. For purposes of illustration and not limitation of the invention, the point of attachment is selected from the points of attachment described in the schemes and examples.

(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 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 1.239.239; 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 1.B.154.157; 1.B.154.157; 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.157.16 9; 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.240.1 57; 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. 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 1.237.240; 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 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.157.16 9; 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.240.1 57; 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 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 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.157.16 9; 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.240.1 57; 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 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 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.157.16 9; 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.240.1 57; 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 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. 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. 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 1.237.240; 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 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 1.239.239; 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 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.157.16 9; 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. 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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 prodrug
1.O.228.228; 1.O.228.229; 1.O.228.230; 1.O.228.231; 1.O.228.236; 1.O.228.237; 1.O.228.238; 1.O.228.239; 1. 1.O.228.157; 1.O.228.169; 1.O.228.172; 1.O.228.175; 1.O.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.O.230.228; 1. 1.O.230.230; 1.O.230.231; 1.O.230.236; 1.O.230.237; 1.O.230.238; 1.O.230.239; 1.O.230.154; 1.O. 230.157; 1.O.230.166; 1.O.230.169; 1.O.230.172; 1.O.230.175; 1.O.230.240; 1.O.230.244; 1.O.231.228; 1.O.231.229; 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.O.238.229; 1.O.238.230; 1.O.238.231; 1.O.238.236; 1.O.238.237; 1.O.238.238 1.O.238.239; 1.O.238.154; 1.O.238.157; 1.O.238.166; 1.O.238.169; 1.O.238.172; 1.O.238.175; 1.O.238.240; 1 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.O.154.228; 1.O.154.229; 1.O.154.230; 1.O.154.231; 1.O.154.236; 1.O.154.237; 1.O.154.238; 1.O.154.239; 1 .O.154.154; 1.O.154.157; 1.O.154.166; 1.O.154.169; 1.O.154.172; 1.O.154.175; 1.O.154.240; 1.O.154.244; 1.O .157.228; 1.O.157.229; 1.O.157.230; 1.O.157.231; 1.O.157.236; 1.O.157.237; 1.O.157.238; 1.O.157.239; 1.O.157.154 ; 1.O.157.157; 1.O.157.166; 1.O.157.16 9; 1.O.157.172; 1.O.157.175; 1.O.157.240; 1.O.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.O.166.240; 1.O.166.244; 1.O.169.228; 1.O.169.229; 1.O.169.230; 1.O.169.231; 1.O. 169.236; 1.O.169.237; 1.O.169.238; 1.O.169.239; 1.O.169.154; 1.O.169.157; 1.O.169.166; 1.O.169.169; 1.O.169.172; 1.O.169.175; 1.O.169.240; 1.O.169.244; 1.O.172.228; 1.O.172.229; 1.O.172.230; 1.O.172.231; 1.O.172.236; 1. O.172.237; 1.O.172.238; 1.O.172.239; 1.O.172.154; 1.O.172.157; 1.O.172.166; 1.O.172.169; 1.O.172.172; 1.O. 172.175; 1.O.172.240; 1.O.172.244; 1.O.175.228; 1.O.175.229; 1.O.175.230; 1.O.175.231; 1.O.175.236; 1.O.175.237; 1.O.175.238; 1.O.175.239; 1.O.175.154; 1.O.175.157; 1.O.175.166; 1.O.175.169; 1.O.175.172; 1.O.175.175; 1. O.175.240; 1.O.175.244; 1.O.240.228; 1.O.240.229; 1.O.240.230; 1.O.240.231; 1.O.240.236; 1.O.240.237; 1.O. 240.238; 1.O.240.239; 1.O.240.154; 1.O.240.1 57; 1.O.240.166; 1.O.240.169; 1.O.240.172; 1.O.240.175; 1.O.240.240; 1.O.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.O.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.O.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.240.15 7; 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 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 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 1.239.239; 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 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.157.16 9; 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.240.1 57; 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 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 1.157.228; 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.157.16 9; 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. 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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 2.237.240; 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 2.239.239; 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 2.157.228; 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.157.16 9; 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.240.1 57; 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 2.237.240; 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 2.239.239; 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.157.16 9; 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.240.1 57; 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 2.237.240; 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 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 2.239.239; 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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 2.237.240; 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 2.239.239; 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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.240.15 7; 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 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.O.230.231; 2.O.230.236; 2.O.230.237; 2.O.230.238; 2.O.230.239; 2.O.230.154; 2.O. 230.157; 2.O.230.166; 2.O.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 2.237.240; 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 2.239.239; 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.O.154.228; 2.O.154.229; 2.O.154.230; 2.O.154.231; 2.O.154.236; 2.O.154.237; 2.O.154.238; 2.O.154.239; 2 2.O.154.154; 2.O.154.157; 2.O.154.166; 2.O.154.169; 2.O.154.172; 2.O.154.175; 2.O.154.240; 2.O.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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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 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 2.237.240; 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 2.239.239; 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 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 2.157.228; 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.157.16 9; 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.240.1 57; 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 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 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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.240.228; 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.240.15 7; 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 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. 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 3.239.239; 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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.O.230.237; 3.O.230.238; 3.O.230.239; 3.O.230.154; 3.O. 230.157; 3.O.230.166; 3.O.230.169; 3.O.230.172; 3.O.230.175; 3.O.230.240; 3.O.230.244; 3.O.231.228; 3.O.231.229; 3.O.231.230; 3.O.231.231; 3.O.231.236; 3.O.231.237; 3.O.231.238; 3.O.231.239; 3.O.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.O.154.230; 3.O.154.231; 3.O.154.236; 3.O.154.237; 3.O.154.238; 3.O.154.239; 3 .O.154.154; 3.O.154.157; 3.O.154.166; 3.O.154.169; 3.O.154.172; 3.O.154.175; 3.O.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.157.16 9; 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.O.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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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.240.228; 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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 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 4.237.240; 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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.O.230.230; 4.O.230.231; 4.O.230.236; 4.O.230.237; 4.O.230.238; 4.O.230.239; 4.O.230.154; 4.O. 230.157; 4.O.230.166; 4.O.230.169; 4.O.230.172; 4.O.230.175; 4.O.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.O.237.230; 4.O.237.231; 4.O.237.236; 4.O.237.237; 4 .O.237.238; 4.O.237.239; 4.O.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.O.154.229; 4.O.154.230; 4.O.154.231; 4.O.154.236; 4.O.154.237; 4.O.154.238; 4.O.154.239; 4 .O.154.154; 4.O.154.157; 4.O.154.166; 4.O.154.169; 4.O.154.172; 4.O.154.175; 4.O.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.157.16 9; 4.O.157.172; 4.O.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.166.228; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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.157.16 9; 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. 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.240.1 57; 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 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.240.15 7; 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 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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.O.230.231; 5.O.230.236; 5.O.230.237; 5.O.230.238; 5.O.230.239; 5.O.230.154; 5.O. 230.157; 5.O.230.166; 5.O.230.169; 5.O.230.172; 5.O.230.175; 5.O.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.O.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.O.154.239; 5 .O.154.154; 5.O.154.157; 5.O.154.166; 5.O.154.169; 5.O.154.172; 5.O.154.175; 5.O.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.157.16 9; 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.240.1 57; 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 5.P.172.238; 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.240.15 7; 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 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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 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.240.15 7; 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 6.166.172; 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.240.15 7; 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 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.O.231.229; 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.157.16 9; 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.240.1 57; 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.157.16 9; 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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.157.16 9; 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. 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.240.1 57; 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 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.157.16 9; 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.240.1 57; 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.54.24 7; 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 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.54.24 7; 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 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.54.24 7; 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.54.24 7; 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 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.54.24 7; 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.54.24 7; 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 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. 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. 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.54.24 7; 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 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.54.24 7; 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 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.54.24 7; 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. 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.54.24 7; 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. 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. 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.54.24 7; 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 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.54.24 7; 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. 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.54.24 7; 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 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. 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. 28.196; 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.54.24 7; 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. 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. 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 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.54.24 7; 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 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.54.24 7; 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. 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.54.24 7; 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 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. 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.54.24 7; 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. 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 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.54.24 7; 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. 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. 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; 1 0.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 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 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; 1 0.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; 1 0.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 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.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; 1 0.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.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; 1 0.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. 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 .A.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 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. 11.158; 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; 1 1.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 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. 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. 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. 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; 1 1.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. 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. 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 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. 11.158; 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. 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 .BF.55.223; 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. 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; 1 1.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. 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 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. 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. 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 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; 1 2.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 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; 1 2.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; 1 2.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. 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 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 .BF.55.223; 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.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; 1 2.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. 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.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. 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.2 36.154; 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.2 36.154; 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 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.2 36.154; 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.2 36.154; 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 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.2 36.154; 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 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.2 36.154; 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.2 36.154; 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 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.2 36.154; 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. 22.9.228; 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.2 36.154; 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 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.2 36.154; 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.2 36.154; 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 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.23 6.154; 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.1 75.157; 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 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; 1 4.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 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. 14.158; 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; 14AN.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. 14.158; 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; 1 4.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 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. 14.158; 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 .BF.55.223; 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; 14BF.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; 14BF.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; 1 4.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 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 of the above documents and patents are expressly incorporated by reference in their citations herein. Items or pages specifically cited in the work cited 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 will be apparent that the methods and compositions of the following claims may be subject to certain modifications within the scope and spirit of the present invention.

In the following claims, the subscripts and superscripts for a given variable are different. For example, R ₁ is different from R ¹ .

Claims (249)

A conjugate comprising an anticancer compound linked to one or more phosphonate groups, or a pharmaceutically acceptable salt or solvate thereof. One or more A ⁰ groups:
(Wherein A ⁰ is A ¹ , A ² , or W ³ when the conjugate comprises at least one A ¹ ;
A ¹ is,

Is;
A ² is,

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 ));
Y ² is independently a bond, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) ( R ^x )), —S (O) _{M 2} —, or —S (O) _{M 2} —S (O) _{M 2} —; when Y ² is bonded to two phosphorus atoms, Y ² is C (R ² ) May be (R ² );
R ^x is independently H, R ¹ , R ² , W ³ , a protecting group, or the formula:

Is;
R ^y is independently 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 R ⁴ , and each R ⁴ is independently substituted with 0-3 R ³ groups or is both 2 at a carbon atom. Two R ² groups form a 3-8 carbon ring, which can be substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , and when R ³ is attached 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 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 and 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 _M2 R ⁵ , or —SO _M2 W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, W ⁵ is independently substituted with 0-3 R ² groups;
W ⁶ is independently W ³ 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 any one compound of formula 500-601 substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. Item 4. The conjugate according to Item 1, or a pharmaceutically acceptable salt or solvate thereof. formula:
[DRUG]-(A ⁰ ) _nn
3. A conjugate according to claim 2 or a pharmaceutically acceptable salt thereof, wherein DRUG is any one compound of formula 500-601; nn is 1, 2, or 3. Salt or solvate. One ^{A 0} is ^{A 1, X 50} is an H, F or ^{Cl; X 51} is H or Cl, having any one of formulas 1-336, conjugate according to claim 2 . Each ^{A 1} has the formula:

The conjugate according to any one of claims 2 to 4, wherein Each ^{A 1} has the formula:

The conjugate according to any one of claims 2 to 4, wherein Each ^{A 1} has the formula:

The conjugate according to any one of claims 2 to 4, wherein Each ^{A 1} has the formula:

The conjugate according to any one of claims 2 to 4, wherein Each ^{A 1} has the formula:

^{5. A} compound according to claim 2, wherein W ^5a is a carbocyclic or heterocyclic ring, and W ^5a is independently substituted with 0 or 1 R ² group. The conjugate according to 1. The conjugate according to any one of claims 2 to 4, wherein M12a is 1. Each ^{A 1} has the formula:

The conjugate according to any one of claims 2 to 4, wherein Each ^{A 1} has the formula:

The conjugate according to any one of claims 2 to 4, wherein Each ^{A 1} has the formula:

The conjugate according to any one of claims 2 to 4, wherein W ^5a is a carbocyclic ring independently substituted with 0 or 1 R ² group. Each ^{A 1} has the formula:

Wherein Y ^2b is O or N (R ² );
The conjugate according to any one of claims 2 to 4, wherein M12d is 1, 2, 3, 4, 5, 6, 7, or 8. Each ^{A 1} has the formula:

The conjugate according to any one of claims 2 to 4, wherein W ^5a is a carbocyclic ring independently substituted with 0 or 1 R ² group. Each ^{A 1} has the formula:

^{5. A} compound according to claim 2, wherein W ^5a is a carbocyclic or heterocyclic ring, and W ^5a is independently substituted with 0 or 1 R ² group. The conjugate according to 1. Each ^{A 1} has the formula:

Wherein Y ^2b is O or N (R ² );
The conjugate according to any one of claims 2 to 4, wherein M12d is 1, 2, 3, 4, 5, 6, 7, or 8. Each ^{A 2} has the formula:

The conjugate according to any one of claims 2 to 17, which is Each ^{A 2} has the formula:

The conjugate according to any one of claims 2 to 17, which is 18. The conjugate according to any one of claims 2 to 17, wherein each M12b is 1. M12b is 0, ^{Y 2} is a bond, ^{W 5} is between carbocyclic or heterocyclic, ^{W 5} is one independently optionally and, substituted with two or three ^{R 2} groups 21. The conjugate according to claim 20, wherein: Each ^{A 2} has the formula:

Wherein W ^5a is a carbocycle or heterocycle, and W ^5a is optionally and independently substituted with one, two, or three R ² groups. The conjugate according to any one of claims 17 to 17. 23. The conjugate according to claim 22, wherein M12b is 1. Each A ² is phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl, and substituted pyridyl, conjugate according to any one of claims 2 to 17. Each ^{A 2} has the formula:


The conjugate according to any one of claims 2 to 17, which is Each ^{A 2} has the formula:

The conjugate according to any one of claims 2 to 17, which is 27. The conjugate according to claim 26, wherein M12b is 1. Each ^{A 3} has the formula:

28. The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} has the formula:

28. The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} has the formula:

( ^Wherein Y ^1a is O or S;
28. The conjugate according to any one of claims 2 to 27, wherein ^Y2a is O, N ( ^Rx ), or S). Each ^{A 3} has the formula:

28. A conjugate according to any one of claims 2 to 27, wherein ^Y2b is O or N ( ^Rx ). Each ^{A 3} has the formula:

; (Where,
Y ^2b is O or N (R ^x );
28. The conjugate according to any one of claims 2 to 27, wherein M12d is 1, 2, 3, 4, 5, 6, 7, or 8. Each ^{A 3} has the formula:

Wherein Y ^2b is O or N (R ^x );
28. The conjugate according to any one of claims 2 to 27, wherein M12d is 1, 2, 3, 4, 5, 6, 7, or 8. 34. The conjugate of claim 33, wherein M12d is 1. Each ^{A 3} has the formula:

28. The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} has the formula:

28. The conjugate according to any one of claims 2 to 27, wherein W ⁵ is a carbocycle, conjugate according to claim 36. Each ^{A 3} has the formula:

28. The conjugate according to any one of claims 2 to 27, wherein W ⁵ is phenyl, conjugate according to claim 38. 40. The conjugate of claim 39, wherein M12b is 1. Each ^{A 3} has the formula:

^Wherein Y ^1a is O or S;
28. The conjugate according to any one of claims 2 to 27, wherein ^Y2a is O, N ( ^Rx ), or S). Each ^{A 3} has the formula:

28. The conjugate according to any one of claims 2 to 27, wherein ^Y2b is O or N ( ^Rx ). Each ^{A 3} has the formula:

Wherein Y ^2b is O or N (R ^x );
28. The conjugate according to any one of claims 2 to 27, wherein M12d is 1, 2, 3, 4, 5, 6, 7, or 8. R ¹ is H, conjugate according to claim 43. 45. The conjugate of claim 44, wherein M12d is 1. Each ^{A 3} has the formula:

Is (wherein the phenyl carbocycle is 0,1, 2, or 3 is substituted with R ² groups), the conjugate of any one of claims 2 to 27. Each ^{A 3} has the formula:

Is (wherein the phenyl carbocycle is 0,1, 2, or 3 is substituted with R ² groups), the conjugate of any one of claims 2 to 27. Each ^{A 3} has the formula:

28. The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} has the formula:

28. The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} has the formula:

28. The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} has the formula:

^Wherein Y ^1a is O or S;
Y ^2a is O, N ^(R 2), or S), conjugate according to any one of claims 2 to 27. Each ^{A 3} has the formula:

^Wherein Y ^1a is O or S;
Y ^2b is O or N (R ² );
28. The conjugate according to any one of claims 2 to 27, wherein ^Y2c is O, N ( ^Ry ), or S). Each ^{A 3} has 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 );
28. The conjugate according to any one of claims 2 to 27, wherein M12d is 1, 2, 3, 4, 5, 6, 7, or 8. Each ^{A 3} has the formula:

Wherein Y ^2b is O or N (R ² );
28. The conjugate according to any one of claims 2 to 27, wherein M12d is 1, 2, 3, 4, 5, 6, 7, or 8. Each ^{A 3} has the formula:

^{(Wherein, Y 2b} is O or N ^{(R 2)} is a) a conjugate according to any one of claims 2 to 27. Each ^{A 3} has the formula:

28. The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} has the formula:

28. The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} has the formula:

^Wherein Y ^1a is O or S;
Y ^2a is O, N ^(R 2), or S), conjugate according to any one of claims 2 to 27. Each ^{A 3} has the formula:

^Wherein Y ^1a is O or S;
Y ^2b is O or N (R ² );
28. The conjugate according to any one of claims 2 to 27, wherein ^Y2c is O, N ( ^Ry ), or S). Each ^{A 3} has 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 );
28. The conjugate according to any one of claims 2 to 27, wherein M12d is 1, 2, 3, 4, 5, 6, 7, or 8. Each ^{A 3} has the formula:

Wherein Y ^2b is O or N (R ² );
28. The conjugate according to any one of claims 2 to 27, wherein M12d is 1, 2, 3, 4, 5, 6, 7, or 8. Each ^{A 3} has the formula:

^{(Wherein, Y 2b} is O or N ^{(R 2)} is a) a conjugate according to any one of claims 2 to 27. A ⁰ is the formula:

4. A conjugate according to claim 3, wherein each R is independently alkyl. formula:

(Where
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 a 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 - a and;
R ^x is independently H, R ² , W ³ , a protecting group, or the formula:

Is;
R ^y is independently H, W ³ , R ² or a protecting group;
R ² is independently H, R ³ or R ⁴ , and each R ⁴ is independently substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , and when R ³ is attached 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 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 and 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 a carbocyclic or heterocyclic ring, W ⁵ is independently substituted with 0-3 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;
The conjugate according to claim 1, claim 2, claim 3, or claim 4, wherein L is a direct bond or a linking group), or a pharmaceutically acceptable salt or solvate thereof. Each R ^x is represented by the formula:

^Wherein Y ^1a is O or S;
^66. The conjugate of claim 64, wherein ^Y2c is O, N ( ^Ry ), or S). Each R ^x is represented by the formula:

^Wherein Y ^1a is O or S;
^66. The conjugate of claim 64, wherein ^Y2d is O or N ( ^Ry ). Each R ^x is represented by the formula:

65. The conjugate according to claim 64, wherein 68. The conjugate according to any one of claims 65 to 67, wherein each ^Ry is independently H or an alkyl of 1 to 10 carbons. Each R ^x is represented by the formula:

65. The conjugate according to claim 64, wherein Each R ^x is represented by the formula:

65. The conjugate according to claim 64, wherein Each R ^x is represented by the formula:

65. The conjugate according to claim 64, wherein Each ^{Y 1} is O or S, conjugate according to claim 64. Each ^{Y 2} is O, N ^(R y), or S, The conjugate of claim 64. 74. The conjugate according to any one of claims 64 to 73, wherein nn is 1. 74. The conjugate according to any one of claims 64 to 73, wherein nn is 2. 74. The conjugate according to any one of claims 64 to 73, wherein nn is 3. 65. The conjugate according to claim 64, wherein the anticancer compound is any one compound of formula 500-601. 78. The conjugate of claim 77, wherein the molecular weight of each L is from about 20 daltons to about 400 daltons. 78. The conjugate of claim 77, wherein each L has a length of about 5 to about 300 inches. 78. The conjugate of claim 77, wherein each L from about 5 to about 200 separates any one compound of Formula 500 to 601 from the phosphonate group phosphorus. Each L is a divalent, branched or unbranched, saturated or unsaturated hydrocarbon having 2 to 25 carbon atoms, wherein one or more of the carbon atoms are optionally (—O—) Wherein the chain is optionally one or more (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkanoyl on the carbon, ( C ₁ -C ₆ ) alkanoyloxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkylthio, azide, cyano, nitro, halo, hydroxyl, oxo (═O), carboxy, aryl, aryloxy 78. The conjugate of claim 77, substituted with a substituent selected from:, heteroaryl, and heteroaryloxy. Each L is of 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 (═O) —, —C (═O) 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 ( 78. The conjugate of claim 77, wherein: O) _M2- , or a direct bond; each R is independently H or alkyl of 1-10 carbons). 83. The conjugate of claim 82, wherein each A is an alkylene of 1 to 10 carbons. 78. The conjugate of claim 77, wherein each L is a divalent radical formed from a peptide. 78. The conjugate of claim 77, wherein each L is a divalent radical formed from an amino acid. Each L is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L 78. The conjugate of claim 77, which is a divalent radical formed from leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine, or poly-L-lysine-L-tyrosine. Each L is of the formula W— (CH ₂ ) _n , wherein n is between about 1 and about 10; W is —N (R) C (═O) —, —C (═O) 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) _M2- N ( R) -, - N (R ) -S (O) M2 -, or a direct bond; each R is independently H or _(C 1 -C ₆₎ alkyl, according to claim 77 Conjugate. 78. The conjugate of claim 77, wherein each L is methylene, ethylene, or propylene. 78. The conjugate of claim 77, wherein each L is bonded to P at a carbon atom of L. 90. The conjugate according to any one of claims 1 to 89, isolated or purified. The conjugate according to any one of claims 1 to 90, which is not an anti-inflammatory compound. 100. A conjugate according to any one of claims 1 to 99 which is not anti-infective. 93. A conjugate according to any one of claims 1 to 92 which is not a compound active in an immune-mediated condition. 94. The conjugate according to any one of claims 1 to 93, which is not a compound active in metabolic diseases. 95. The conjugate according to any one of claims 1 to 94, which is not an antiviral agent. 96. The conjugate according to any one of claims 1 to 95, which is not a nucleoside. 99. A conjugate according to any one of claims 1 to 96 which is not an IMPDH inhibitor. 98. The conjugate according to any one of claims 1 to 97, which is not an antimetabolite. 99. A conjugate according to any one of claims 1 to 98 which is not a PNP inhibitor. The anti-cancer compound is any one of formulas 501, 519, 597, 541, 518, 558, 591, 593, 592, 503, 504, 505, 506, 542, 544, 545, 546, 516, or 512. 101. The conjugate according to any one of claims 1 to 100, which is not a compound. An anti-cancer conjugate as described herein. A compound of formula MBF. 103. The compound of claim 102, selected from Table 100. 103. A pharmaceutical comprising a pharmaceutically acceptable excipient and a conjugate according to any one of claims 1 to 89 and 101 to 101 or a compound according to claim 102 or 103. Composition. A unit comprising the conjugate according to any one of claims 1 to 89 and claim 91 to 101 or the compound according to claim 102 or claim 103 and a pharmaceutically acceptable excipient. Dosage form. Contacting the sample in need of treatment with a conjugate according to any one of claims 1 to 89 and claims 91 to 101 or a compound according to claim 102 or 103. , A method of inhibiting tumor growth in vitro or in vivo. 107. The method of claim 106, wherein the contacting is performed in vivo. The tumor is a mammal breast, lung, thyroid, lymph node, urogenital system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus Small intestine, colon, rectum, pancreas, liver, smooth muscle, central and peripheral nervous system, brain, spinal cord, nerve, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity 108. The method of any one of claims 106-107, wherein the method is present on the tongue, larynx, hypopharynx, soft tissue, skin, cervix, anus, retina, and / or heart. 101. A method for treating cancer of an animal comprising administering the compound of any one of claims 1 to 89 and 91 to 101 or the compound of claim 102 or 103 to a mammal. How to treat a symptom or effect. 109. A treatment comprising the step of administering to a mammal a compound according to any one of claims 1 to 89 and claim 91 to 101 or a compound according to claim 102 or 103. A method of inhibiting neoplastic disease in a mammal. 111. The method of claim 110, wherein the neoplasm is derived from acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, hairy cell leukemia, or non-Hodgkin lymphoma. 112. The method of any one of claims 106-111, wherein the compound is formulated using a pharmaceutically acceptable carrier. 113. The method of claim 112, wherein the formulation further comprises a second active ingredient. 102. A conjugate according to any one of claims 1 to 89 and claims 91 to 101 or a compound according to claim 102 or 103 for use in drug therapy. 103. A conjugate according to any one of claims 1 to 89 and claims 91 to 101 or a claim 102 or 103 for the preparation of a medicament for inhibiting tumor growth in a mammal. Use of the described compounds. The tumor is a mammal breast, lung, thyroid, lymph node, urogenital system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus Small intestine, colon, rectum, pancreas, liver, smooth muscle, central and peripheral nervous system, brain, spinal cord, nerve, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity 118. The method of claim 115, wherein the method is present on the tongue, larynx, hypopharynx, soft tissue, skin, cervix, anus, retina, and / or heart. 102. A conjugate according to any one of claims 1 to 89 and claims 91 to 101 for preparing a medicament for inhibiting a neoplastic disease in a mammal or claim 102 or claim 103. Use of the compounds described in 1. 118. Use according to claim 117, wherein the neoplasm is derived from acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, hairy cell leukemia, or non-Hodgkin lymphoma. 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-amino Purine, 2-amino-6-chloropurine, 2,6-diaminopurine, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine, 6-thioguanine , 4-thiothymine, 4-thiouracil, ^{O 6} - methylguanine, ^{N 6} - methyl adenine, ^{O 4} - methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, and Pi It is selected from the Zorro [3,4-d] pyrimidine;
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 substituted Selected from alkynyl,
Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
Y ² is independently a bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N—NR ₂ , S, S—S , 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 to} C ₈ alkyl, C ₁ to C ₈ alkyl halides, carboxylates, Surufe DOO, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl Thiol, alkyl sulfone (—SO ₂ R), aryl sulfone (—SO ₂ Ar), aryl sulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO ₂ NR ₂ ), alkyl sulfoxide (—SOR), Ester (—C (═O) OR), amide (—C (═O) NR ₂ ), 5-7 membered lactam, 5-7 membered lactone, nitrile (—CN), azide (—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 -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 When it is a heterocycle, polyethyleneoxy, protecting group (PG), or W ³ or taken together, R ^y forms a carbocycle of 3 to 7 carbon atoms;
R ^x is independently R ^y , a protecting group, or the formula:

Is;
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 heterocyclic or a protecting group;
When W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ , W ³ is W ⁴ or W ⁵ . W ⁵ is a carbocyclic or heterocyclic ring, and W ⁵ is independently substituted with 0 to 3 R ^y groups) or a pharmaceutical product thereof according to claim 1 Acceptable salts or solvates. 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 independently F, Cl , Br, I, OH, -NH 2, -NH 3 +, -NHR, -NR 2, -NR 3 +, C 1 ~C 8 alkyl halides, carboxylates, sulfates, sulfamates, sulfonates, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C _{8 alkylthio, -SO 2 R, -SO 2 Ar} , _{-SOAr, -SAr, -SO 2 NR 2} , -SOR, -CO 2 R, -C (= O) NR 2, 5~7 -membered ring lactam, 5-7 membered ring lactone, -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} heterocyclic, polyethyleneoxy, phosphonate, 120. The conjugate of claim 119, substituted with one or more substituents selected from phosphate and prodrug moieties. 120. The conjugate of claim 119, wherein the protecting group is selected from carboxyl esters, carboxyamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonate esters, carbonates, and carbamates. W ⁵ is the structure:

120. The conjugate of claim 119, selected from 120. The conjugate of claim 119, wherein X is O and ^Ry is H. X is C = CH _2, ^{R y} is H, conjugate according to claim 119. Z ¹ is OH, conjugate according to claim 119. Z ² is _{C 1} -C ₈ alkyl or substituted _{C 1} -C ₈ alkyl, conjugate according to claim 119. Z ² is CH _3, conjugate according to claim 126. The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having Z ¹ is OH, conjugate according to claim 136. Z ² is _{C 1} -C ₈ alkyl or _{C 1} -C ₈ substituted alkyl, conjugate according to claim 136. Z ² is CH _3, conjugate according to claim 138. The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

120. The conjugate of claim 119, having The following formula:

Wherein R ² is H or C ₁ -C ₈ alkyl.
148. The conjugate of claim 147, having: The following formula:
149. The conjugate according to claim 148, comprising: The following formula:

( ^Where Y ^2c is O, N (R ^y ), or S)
149. The conjugate according to claim 148, comprising: The following formula:

150. The conjugate of claim 150, wherein: ^152. The conjugate of claim 151, wherein ^Y2c is O. Y ^2c is N (CH _3), conjugate according to claim 151. R ^y is H or _{C 1} -C ₈ alkyl, conjugate according to claim 151. The substituted triazole has the structure:

120. The conjugate of claim 119, having 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-amino Purine, 2-amino-6-chloropurine, 2,6-diaminopurine, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine, 6-thioguanine , 4-thiothymine, 4-thiouracil, ^{O 6} - methylguanine, ^{N 6} - methyl adenine, ^{O 4} - methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, and Pi It is selected from the Zorro [3,4-d] pyrimidine;
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 substituted Selected from 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 to} C ₈ alkyl, C ₁ to C ₈ alkyl halides, carboxylates, Surufe DOO, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl Thiol, alkyl sulfone (—SO ₂ R), aryl sulfone (—SO ₂ Ar), aryl sulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO ₂ NR ₂ ), alkyl sulfoxide (—SOR), Ester (—C (═O) OR), amide (—C (═O) NR ₂ ), 5-7 membered lactam, 5-7 membered lactone, nitrile (—CN), azide (—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 -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 When it is a heterocycle, polyethyleneoxy, protecting group (PG), or W ³ or taken together, R ^y forms a carbocycle 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 heterocyclic or a protecting group;
When W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ , W ³ is W ⁴ or W ⁵ . Yes; W ⁵ is a carbocyclic or heterocyclic ring, and W ⁵ is independently substituted with 0 to 3 R ^y groups) or a pharmaceutically acceptable salt or solvate thereof. Having a composition. The following formula:

(Wherein PG is an ether-forming group, thioether-forming group, ester-forming group, thioester-forming group, silyl ether-forming group, amide-forming group, acetal-forming group, ketal-forming group, carbonate-forming group, carbamate-forming group, urea-forming group) 156. The composition of claim 156, wherein the composition is a protecting group selected from a group, an amino acid conjugate, and a polypeptide conjugate. 120. The conjugate of claim 119, which can accumulate in human PBMC. The bioavailability of the conjugate or an intracellular metabolite of the conjugate in human PBMC is improved when compared to an analog of a conjugate that does not contain the prodrug moiety (phosphonate group). 158. A conjugate according to 158. 159. The binding of claim 158, wherein the intracellular half-life in human PBMC of the conjugate or an intracellular metabolite of the conjugate is improved when compared to an analog of a conjugate that does not include the prodrug moiety. body. 167. The conjugate of claim 160, wherein the half-life is improved by at least about 50%. 169. The conjugate of claim 160, wherein the half-life is improved by at least about 100%. 159. The conjugate of claim 158, wherein the intracellular half-life of the conjugate metabolite in human PBMC is improved when compared to a metabolite analog that does not include the prodrug moiety. 159. The conjugate of claim 158, wherein the half-life is improved by at least about 50%. 159. The conjugate of claim 158, wherein the half-life is improved by at least about 100%. 159. The conjugate of claim 158, wherein the half-life is improved by more than 100%. 120. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 119, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. 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-amino Purine, 2-amino-6-chloropurine, 2,6-diaminopurine, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine, 6-thioguanine , 4-thiothymine, 4-thiouracil, ^{O 6} - methylguanine, ^{N 6} - methyl adenine, ^{O 4} - methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, and Pi Is selected from the Zorro [3,4-D] pyrimidine,
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 substituted Selected from alkynyl,
Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N—NR ₂ ;
Y ² is independently a bond, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N—NR ₂ , S, S—S , 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 to} C ₈ alkyl, C ₁ to C ₈ alkyl halides, carboxylates, Surufe DOO, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl Thiol, alkyl sulfone (—SO ₂ R), aryl sulfone (—SO ₂ Ar), aryl sulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO ₂ NR ₂ ), alkyl sulfoxide (—SOR), Ester (—C (═O) OR), amide (—C (═O) NR ₂ ), 5-7 membered lactam, 5-7 membered lactone, nitrile (—CN), azide (—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 -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 When it is a heterocycle, polyethyleneoxy, protecting group (PG), or W ³ or taken together, R ^y forms a carbocycle of 3 to 7 carbon atoms;
R ^x is independently R ^y , a protecting group, or the formula:

Is;
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 heterocyclic or a protecting group;
When W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ , W ³ is W ⁴ or W ⁵ . And W ⁵ is a carbocyclic or heterocyclic ring, and W ⁵ is independently substituted with 0 to 3 R ^y groups) or a pharmaceutical product thereof. Acceptable salts or solvates. 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 independently F, Cl , Br, I, OH, -NH 2, -NH 3 +, -NHR, -NR 2, -NR 3 +, C 1 ~C 8 alkyl halides, carboxylates, sulfates, sulfamates, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C _{8 alkylthio, -SO 2 R, -SO 2 Ar} , _{-SOAr, -SAr, -SO 2 NR 2} , -SOR, -CO 2 R, -C (= O) NR 2, 5~7 -membered ring lactam, 5-7 membered ring lactone, -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} heterocyclic, polyethyleneoxy, phosphonate, 169. The conjugate of claim 168, substituted with one or more substituents selected from phosphate and prodrug moieties. 169. The conjugate of claim 168, wherein the protecting group is selected from carboxyl esters, carboxyamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonate esters, carbonates, and carbamates. W ⁵ is the structure:

169. The conjugate of claim 168, selected from. 169. The conjugate of claim 168, wherein X is O and ^Ry is H. formula:

169. The conjugate of claim 168, having Construction:

169. The conjugate of claim 168, having Z ¹ is OH, conjugate according to claim 174. Z ² is CH _3, conjugate according to claim 174. Construction:

174. The conjugate of claim 173, wherein: Z ² is _{C 1} -C ₈ alkyl _{C 1} -C ₈ substituted alkyl, conjugate according to claim 177. Construction:
178. The conjugate of claim 177, wherein: Construction:

178. The conjugate of claim 177, wherein: Construction:

174. The conjugate of claim 173, wherein: Construction:

184. The conjugate of claim 181 having Construction:

184. The conjugate of claim 182 having Construction:

184. The conjugate of claim 183 having Construction:

^{(R 2} is H or _{C 1} -C ₈ alkyl) with a conjugate according to claim 184. Construction:

186. The conjugate of claim 185, wherein Construction:

^187. The conjugate of claim 186, wherein ^Y2c is O, N ( ^Ry ), or S. Construction:

188. The conjugate of claim 187, having ^189. The conjugate according to claim 188, wherein ^Y2c is O. Y ^2c is N (CH _3), conjugate according to claim 188. The substituted triazole has the structure:

169. The conjugate of claim 168, having 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-amino Purine, 2-amino-6-chloropurine, 2,6-diaminopurine, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine, 6-thioguanine , 4-thiothymine, 4-thiouracil, ^{O 6} - methylguanine, ^{N 6} - methyl adenine, ^{O 4} - methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, and Pi Is selected from the Zorro [3,4-D] pyrimidine,
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 substituted Selected from 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 to} C ₈ alkyl, C ₁ to C ₈ alkyl halides, carboxylates, Surufe DOO, sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl Thiol, alkyl sulfone (—SO ₂ R), aryl sulfone (—SO ₂ Ar), aryl sulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO ₂ NR ₂ ), alkyl sulfoxide (—SOR), Ester (—C (═O) OR), amide (—C (═O) NR ₂ ), 5-7 membered lactam, 5-7 membered lactone, nitrile (—CN), azide (—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 -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 When it is a heterocycle, polyethyleneoxy, protecting group (PG), or W ³ or taken together, R ^y forms a carbocycle 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 heterocyclic or a protecting group;
When W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ , W ³ is W ⁴ or W ⁵ . W ⁵ is a carbocyclic or heterocyclic ring, and W ⁵ is independently substituted with 0 to 3 R ^y groups) or a pharmaceutically or conjugate according to claim 1 An acceptable salt or solvate. Formula IIa:

(Wherein PG is an ether-forming group, thioether-forming group, ester-forming group, thioester-forming group, silyl ether-forming group, amide-forming group, acetal-forming group, ketal-forming group, carbonate-forming group, carbamate-forming group, urea-forming group) 195. A conjugate according to claim 192 having a protecting group selected from a group, an amino acid conjugate, and a polypeptide conjugate. 169. The conjugate of claim 168, or a pharmaceutically acceptable salt or solvate thereof, that can accumulate in human PBMC. The bioavailability of the conjugate or an intracellular metabolite of the conjugate in human PBMC is improved when compared to an analog of a conjugate that does not contain the prodrug moiety (phosphonate group). 194. A conjugate according to 194. 195. The binding of claim 194, wherein the intracellular half-life in human PBMC of the conjugate or an intracellular metabolite of the conjugate is improved when compared to an analog of a conjugate that does not include the prodrug moiety. body. 196. The conjugate of claim 196, wherein the half-life is improved by at least about 50%. 196. The conjugate of claim 196, wherein the half-life is improved by at least about 100%. 195. The conjugate of claim 194, wherein the intracellular half-life of the conjugate metabolite in human PBMC is improved when compared to an analogue of a metabolite that does not include the prodrug moiety. 200. The conjugate of claim 199, wherein the half-life is improved by at least about 50%. 200. The conjugate of claim 199, wherein the half-life is improved by at least about 100%. 200. The conjugate of claim 199, wherein the half-life is improved by over 100%. 169. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 168 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. 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-amino Purine, 2-amino-6-chloropurine, 2,6-diaminopurine, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine, 6-thioguanine , 4-thiothymine, 4-thiouracil, ^{O 6} - methylguanine, ^{N 6} - methyl adenine, ^{O 4} - methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, and Pi It is selected from the Zorro [3,4-d] pyrimidine;
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, S—S, S (O) or S (O) 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 Alkyl halides, carboxylates, sulfates, Sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl thiols, Alkyl sulfone (—SO ₂ R), aryl sulfone (—SO ₂ Ar), aryl sulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO ₂ NR ₂ ), alkyl sulfoxide (—SOR), ester ( -C (= O) OR), amide _{(-C (= O) NR 2} ), 5~7 membered ring lactam, 5-7 membered ring lactone, 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 ~ 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 together, R ^y forms a carbocycle of 3 to 7 carbon atoms;
R ^x is independently R ^y , a protecting group, or the formula:

Is;
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 heterocyclic or a protecting group;
When W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ , W ³ is W ⁴ or W ⁵ . And W ⁵ is a carbocyclic or heterocyclic ring, and W ⁵ is independently substituted with 0 to 3 R ^y groups) or a pharmaceutical product thereof. Acceptable salts or solvates. 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 independently F, Cl , Br, I, OH, -NH 2, -NH 3 +, -NHR, -NR 2, -NR 3 +, C 1 ~C 8 alkyl halides, carboxylates, sulfates, sulfamates, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C _{8 alkylthio, -SO 2 R, -SO 2 Ar} , _{-SOAr, -SAr, -SO 2 NR 2} , -SOR, -CO 2 R, -C (= O) NR 2, 5~7 -membered ring lactam, 5-7 membered ring lactone, -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} heterocyclic, polyethyleneoxy, phosphonate, 205. The conjugate of claim 204, substituted with one or more substituents selected from phosphate and prodrug moieties. 205. The conjugate of claim 204, wherein the protecting group is selected from carboxyl esters, carboxyamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonate esters, carbonates, and carbamates. W ⁵ is the structure:

205. A conjugate according to claim 204, selected from: 205. The conjugate of claim 204, wherein X is O and each ^Ry is H. The conjugate has the structure:

205. The conjugate of claim 204, which is a resolved enantiomer having: The conjugate has the structure:

205. The conjugate of claim 204, which is a resolved enantiomer having: Construction:

209. The conjugate of claim 209, comprising: Construction:

209. The conjugate of claim 209, comprising: Construction:

223. The conjugate of claim 212, wherein: Construction:

213. The conjugate of claim 213, having Construction:

215. The conjugate of claim 214, wherein: Construction:

; (Wherein, ^{R 2} is H or _{C 1} -C ₈ alkyl) with a conjugate according to claim 215. Construction:

217. The conjugate of claim 216, having Construction:

217. The conjugate of claim 217, having 218. The conjugate of claim 217, wherein Z is H. 218. A conjugate according to claim 217, wherein B is adenine. Construction:

^218. The conjugate of claim 217, wherein ^Y2c is O, N ( ^Ry ), or S. Construction:

223. The conjugate of claim 221 having ^223. The conjugate of claim 222, wherein ^Y2c is O. Y ^2c is N (CH _3), conjugate according to claim 222. The substituted triazole has the structure:

205. A conjugate according to claim 204, comprising: 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-amino Purine, 2-amino-6-chloropurine, 2,6-diaminopurine, hydroxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyridine, 6-thioguanine , 4-thiothymine, 4-thiouracil, ^{O 6} - methylguanine, ^{N 6} - methyl adenine, ^{O 4} - methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, and Pi It is selected from the Zorro [3,4-d] pyrimidine;
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, S—S, S (O) or S (O) 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 Alkyl halides, carboxylates, sulfates, Sulfamate, sulfonate, 5-7 membered ring _sultam, C 1 -C ₈ alkyl _sulfonate, C 1 -C ₈ alkylamino, 4-dialkylamino _pyridinium, C 1 -C ₈ alkyl _hydroxyl, C 1 -C ₈ alkyl thiols, Alkyl sulfone (—SO ₂ R), aryl sulfone (—SO ₂ Ar), aryl sulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO ₂ NR ₂ ), alkyl sulfoxide (—SOR), ester ( -C (= O) OR), amide _{(-C (= O) NR 2} ), 5~7 membered ring lactam, 5-7 membered ring lactone, 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 ~ 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 together, R ^y forms a carbocycle 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 heterocyclic or a protecting group;
PG is a protecting group selected from ether-forming groups, ester-forming groups, silyl ether-forming groups, amide-forming groups, acetal-forming groups, ketal-forming groups, carbonate-forming groups, carbamate-forming groups, amino acids, and polypeptides) The conjugate according to claim 1, comprising: 205. The conjugate of claim 204, or a pharmaceutically acceptable salt or solvate thereof, that can accumulate in human PBMC. 227. The bioavailability of the conjugate or an intracellular metabolite of the conjugate in human PBMC is improved when compared to an analog of a conjugate that does not include the prodrug moiety. Conjugate. 227. The binding of claim 227, wherein the intracellular half-life in human PBMC of the conjugate or an intracellular metabolite of the conjugate is improved when compared to an analog of a conjugate that does not include the prodrug moiety. body. 229. The conjugate of claim 229, wherein the half-life is improved by at least about 50%. 229. The conjugate of claim 229, wherein the half-life is improved by at least about 100%. 227. The conjugate of claim 227, wherein the intracellular half-life of the conjugate metabolite in human PBMC is improved when compared to a metabolite analog that does not comprise the prodrug moiety. 235. The conjugate of claim 232, wherein the half life is improved by at least about 50%. 235. The conjugate of claim 232, wherein the half life is improved by at least about 100%. 235. The conjugate of claim 232, wherein the half-life is improved by over 100%. 205. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 204 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. 235. A method of inhibiting tumor growth in vitro or in vivo comprising contacting a sample in need of treatment with a conjugate according to any one of claims 119-235. 238. The method of claim 237, wherein the contacting is performed in vivo. The tumor is a mammal breast, lung, thyroid, lymph node, urogenital system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus Small intestine, colon, rectum, pancreas, liver, smooth muscle, central and peripheral nervous system, brain, spinal cord, nerve, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity 237. The method of claim 237, present in the tongue, larynx, hypopharynx, soft tissue, skin, cervix, anus, retina, and / or heart. 219. A method of treating a cancer symptom or effect in an animal comprising administering the conjugate of any one of claims 119 to 235 to the animal. 235. A method of inhibiting neoplastic disease in a mammal in need of treatment comprising the step of administering to the animal a conjugate according to any one of claims 119 to 235. 242. The method of claim 241, wherein the neoplasm is derived from acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, hairy cell leukemia, or non-Hodgkin lymphoma. 243. The method of claim 242, wherein the compound is formulated using a pharmaceutically acceptable carrier. 244. The method of claim 243, wherein the formulation further comprises a second active ingredient. 235. The conjugate according to any one of claims 119 to 235 for drug therapy. 235. Use of a conjugate according to any one of claims 119 to 235 for the preparation of a medicament for inhibiting mammalian tumor growth. The tumor is a mammal breast, lung, thyroid, lymph node, urogenital system, kidney, ureter, bladder, ovary, testis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus Small intestine, colon, rectum, pancreas, liver, smooth muscle, central and peripheral nervous system, brain, spinal cord, nerve, head, neck, ear, eye, nasopharynx, oropharynx, salivary gland, cardiovascular system, oral cavity 249. Use of a conjugate according to claim 246, present in the tongue, larynx, hypopharynx, soft tissue, skin, cervix, anus, retina, and / or heart. 235. Use of a conjugate according to any one of claims 119 to 235 for the preparation of a medicament for inhibiting a neoplastic disease in a mammal. 249. Use of a conjugate according to claim 248, wherein the neoplasm is derived from acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T cell lymphoma, hairy cell leukemia, or non-Hodgkin lymphoma. .