JP2007536194A - Immunomodulatory phosphonate conjugates - Google Patents

Abstract

The present invention includes not only phosphorus-substituted compounds having immunomodulatory activity, compositions containing such compounds, and methods of treatment (including the step of administering such compounds), but also such compounds Relates to processes and intermediates useful for preparing. The present invention provides novel phosphonate-containing analogs of immunomodulatory (eg, immunosuppressive) compounds. While these compounds have the utility of related immunomodulatory compounds, because of the presence of phosphonate groups, they typically provide cellular accumulation of the phosphonate compound. Thus, the compounds of the present invention may improve immunomodulatory properties, pharmacokinetic properties, oral bioavailability, efficacy or long-term effective half-life in vivo or combinations thereof.

Description

  This application is based on U.S. Patent Law Section 119 (e), US Provisional Patent Application Nos. 60/465424, 60/465373, 60/465420, 60/465380, 60/465433. No. 60/46581, No. 60/465377, No. 60/46581, No. 60/465532, No. 60/465844, No. 60/465531, and No. 60/465574 Filed on May 25); and US Provisional Patent Applications Nos. 60/493303, 60/493310, 60/493309, and 60/493302, all of which were filed on August 7, 2003 And US provisional patent applications Nos. 60/495533, 60/495529, 60/495455, 0/495537, 60/495456, 60/495398, 60/495425, 60/495427, 60/495561, 60/495393, 60/495416, 60/495 495614 and 60/495417 (which were all filed on August 15, 2003); and US Provisional Patent Applications Nos. 60 / 514,054, 60/513971, 60/514394, 60/513975, 60/514453, 60/514202, 60/513948, 60/514424, 60/514280, 60/514144, 60/5131979, 60/514 No. 514075, No. 60/513946, No. 60/514051, No. 60/5141 No. 1, No. 60/514325, No. 60 / 514,44, No. 60/514201, No. 60/514522, No. 60/514140, No. 60/514175, No. 60/514113, No. 60/513562 60/513592, 60/513563, 60/513579, 60/513561, 60/513589, 60/513593, 60/513588, 60/514258, No. 60 / 514,021 and No. 60/514298, all filed on Oct. 24, 2003; and US Provisional Patent Applications Nos. 60/532230, 60/531960, 60/532160. 60/531940 and 60/531932 (all of which are 2003) Filed Dec. 1); and U.S. Provisional Patent Application No. 60/532591 (which was filed on Dec. 23, 2003); and U.S. Provisional Patent Application No. 60/536005 (which is (Claimed on January 12, 2004) to claim the benefit of priority. The contents of all provisional patent applications listed above are incorporated herein by reference.

(Field of Invention)
The present invention relates generally to compounds having immunomodulatory (eg, immunosuppressive) activity.

(Background of the Invention)
Improving the delivery of drugs and other drugs to target cells and tissues has been the focus of much research for many years. Many attempts have been made to develop effective methods for introducing biologically active molecules into cells, both in vivo and in vitro, but none have proven to be fully satisfactory. . Optimizing the association of inhibitory drugs with intracellular targets is often difficult or inefficient, for example, with minimal intracellular redistribution of drugs to neighboring cells.

  Most drugs currently administered parenterally to patients are not targeted, resulting in systemic delivery of the drug to the cells and tissues of the body where the drug is not necessary and often undesirable. This results in adverse side effects of the drug and often limits the dose of drug (eg, glucocorticoids and other anti-inflammatory drugs) that can be administered. In contrast, oral administration of drugs is generally considered to be a convenient and economical method of administration, but oral administration is (a) cell and tissue barriers (eg, blood / brain, epithelium, cell membrane) ) Can result in either undesirable systemic distribution due to drug uptake via (b), or (b) temporary retention of the drug in the gastrointestinal tract. Thus, the main objective was to develop a method for specifically targeting drugs to cells and tissues. The benefits of such treatment include avoiding the overall physiological effects of inappropriate delivery of such agents to other cells and tissues (eg, uninfected cells).

  Autoimmune diseases and transplant rejection remain major public health problems around the world. Although drugs with immunosuppressive activity are widely used and have been effective, their clinical usefulness is limited due to their toxicity and other side effects. Currently, novel immunosuppressive agents (ie, drugs with improved immunosuppressive activity and pharmacokinetic properties, improved oral bioavailability, higher efficacy and extended in vivo effect half-life) There is a need for The new immunosuppressant should have lower side effects, a simpler dosing regimen, and / or be orally active.

(Summary of the Invention)
Intracellular targeting can be achieved by methods and compositions that allow the accumulation or retention of bioactive agents inside the cell. The present invention provides novel phosphonate-containing analogs of immunomodulatory (eg, immunosuppressive) compounds. While these compounds have the utility of related immunomodulatory compounds, because of the presence of phosphonate groups, they typically provide cellular accumulation of the phosphonate compound. Therefore, the compounds of the present invention may improve immunomodulatory properties, pharmacokinetic properties, oral bioavailability, efficacy or long-term effective half-life in vivo or combinations thereof. The compounds of the present invention may also have different tolerance profiles, fewer side effects, a simple dosing schedule or high oral activity.

  The present invention generally relates to the accumulation or retention of therapeutic compounds inside cells. The present invention more particularly relates to achieving high concentrations of phosphonate-containing molecules in target cells. Such effective targeting may be applicable to various therapeutic formulations and procedures.

  Accordingly, in one embodiment, the invention provides a compound of the invention that is a conjugate containing an immunomodulatory compound (eg, an immunosuppressive compound) linked to one or more phosphonate groups.

  The composition of the invention contains an immunomodulatory compound having at least one phosphonate group. Accordingly, in one embodiment of the invention, conjugates or pharmaceutically acceptable salts thereof containing an immunomodulatory compound (eg, an immunosuppressive compound) linked to one or more phosphonate groups are provided. To do.

  In another embodiment, this invention provides a compound of any one of formulas 500-547; or a pharmaceutically acceptable salt thereof:

該化合物は、リンカーを介して、直接的または間接的のいずれかで、１個またはそれ以上のホスホネート基で置換されている；そして該置換基は、必要に応じて、１個またはそれ以上のＡ^０基で置換されており、ここで：
Ａ^０は、Ａ^１、Ａ^２またはＷ^３であるが、但し、該抱合体は、少なくとも１個のＡ^１を含み；

The compound is substituted with one or more phosphonate groups, either directly or indirectly, via a linker; and the substituent is optionally substituted with one or more phosphonate groups. Substituted with an A ⁰ group, where:
A ⁰ is A ¹ , A ² or W ³ provided that the conjugate comprises at least one A ¹ ;

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｓ（Ｏ）_Ｍ２−または−Ｓ（Ｏ）_Ｍ２−Ｓ（Ｏ）_Ｍ２−である；そしてＹ^２が２個のリン原子と結合するとき、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得る；
Ｒ^ｘは、別個に、Ｈ、Ｒ^１、Ｒ^２、Ｗ^３、保護基または式：

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 is; and ^{when Y 2} is bonded to two phosphorus atoms, ^{Y 2} also, C (R ²⁾ may be a ^{(R 2);}
R ^x is independently H, R ¹ , R ² , W ³ , a protecting group or the formula:

であり：
ここで：
Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^１は、別個に、Ｈまたは１個〜１８個の炭素原子を有するアルキルである；
Ｒ^２は、別個に、Ｈ、Ｒ^１、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されているか、または炭素原子で一緒になって、２個のＲ^２基は、３個〜８個の炭素を有する環を形成し、そして該環は、０個〜３個のＲ^３基で置換され得る；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されるとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^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または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子を有するアルキル、２個〜１８個の炭素原子を有するアルケニル、または２個〜１８個の炭素原子を有するアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_Ｍ２Ｒ^５または-ＳＯ_Ｍ２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ_２基で置換されている；
Ｗ^６は、Ｗ^３であり、Ｗ^３は、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；そして
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。

Is:
here:
R ^y is independently H, W ³ , R ² or a protecting group;
R ¹ is independently H or alkyl having 1 to 18 carbon atoms;
R ² is independently H, R ¹ , R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups or 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, or alkynyl having 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO _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 embodiment, the present invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof:
[DRUG]-(A ⁰ ) _nn
here,
DRUG is a compound of any one of formulas 500-547;
nn is 1, 2 or 3;
here,
A ⁰ is A ¹ , A ² or W ³ provided that the conjugate comprises at least one A ¹ ;
A ¹ is:

Ａ^２は、以下である：

A ² are the following:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｓ（Ｏ）_Ｍ２−または−Ｓ（Ｏ）_Ｍ２−Ｓ（Ｏ）_Ｍ２−である；そしてＹ^２が２個のリン原子と結合するとき、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得る；
Ｒ^ｘは、別個に、Ｈ、Ｒ^１、Ｒ^２、Ｗ^３、保護基または次式である：

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 is; and ^{when Y 2} is bonded to two phosphorus atoms, ^{Y 2} also, C (R ²⁾ may be a ^{(R 2);}
R ^x is independently H, R ¹ , R ² , W ³ , a protecting group or the following formula:

ここで：
Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^１は、別個に、Ｈまたは１個〜１８個の炭素原子を有するアルキルである；
Ｒ^２は、別個に、Ｈ、Ｒ^１、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されているか、または炭素原子で一緒になって、２個のＲ^２基は、３個〜８個の炭素を有する環を形成し、そして該環は、０個〜３個のＲ^３基で置換され得る；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されるとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^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または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子を有するアルキル、２個〜１８個の炭素原子を有するアルケニル、２個〜１８個の炭素原子を有するアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_Ｍ２Ｒ^５または-ＳＯ_Ｍ２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ_２基で置換されている；
Ｗ^６は、Ｗ^３であり、Ｗ^３は、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；そして
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。

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;
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 embodiment, this invention provides a compound of any one of formulas 1-151:

ここで：
Ａ^０は、Ａ^１である；

here:
A ⁰ is A ¹ ;

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｓ（Ｏ）_Ｍ２−または−Ｓ（Ｏ）_Ｍ２−Ｓ（Ｏ）_Ｍ２−である；そしてＹ^２が２個のリン原子と結合するとき、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得る；
Ｒ^ｘは、別個に、Ｈ、Ｒ^２、Ｗ^３、保護基または次式である：

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 is; and ^{when Y 2} is bonded to two phosphorus atoms, ^{Y 2} also, C (R ²⁾ may be a ^{(R 2);}
R ^x is independently H, R ² , W ³ , a protecting group or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^１は、別個に、Ｈまたは１個〜１８個の炭素原子を有するアルキルである；
Ｒ^２は、別個に、Ｈ、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されるとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^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または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子を有するアルキル、２個〜１８個の炭素原子を有するアルケニル、または２個〜１８個の炭素原子を有するアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｒ^５ａは、別個に、１個〜１８個の炭素原子を有するアルキレン、２個〜１８個の炭素原子を有するアルケニレンまたは２個〜１８個の炭素原子を有するアルキニレンであり、アルキレン、アルケニレンまたはアルキニレンのいずれか１つは、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ^２基で置換されている；
Ｗ^６は、Ｗ^３であり、Ｗ^３は、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
各Ｘ^５０は、別個に、水素、Ｆ、Ｃｌ、ＣＦ_３、ＣＮ、メチルまたは第三級ブチルである；
Ｘ^５１は、水素、ハロ、トリフルオロメチル、（Ｃ１〜Ｃ３）アルキル、シアノまたは（Ｃ１〜Ｃ３）アルコキシである；
Ｘ^５２は、水素、フルオロ、クロロ、ブロモ、メチルまたはトリフルオロメチルである；
Ｘ^５３は、−Ｏ−または−Ｓ−である；
Ｘ^５４およびＸ^５５は、別個に、水素またはＣ_１〜Ｃ_１８アシルから選択される；
Ｘ^５６は、水素、Ｃ_１〜Ｃ_１８アシルまたは

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 ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, 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, or alkynyl having 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
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 ₂ R ⁵ or —SO ₂ 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;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Each X ⁵⁰ is independently hydrogen, F, Cl, CF ₃ , CN, methyl or tertiary butyl;
X ⁵¹ is hydrogen, halo, trifluoromethyl, (C1-C3) alkyl, cyano or (C1-C3) alkoxy;
X ⁵² is hydrogen, fluoro, chloro, bromo, methyl or trifluoromethyl;
X ⁵³ is —O— or —S—;
X ⁵⁴ and X ⁵⁵ are independently selected from hydrogen or C ₁ -C ₁₈ acyl;
X ⁵⁶ is hydrogen, C ₁ -C ₁₈ acyl or

である；または
Ｘ^５４は、水素であり、そしてＸ^５５およびＸ^５６は、一緒になって、

Or X ⁵⁴ is hydrogen and X ⁵⁵ and X ⁵⁶ are taken together,

である；
Ｘ^５７は、Ｈ、アミノ、ヒドロキシまたはハロゲンであり、該ハロゲンは、ＣｌおよびＢｒから選択される；
Ｘ^５８は、水素、Ｆ、Ｃｌ、ＣＦ_３、シアノ、メチルまたはｔ−ブチルである；
Ｘ^５９は、水素、ＣＨ_２ＯＨである；
Ｘ^６０は、ＣＯ（ＣＨ_２）_６ＣＯＮＭｅ（ＣＨ_２）_２ＳＯ_３Ｈである；
Ｘ^６２は、メチル、クロロまたはトリフルオロメチルである；
Ｘ^６３は、Ｈ、メチル、エチル、シクロプロピル、ビニルまたはトリフルオロメチルである；
Ｘ^６４は、Ｈ、メチル、エチル、シクロプロピル、クロロ、ビニル、アリル、３−メチル−１−ブテン−１−イルである；
Ｘ^６５は、水素またはＦである；そして
Ａｒは、アリールまたはヘテロアリールである。

Is
X ⁵⁷ is H, amino, hydroxy or halogen, wherein the halogen is selected from Cl and Br;
X ⁵⁸ is hydrogen, F, Cl, CF _3, cyano, is methyl or t- butyl;
X ⁵⁹ is hydrogen, CH ₂ OH;
X ⁶⁰ is CO (CH ₂ ) ₆ CONMe (CH ₂ ) ₂ SO ₃ H;
^X62 is methyl, chloro or trifluoromethyl;
X ⁶³ is H, methyl, ethyl, cyclopropyl, vinyl or trifluoromethyl;
^X64 is H, methyl, ethyl, cyclopropyl, chloro, vinyl, allyl, 3-methyl-1-buten-1-yl;
X ⁶⁵ is hydrogen or F; and Ar is aryl or heteroaryl.

  The present invention provides a pharmaceutical composition containing 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 provides a method of increasing the cellular accumulation and retention of drug compounds, thereby improving their therapeutic and diagnostic value, the method linking the compound to one or more phosphonate groups. The process of carrying out is included.

  The present invention also provides a method of maintaining immunosuppression, for example after transplantation surgery, comprising the step of administering to an animal (eg, a mammal) an effective amount of a compound of the present invention.

  The invention also provides a method of modulating an immune response in vitro or in vivo, comprising contacting a sample in need of such treatment with a compound of the invention.

  The invention also provides a method of inhibiting an immune response in an animal (eg, a mammal), the method comprising administering to the animal an effective amount of a compound of the invention.

  The invention also provides a method of treating a symptom or effect of an autoimmune disease (eg, psoriasis, rheumatoid arthritis, lupus, lupus erythematosus, multiple sclerosis, diabetes, Crohn's disease, etc.) in an animal (eg, a mammal). And the method includes the step of administering to the animal an effective amount of a compound of the invention.

  The invention also provides a method of treating the symptoms or effects of transplant rejection in an animal (eg, a mammal), the method comprising administering to the animal an effective amount of a compound of the invention.

  The present invention also provides a method of inhibiting human T cell proliferation in an animal (eg, a mammal) and / or downregulating production of Th1 or Th2-type cytokines, said method comprising: Administering a compound of the invention.

  The invention also provides a method of treating atopic dermatitis in an animal (eg, a mammal), the method comprising administering to the animal an effective amount of a compound of the invention.

  The invention also provides a method of inhibiting the function of one or more T-type lymphocytes in an animal (eg, a mammal) comprising administering to the animal an effective amount of a compound of the invention. The process of carrying out is included.

  The invention also provides a method of inhibiting dehydroorotate dehydrogenase in an animal (eg, a mammal), the method comprising administering to the animal an effective amount of a compound of the invention.

  The invention is also used in medical therapy (preferably in maintaining immunosuppression following transplant surgery, in inhibiting immune responses, in treating autoimmune diseases, in treating atopic dermatitis, Immunosuppression following transplantation surgery in animals (eg, mammals) as well as compounds of the invention (used in inhibiting human T cell proliferation or down-regulating production of Th1 or Th2-type cytokines) There is provided the use of a compound of the present invention for the manufacture of a medicament useful for maintaining The present invention also provides the use of a compound of the present invention for the manufacture of a medicament useful for inhibiting an immune response in an animal (eg, a mammal). The present invention also provides the use of a compound of the present invention for the manufacture of a medicament useful for treating an autoimmune disease in an animal (eg, a mammal). The present invention also provides the use of a compound of the present invention for the manufacture of a medicament useful for inhibiting the proliferation of human T cells in an animal or downregulating the production of Th1 or TH2 type cytokines.

  The invention also provides a method of maintaining immunosuppression, for example following transplantation surgery, comprising administering to an animal (eg, a mammal) an effective amount of a compound of the invention. .

  The present invention also provides the processes and novel intermediates disclosed herein that are useful for preparing the compounds of the present invention. Some of the compounds of the present invention are useful for preparing other 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 appended 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-Largen. 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 induced by 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, naphthbenzyl, 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 include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazolin. 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.

"Linker" or "link" means a chemical moiety that contains a covalent bond or atomic chain or group that 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, phosphonthioate 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:

ここで、Ｒ_１は、ＨまたはＣ_１〜Ｃ_１２アルキルであり得る；ｍ１は、１、２、３、４、５、６、７または８であり、そして該フェニル炭素環は、０個〜３個のＲ_２基で置換されている。また、Ｙ_１がＯである実施形態では、乳酸エステルが形成され、Ｙ_１がＮ（Ｒ_２）、Ｎ（ＯＲ_２）またはＮ（Ｎ（Ｒ_２）_２である場合、ホスホンアミデートエステルが得られる。

Where 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 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−カルボキシフェニルのＣ_４〜Ｃ_８エステル；およびＣ_１〜Ｃ_４アルキレン−Ｃ_３〜Ｃ_６アリール（ベンジル、−ＣＨ_２−ピロリル、−ＣＨ_２−チエニル、−ＣＨ_２−イミダゾリル、−ＣＨ_２−オキサゾリル、−ＣＨ_２−イソキサゾリル、−ＣＨ_２−チアゾリル、−ＣＨ_２−イソチアゾリル、−ＣＨ_２−ピラゾリル、−ＣＨ_２−ピリジニルおよび−ＣＨ_２−ピリミジニルを含めて）であって、これは、そのアリール部分において、３個〜５個のハロゲン原子または１個〜２個の以下から選択される原子または基で置換されている：ハロゲン、Ｃ_１〜Ｃ_１２アルコキシ（メトキシおよびエトキシを含めて）、シアノ、ニトロ、ＯＨ、Ｃ_１〜Ｃ_１２ハロアルキル（１個〜６個のハロゲン原子）；−ＣＨ_２ＣＣｌ_３を含めて）、Ｃ_１〜Ｃ_１２アルキル（メチルおよびエチルを含めて）、Ｃ_２〜Ｃ_１２アルケニルまたはＣ_２〜Ｃ_１２アルキニル；アルコキシエチル［Ｃ_１〜Ｃ_６アルキル（−ＣＨ_２−ＣＨ_２−Ｏ−ＣＨ_３（メトキシエチル）を含めて）］；アルキルであって、これは、アリールについて上で示した基のいずれか、特に、ＯＨまたは１個〜３個のハロ原子で置換されている（−ＣＨ_３、−ＣＨ（ＣＨ_３）_２、−Ｃ（ＣＨ_３）_３、−ＣＨ_２ＣＨ_３、−（ＣＨ_２）_２ＣＨ_３、−（ＣＨ_２）_３ＣＨ_３、−（ＣＨ_２）_４ＣＨ_３、−（ＣＨ_２）_５ＣＨ_３、−ＣＨ_２ＣＨ_２Ｆ、−ＣＨ_２ＣＨ_２Ｃｌ、−ＣＨ_２ＣＦ_３および−ＣＨ_２ＣＣｌ_３を含めて）；

; 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−プロピルモルホリノ、２，３−、ジヒドロ−６−ヒドロキシインデン、セサモール、カテコールモノエステル、−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_２Ｒ^１）−ＣＨ_２（ＯＣ（Ｏ）ＣＨ_２Ｒ^１）、コレステリル、エノールピルベート（ＨＯＯＣ−Ｃ（＝ＣＨ_２）−）、グリセロール；
５個または６個の炭素単糖類、二糖類またはオリゴ糖類（３個〜９個の単糖類残基）；
トリグリセリド（例えば、α−Ｄ−β−ジグリセリド）（ここで、グリセリド脂質を構成する脂肪酸は、一般に、天然に生じる飽和または不飽和Ｃ_６〜２６、Ｃ_６〜１８またはＣ_６〜１０脂肪酸（例えば、リノール酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、パルミトイル酸、リノレン酸などの脂肪酸）である）であって、これらは、そのトリグリセリドのグリセリル酸素を介して、その親化合物のアシルに結合している；
リン脂質であって、これは、リン脂質のホスフェートを介して、カルボキシル基に結合している；
フタリジル（これは、Ｃｌａｙｔｏｎら、Ａｎｔｉｍｉｃｒｏｂ．Ａｇｅｎｔｓ Ｃｈｅｍｏ．（１９７４）５（６）：６７０−６７１の図１で示されている）；
環状カーボネート（例えば、（５−Ｒ_ｄ−２−オキソ−１，３−ジオキソレン−４−イル）メチルエステル（Ｓａｋａｍｏｔｏら、Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．（１９８４）３２（６）２２４１−２２４８）であって、ここで、Ｒ_ｄは、Ｒ_１、Ｒ_４またはアリールである）；および

-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

本発明の化合物の水酸基は、必要に応じて、ＷＯ９４／２１６０４で開示されたＩＩＩ基、ＩＶ基またはＶ基の１個で置換されているか、またはイソプロピルで置換されている。

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).

＃−キラル中心は、（Ｒ）、（Ｓ）またはラセミ化合物である。

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_２ＳＣＯＣＨ_３、−ＣＨ_２ＯＣＯＮ（ＣＨ_３）_２、または構造−ＣＨ（Ｒ^１またはＷ^５）Ｏ（（ＣＯ）Ｒ^３７）または−ＣＨ（Ｒ^１またはＷ^５）（（ＣＯ）Ｒ^３８）のアルキル−またはアリール−アシルオキシアルキル基（これらは、その酸性基の酸素に結合している）であって、ここで、Ｒ^３７およびＲ^３８は、アルキル、アリールまたはアルキルアリール基である（米国特許第４９６８７８８を参照）。しばしば、Ｒ^３７およびＲ^３８は、嵩張った基（例えば、分枝アルキル、オルト−置換アリール、メタ−置換アリール、またはそれらの組合せ（１個〜６個の炭素原子を有するノルマル、第二級、イソおよび第三級アルキルを含めて））である。一例には、ピバロイルオキシメチル基がある。経口投与のプロドラッグで特に有用である。このような有用な保護基の例には、アルキルアシルオキシメチルエステルおよびそれらの誘導体があり、これらには、−ＣＨ（ＣＨ_２ＣＨ_２ＯＣＨ_３）ＯＣ（Ｏ）Ｃ（ＣＨ_３）_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_２ＯＣ（Ｏ）Ｃ_１０Ｈ_１５、−ＣＨ_２ＯＣ（Ｏ）Ｃ（ＣＨ_３）_３、−ＣＨ（ＣＨ_２ＯＣＨ_３）ＯＣ（Ｏ）Ｃ（ＣＨ_３）_３、−ＣＨ（ＣＨ（ＣＨ_３）_２）ＯＣ（Ｏ）Ｃ（ＣＨ_３）_３、−ＣＨ_２ＯＣ（Ｏ）ＣＨ_２ＣＨ（ＣＨ_３）_２、−ＣＨ_２ＯＣ（Ｏ）Ｃ_６Ｈ_１１、−ＣＨ_２ＯＣ（Ｏ）Ｃ_６Ｈ_５、−ＣＨ_２ＯＣ（Ｏ）Ｃ_１０Ｈ_１５、−ＣＨ_２ＯＣ（Ｏ）ＣＨ_２ＣＨ_３、−ＣＨ_２ＯＣ（Ｏ）ＣＨ（ＣＨ_３）_２、−ＣＨ_２ＯＣ（Ｏ）Ｃ（ＣＨ_３）_３および−ＣＨ_２ＯＣ（Ｏ）ＣＨ_２Ｃ_６Ｈ_５が挙げられる。

_{-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 described above or can be 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 alkylester 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 of particular importance.

  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.

ここで、Ｒ^９は、Ｃ_１〜Ｃ_６アルキルである。

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:

例えば、Ａｌｅｘａｎｄｅｒ、Ｊ．ら（１９９６）Ｊ．Ｍｅｄ．Ｃｈｅｍ．３９：４８０−４８６を参照。

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 an amino group of an 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. Conjugates of the parent compound and the polypeptide are generally more immunogenic than the polypeptide in closely homologous animals, and therefore 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 conjugate should be immunogenic in at least one such animal. 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

がある。

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 species or tripeptide species can be selected based on known transport properties and / or sensitivity 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 via 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は、以下である：

A ² are the following:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｓ（Ｏ）_Ｍ２−または−Ｓ（Ｏ）_Ｍ２−Ｓ（Ｏ）_Ｍ２−である；
Ｒ^ｘは、別個に、Ｈ、Ｒ^１、Ｗ^３、保護基または次式である：

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:

ここで：
Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^１は、別個に、Ｈまたは１個〜１８個の炭素原子を有するアルキルである；
Ｒ^２は、別個に、Ｈ、Ｒ^１、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されているか、または炭素原子で一緒になって、２個のＲ^２基は、３個〜８個の炭素を有する環を形成し、そして該環は、０個〜３個のＲ^３基で置換され得る；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されるとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^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または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子を有するアルキル、２個〜１８個の炭素原子を有するアルケニル、２個〜１８個の炭素原子を有するアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｒ^５ａは、別個に、１個〜１８個の炭素原子を有するアルキレン、２個〜１８個の炭素原子を有するアルケニレンまたは２個〜１８個の炭素原子を有するアルキニレンであり、アルキレン、アルケニレンまたはアルキニレンのいずれか１つは、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_Ｍ２Ｒ^５または-ＳＯ_Ｍ２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ_２基で置換されている；
Ｗ^６は、Ｗ^３であり、Ｗ^３は、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；そして
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。

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:

本発明の他の特定の実施形態では、Ａ^１は、次式である：

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

本発明の他の特定の実施形態では、Ａ^１は、次式である：

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

本発明の他の特定の実施形態では、Ａ^１は、次式である：

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

本発明の他の特定の実施形態では、Ａ^１は、次式である：

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

そして、Ｗ^５ａは、炭素環または複素環であり、ここで、Ｗ^５ａは、別個に、０個または１個のＲ^２基で置換されている。Ｍ１２ａの特定の値は、１である。

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:

本発明の他の特定の実施形態では、Ａ^１は、次式である：

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

本発明の他の特定の実施形態では、Ａ^１は、次式である：

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

ここで：Ｗ^５ａは、炭素環であり、該炭素環は、別個に、０個または１個のＲ^２基で置換されている。

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:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

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:

ここで：Ｗ^５ａは、炭素環であり、該炭素環は、別個に、０個または１個のＲ^２基で置換されている。

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:

ここで、Ｗ^５ａは、炭素環または複素環であり、ここで、Ｗ^５ａは、別個に、０個または１個のＲ^２基で置換されている。

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:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

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:

本発明の他の特定の実施形態では、Ａ^２は、次式である：

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

本発明の他の特定の実施形態では、各Ｍ１２ｂは、１である。

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:

ここで、Ｗ^５ａは、炭素環または複素環であり、ここで、Ｗ^５ａは、必要に応じて、別個に、１個、２個または３個のＲ^２基で置換されている。

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:

本発明の他の特定の実施形態では、Ａ^２は、次式である：

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

本発明の他の特定の実施形態では、Ｍ１２ｂは、１である。

In another specific embodiment of the invention M12b is 1.

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

本発明の他の特定の実施形態では、Ａ^３は、次式である：

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

本発明の他の特定の実施形態では、Ａ^３は、次式である：

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

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ａは、Ｏ、Ｎ（Ｒ^ｘ）またはＳである。

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:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^ｘ）である。

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

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

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^ｘ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

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:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^ｘ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

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:

本発明の他の特定の実施形態では、Ａ^３は、次式である：

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

本発明の他の特定の実施形態では、Ｗ^５は、炭素環である。

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

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

本発明の他の特定の実施形態では、Ｗ^５は、フェニルである。

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

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

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ａは、Ｏ、Ｎ（Ｒ^ｘ）またはＳである。

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:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^ｘ）である。

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

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

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^ｘ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

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:

ここで、該フェニル炭素環は、０個、１個、２個または３個のＲ^２基で置換されている。

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:

本発明の他の特定の実施形態では、Ａ^３は、次式である：

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

本発明の他の特定の実施形態では、Ａ^３は、次式である：

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

本発明の他の特定の実施形態では、Ａ^３は、次式である：

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

本発明の他の特定の実施形態では、Ａ^３は、次式である：

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

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ａは、Ｏ、Ｎ（Ｒ^２）またはＳである。

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:

ここで、Ｙ^１ａは、ＯまたはＳである；Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＹ^２ｃは、Ｏ、Ｎ（Ｒ^ｙ）またはＳである。

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:

ここで、Ｙ^１ａは、ＯまたはＳである；Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；Ｙ^２ｄは、ＯまたはＮ（Ｒ^ｙ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

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:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

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:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である。

Here, Y ^2b is O or N (R ² ).

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

本発明の他の特定の実施形態では、Ａ^３は、次式である：

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

本発明の他の特定の実施形態では、Ａ^３は、次式である：

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

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ａは、Ｏ、Ｎ（Ｒ^２）またはＳである。

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:

ここで、Ｙ^１ａは、ＯまたはＳである；Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＹ^２ｃは、Ｏ、Ｎ（Ｒ^ｙ）またはＳである。

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:

ここで、Ｙ^１ａは、ＯまたはＳである；Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；
Ｙ^２ｄは、ＯまたはＮ（Ｒ^ｙ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

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:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

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:

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^２）である。

Here, Y ^2b is O or N (R ² ).

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

ここで、Ｙ^２ｂは、ＯまたはＮ（Ｒ^Ｘ）である；そしてＭ１２ｄは、１、２、３、４、５、６、７または８である。

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:

ここで、該フェニル炭素環は、０個、１個、２個または３個のＲ^２基で置換されている。

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:

ここで、該フェニル炭素環は、０個、１個、２個または３個のＲ^２基で置換されている。

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:

本発明の他の特定の実施形態では、Ａ^０は、次式である：

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

ここで、各Ｒは、別個に、（Ｃ_１〜Ｃ_６）アルキルである。

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:

ここで：
Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^１は、別個に、Ｈまたは１個〜１８個の炭素原子を有するアルキルである；
Ｒ^２は、別個に、Ｈ、Ｒ^１、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されているか、または炭素原子で一緒になって、２個のＲ^２基は、３個〜８個の炭素を有する環を形成し、そして該環は、０個〜３個のＲ^３基で置換され得る；
本発明の他の特定の実施形態では、Ｒ^ｘは、次式である：

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:

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ｃは、Ｏ、Ｎ（Ｒ^ｙ）またはＳである。

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:

ここで、Ｙ^１ａは、ＯまたはＳである；そしてＹ^２ｄは、ＯまたはＮ（Ｒ^ｙ）である。

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:

本発明の他の特定の実施形態では、Ｒ^ｙは、水素または１個〜１０個の炭素を有するアルキルである。

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:

本発明の他の特定の実施形態では、Ｒ^ｘは、次式である：

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

本発明の他の特定の実施形態では、Ｒ^ｘは、次式である：

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

本発明の他の特定の実施形態では、Ｙ^１は、ＯまたはＳである。

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:

ここで：
ｍ１ａ、ｍ１ｂ、ｍ１ｃ、ｍ１ｄおよびｍ１ｅは、別個に、０または１である；
ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｒ^ｙは、Ｈ、Ｗ^３、Ｒ^２または保護基である；
但し：
もし、ｍ１ａ、ｍ１２ｃおよびｍ１ｄが０なら、ｍ１ｂ、ｍ１ｃおよびｍ１ｅは、０である；
もし、ｍ１ａおよびｍ１２ｃが０であり、そしてｍ１ｄが０ではないなら、ｍ１ｂおよびｍ１ｃは、０である；
もし、ｍ１ａおよびｍ１ｄが０であり、ｍ１２ｃが０ではないなら、ｍ１ｂと、ｍ１ｃおよびｍ１ｅの少なくとも１個とは、０である；
もし、ｍ１ａが０であり、そしてｍ１２ｃおよびｍ１ｄが０ではないなら、ｍ１ｂは、０である；
もし、ｍ１２ｃおよびｍ１ｄが０であり、そしてｍ１ａが０ではないなら、ｍ１ｂ、ｍ１ｃおよびｍ１ｅの少なくとも２個は、０である；
もし、ｍ１２ｃが０であり、そしてｍ１ａおよびｍ１ｄが０ではないなら、ｍ１ｂおよびｍ１ｃの少なくとも１個は、０である；そして
もし、ｍ１ｄが０であり、そしてｍ１ａおよびｍ１２ｃが０ではないなら、ｍ１ｃおよびｍ１ｅの少なくとも１個は、０である。

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 500-547;
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:

Ａ^２は、以下である：

A ² are the following:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｓ（Ｏ）_Ｍ２−または−Ｓ（Ｏ）_Ｍ２−Ｓ（Ｏ）_Ｍ２−である；
Ｒ^ｘは、別個に、Ｈ、Ｒ^１、Ｗ^３、保護基または次式である：

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:

ここで：
Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^１は、別個に、Ｈまたは１個〜１８個の炭素原子を有するアルキルである；
Ｒ^２は、別個に、Ｈ、Ｒ^１、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されているか、または炭素原子で一緒になって、２個のＲ^２基は、３個〜８個の炭素を有する環を形成し、そして該環は、０個〜３個のＲ^３基で置換され得る；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されるとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^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または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子を有するアルキル、２個〜１８個の炭素原子を有するアルケニル、２個〜１８個の炭素原子を有するアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｒ^５ａは、別個に、１個〜１８個の炭素原子を有するアルキレン、２個〜１８個の炭素原子を有するアルケニレンまたは２個〜１８個の炭素原子を有するアルキニレンであり、アルキレン、アルケニレンまたはアルキニレンのいずれか１つは、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ_２基で置換されている；
Ｗ^６は、Ｗ^３であり、Ｗ^３は、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；そして
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。

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 ₂ R ⁵ or —SO ₂ 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 embodiment, this invention provides a compound of any one of formulas 1-151:
here:
A ⁰ is A ¹ ;
A ¹ is:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｓ（Ｏ）_Ｍ２−または−Ｓ（Ｏ）_Ｍ２−Ｓ（Ｏ）_Ｍ２−である；
Ｒ^ｘは、別個に、Ｈ、Ｗ^３、保護基または次式である：

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, W ³ , a protecting group or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^１は、別個に、Ｈまたは１個〜１８個の炭素原子を有するアルキルである；
Ｒ^２は、別個に、Ｈ、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されるとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^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または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子を有するアルキル、２個〜１８個の炭素原子を有するアルケニル、２個〜１８個の炭素原子を有するアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｒ^５ａは、別個に、１個〜１８個の炭素原子を有するアルキレン、２個〜１８個の炭素原子を有するアルケニレンまたは２個〜１８個の炭素原子を有するアルキニレンであり、アルキレン、アルケニレンまたはアルキニレンのいずれか１つは、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ^２基で置換されている；
Ｗ^６は、Ｗ^３であり、Ｗ^３は、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；そして
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。

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 ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, 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 ₂ R ⁵ or —SO ₂ 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 specific embodiment, the invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof:
^{[DRUG] - [L-P} (= Y 1) -Y 2 -R x] nn
here,
DRUG is a compound of any one of formulas 500-547;
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, W ³ , a protecting group or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^２は、別個に、Ｈ、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されるとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^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または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子を有するアルキル、２個〜１８個の炭素原子を有するアルケニル、２個〜１８個の炭素原子を有するアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ^２基で置換されている；
Ｍ２は、１、２または３である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
ｎｎは、１、２または３である；そして
Ｌは、連結基である。

R ^y is independently H, W ³ , R ² or a protecting group;
R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, 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;
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, where W ⁵ is independently substituted with 0 to 3 R ² groups;
M2 is 1, 2 or 3;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
nn is 1, 2 or 3; and L is a linking group.

In another specific embodiment, the present invention provides a compound of formula: or a pharmaceutically acceptable salt thereof:
[DRUG]-(A ⁰ ) _nn
DRUG is any one compound of Formula 500-547; and 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:

Ａ^２は、以下である：

A ² are the following:

Ａ^３は、以下である：

A ³ are the following:

Ｙ^１は、別個に、Ｏ、Ｓ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）またはＮ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｙ^２は、別個に、結合、Ｏ、Ｎ（Ｒ^ｘ）、Ｎ（Ｏ）（Ｒ^ｘ）、Ｎ（ＯＲ^ｘ）、Ｎ（Ｏ）（ＯＲ^ｘ）、Ｎ（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））、−Ｓ（Ｏ）_Ｍ２−または−Ｓ（Ｏ）_Ｍ２−Ｓ（Ｏ）_Ｍ２−である；
Ｒ^ｘは、別個に、Ｈ、Ｗ^３、保護基または次式である：

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, W ³ , a protecting group or the following formula:

Ｒ^ｙは、別個に、Ｈ、Ｗ^３、Ｒ^２または保護基である；
Ｒ^２は、別個に、Ｈ、Ｒ^３またはＲ^４であり、ここで、各Ｒ^４は、別個に、０個〜３個のＲ^３基で置換されている；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃまたはＲ^３ｄであるが、但し、Ｒ^３がヘテロ原子に結合されるとき、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄである；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３または−ＮＯ_２である；
Ｒ^３ｂは、Ｙ^１である；
Ｒ^３ｃは、−Ｒ^ｘ、−Ｎ（Ｒ^ｘ）（Ｒ^ｘ）、−ＳＲ^ｘ、−Ｓ（Ｏ）Ｒ^ｘ、−Ｓ（Ｏ）_２Ｒ^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または−Ｎ（Ｒ^ｘ）Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^ｘ、−Ｃ（Ｙ^１）ＯＲ^ｘまたは−Ｃ（Ｙ^１）（Ｎ（Ｒ^ｘ）（Ｒ^ｘ））である；
Ｒ^４は、１個〜１８個の炭素原子を有するアルキル、２個〜１８個の炭素原子を有するアルケニル、２個〜１８個の炭素原子を有するアルキニルである；
Ｒ^５は、Ｒ^４であり、ここで、各Ｒ^４は、０個〜３個のＲ^３基で置換されている；
Ｗ^３は、Ｗ^４またはＷ^５である；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５または−ＳＯ_２Ｗ^５である；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、別個に、０個〜３個のＲ_２基で置換されている；
Ｗ^６は、Ｗ^３であり、Ｗ^３は、別個に、１個、２個または３個のＡ^３基で置換されている；
Ｍ２は、０、１または２である；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、別個に、０または１である；そして
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。

R ^y is independently H, W ³ , R ² or a protecting group;
R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ^{3 is} R ^3a, R ^3b, 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;
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, 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 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 be a saturated, unsaturated or aromatic ring, including mono- or bicyclic carbocycles or heterocycles. W ⁵ can have 3 to 10 ring atoms (eg, 3 to 7 ring atoms). These W ⁵ rings are saturated when containing 3 ring atoms, saturated or monounsaturated when containing 4 ring atoms, and saturated when containing 5 ring atoms. Monounsaturated or diunsaturated, and when containing 6 ring atoms, is saturated, monounsaturated, diunsaturated or aromatic.

W ⁵ heterocycle has 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms (which are selected from N, O, P and S)) Having a single ring or 2 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms, which are selected from N, O, P and S) It can be a ring. W ⁵ heterocycles contain 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms, which are selected from N, O and S) Or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms (which are selected from N and S)). W ⁵ heterobicycles contain 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms, which are selected from N, O and S) Having these (arranged as bicyclo [4,5], [5,5], [5,6] or [6,6] system); or 9-10 ring atoms (8- Having 9 carbon atoms and 1 to 2 heteroatoms (which are selected from N and S), which are arranged as a bicyclo [5,6] or [6,6] system ) This 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. . W ⁵ also includes, but is not limited to, for example:

Ｗ^５炭素環および複素環は、別個に、上で定義されたような０個〜３個のＲ^２基で置換され得る。例えば、置換Ｗ^５炭素環には、以下が挙げられる：

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

置換フェニル炭素環の例には、以下が挙げられる：

Examples of substituted phenyl carbocycles include the following:

（連結基およびリンカー）
本発明は、直接（例えば、共有結合を介して）または連結基（すなわち、リンカー）を介して、いずれかで、１個またはそれ以上のホスホネート基に連結された抗炎症性化合物を含有する抱合体を提供する。このリンカーの性質は、このホスホネート含有化合物が治療薬として機能する性能を妨害しないという条件で、重要ではない。このホスホネートまたはリンカーは、この化合物の水素または他の部分を除去してホスホネートまたはリンカーの結合のための開いた原子価を提供することにより、その化合物上の任意の合成的に実行可能な位置で、この化合物（例えば、式５００〜５４７の化合物）に連結できる。

(Linking group and linker)
The present invention includes an anti-inflammatory compound linked to one or more phosphonate groups, either directly (eg, via a covalent bond) or via a linking group (ie, a linker). Provide coalescence. The nature of the linker is not critical provided that the phosphonate-containing compound does not interfere with its ability to function as a therapeutic agent. The phosphonate or linker can be at any synthetically feasible position on the compound by removing the hydrogen or other moiety of the compound to provide an open valence for attachment of the phosphonate or linker. , Can be linked to this compound (eg, compounds of formula 500-547).

In one embodiment of the invention, the linking group or linker (which may be represented as “L”) is all or any of the A ⁰ , A ¹ , A ² or W ³ groups described herein. Some can be included.

  In another embodiment of the invention the linking group or linker has a molecular weight of about 20 daltons to about 400 daltons.

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

In another embodiment of the invention the linking group or linker separates DRUG and P (= Y ¹ ) residues by a length of about 5 angstroms to about 200 angstroms (inclusive).

In another embodiment of the invention said linking group or linker is a divalent branched or unbranched saturated or unsaturated hydrocarbon chain, said hydrocarbon chain having 2 to 25 carbon atoms. Where one or more of the carbon atoms (eg, 1, 2, 3 or 4) are optionally replaced with (—O—), where The chain is optionally substituted on the carbon with one or more (eg, 1, 2, 3 or 4) substituents, wherein the substituents are (C ₁ -C _{6) alkoxy, (C} 3 ~C _{6) cycloalkyl, (C} 1 ~C _{6) alkanoyl, (C} 1 ~C _{6) alkanoyloxy, (C} 1 ~C ₆₎ alkoxycarbonyl, _(C 1 ~ C ₆₎ alkylthio, azido, cyano, nitro, halo, hydroxy, oxo (= O , Carboxy, aryl, aryloxy, heteroaryl and heteroaryloxy.

In another embodiment of the present invention the linking group or linker is of the formula W-A, 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, wherein, 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; wherein each R is independently, 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 this invention the linking group or linker is of the formula W— (CH ₂ ) _n , wherein n is between about 1 and about 10; and 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; wherein each R is independently, H or _(C 1 _~C 6) Alkyl.

  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 via a carbon atom of the linker.

(Compound)
The compounds of the present invention include those having immunomodulatory activity. The compounds of the invention comprise one or more (eg, 1, 2, 3 or 4) phosphonate groups, which can be prodrug moieties.

  Typically, the compounds of the invention have a molecular weight of from about 400 amu to about 10,000 amu; in certain embodiments of the invention, the compound has a molecular weight of less than about 5000 amu; In embodiments, the compound has a molecular weight of less than about 2500 amu; in other specific embodiments of the invention, the compound has a molecular weight of less than about 1000 amu; in other specific embodiments of the invention, the compound is In other specific embodiments of the invention, the compound has a molecular weight of less than about 600 amu; and in other specific embodiments of the invention, the compound has a molecular weight of less than about 600 amu. It has a molecular weight and a molecular weight higher than about 400 amu.

  The compounds of the present invention also typically have a log D (polarity) of less than about 5. In one embodiment, the invention provides a compound having a log D of less than about 4; in another embodiment, the invention provides a compound having a log D of less than about 3; The invention provides compounds having a log D greater than about −5; in another embodiment, the invention provides compounds having a log D greater than about −3; and in another embodiment, the invention provides a compound having a log D greater than about −5; Compounds having a log D greater than about 0 and less than about 3 are provided.

Substituents selected within the compounds of the invention are present to a recursive extent. In this context, “recursive substituent” means that a substituent may describe other instances of itself. Due to the recursive nature of such substituents, in theory there can be many in any given claim. For example, R ^x contains an R ^y substituent. R ^y can be R ² , which in turn can be R ³ . If R ³ is selected to be R ^3c , the second case of R ^x can be selected. One skilled in the art of medicinal chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the target compound. Such properties include, but are not limited to, physical properties (eg, molecular weight, solubility or log P), application properties (eg, activity against the target of interest) and practical properties (eg, ease of synthesis). It is done.

By way of example, and not limitation, in the specific claims, W ³ , R ^y and R ³ are all recursive substituents. Typically, each of these is separately, within the scope of the claims, 20, 19, 18, 17, 16, 15, 13, 13, 12, 10 There may be times 9, 9, 8, 7, 5, 4, 3, 2, 1 or 0 times. More typically, each of these may be present 12 times or less, separately, within a given claim. More typically, the range of the predetermined claims, ^{W 3} is present to 8 times 0 times, ^{R y} is present to 6 times 0 times, ^{R 3} is present 10 times 0 times. Even more typically, in certain claims, W ³ is present 0 to 6 times, R ^y is present 0 to 4 times, and R ³ is present 0 to 8 times.

  Recursive substituents are an intended aspect of the invention. Those skilled in the art of medicinal chemistry understand the versatility of such substituents. To the extent that recursive substituents are present in the claims of this invention, the total number is determined as indicated above.

Whenever a compound described herein is substituted with more than one of the same designated groups (eg, “R ¹ ” or “R ^6a ”), the groups can be the same or different, ie, each It can be seen that the groups are selected separately. Wavy lines indicate sites of covalent bonding to adjacent groups, moieties or atoms.

  The term “immunomodulatory compound” also includes pimecrolimus, everolimus, sirolimus, tacrolimus, prednisolone, VX-148, merimepodiv, brequinal, thalidomide, BCX-1777, levimid, diprolene, diprolene Acid acromethasone, hydrocortisone, dexamethasone, leflunomide, methylprednisolone streptanoate, prednisone, clobetasol, MNA-715 (FK778), SMP-114, terifluronide, halobetasol, ciclesonide, deflazacortolide (t) , Triamcinolone acetonide, fluticasone, furoate Tazone, methylprednisolone aceponate, cyclosporin A, tacrolimus, mycophenolate, ANA-245, immunosuppressive macrolide, methotrexate, PNP-405, MDL-74428, 9- (3,3-dimethyl-5-phospho Nopentyl) guanine, DADMe-IMMG, CP-690, 550, mycophenate, cyclosporine and mizoribine.

  In one embodiment of the invention, the compound is in an isolated and purified state. In general, the term “isolated and purified” means that the compound is substantially free of biological material (eg, blood, cells, etc.). In one particular embodiment of the invention, the term means that the compound or conjugate of the invention is at least about 50% by weight pure in the mixture; in another embodiment, the term Means that the compound or conjugate of the invention is at least about 75% by weight pure in the mixture; in another embodiment, the term refers to the compound or conjugate of the invention being at least about 90% by weight in the mixture. In another embodiment, the term means that the compound or conjugate of the invention is at least about 98% by weight pure in the mixture; in another embodiment, This term means that the compound or conjugate of the invention is at least about 99% by weight pure in the mixture. In other specific embodiments, the invention provides compounds or conjugates of the invention prepared synthetically (eg, ex vivo).

(Intracellular targeting)
The phosphonate groups of the compounds of the invention can be cleaved stepwise in vivo after they reach the desired desired site (ie, inside the cell). One mechanism of action inside the cell may involve an initial cleavage (eg, by an esterase) to provide a negatively charged “locked-in” intermediate. Thus, cleavage of the terminal ester grouped in the compounds of the present invention provides an unstable intermediate that releases a negatively charged “fixed” intermediate.

  After passing inside the cell, intracellular enzymatic cleavage or modification of the phosphonate or prodrug compound can result in intracellular accumulation of the cleaved or modified compound by a “capture” mechanism. The cleaved or modified compound then has a charge that reduces the rate at which the cleaved or modified compound can escape from the cell compared to the rate at which the compound enters as a phosphonate prodrug. It can be “fixed” in the cell by a significant change in polarity, or other physical property. Other mechanisms by which the therapeutic effect is achieved may also be operable. Enzymes capable of enzyme activation including the phosphonate prodrug compounds of the present invention include, but are not limited to, amidase, esterase, microbial enzyme, phospholipase, cholinesterase, and phosphatase.

  From the foregoing it is clear that many different drugs can be derivatized in accordance with the present invention. A number of such agents are specifically mentioned herein. However, it should be understood that the lineage of drugs for derivatization according to the present invention and the discussion of their particular members are merely exemplary and are not to be construed as exhaustive.

  In one embodiment of the invention, the compound is not an antiviral compound. In another embodiment, the compound is not a nucleoside compound. In another embodiment, the compound is not an IMPDH inhibitor compound. In another embodiment, the compound is not an antimetabolite compound. In another embodiment, the compound is not a PNP inhibitor. In another embodiment, the compound is not a substituted compound of any one of formulas 500-533, 535-541, or 543-547. In another embodiment, the compound is not a substituted compound of any one of formulas 1-104, 107-124 or 128-151.

(Stereoisomers)
The compounds of the present invention may have chiral centers (eg, chiral carbon or phosphorus atoms). Therefore, the compounds of the present invention include racemic mixtures of all stereoisomers (including enantiomers, diastereomers and atropisomers). In addition, the compounds of the invention include enriched or resolved enantiomers at any or all asymmetric chiral atoms. In other words, the chiral centers apparent from their depictions are provided as their chiral isomers or racemic mixtures. Not only both racemic and diastereomeric mixtures, but also the individual optical isomers isolated or synthesized, which are substantially free of their enantiomeric partners or diastereomeric bar toners, are all of the present invention. Is within the range. These racemic mixtures can be obtained by well-known techniques such as separation of diastereomeric salts formed using optically active auxiliary agents (eg acids or bases followed by conversion back to their optically active substances). Are separated into individual substantially optically pure isomers. In most cases, the desired optical isomer is synthesized by a stereospecific reaction starting with the appropriate stereoisomer of the desired starting material.

  The compounds of the invention may also exist as tautomers in certain cases. Although only one delocalized resonance structure can be depicted, all such shapes are considered within the scope of the present invention. For example, ene-amine tautomers can exist in purine, pyrimidine, imidazole, guanidine, amidine and tetrazole systems, and all possible tautomeric forms thereof are within the scope of the present invention. It is.

(Salts and hydrates)
The compositions of the present invention may optionally contain salts of the compounds herein (especially pharmaceutically acceptable non-toxic salts (eg, Na ⁺ , Li ⁺ , K ⁺ , Ca ⁺² and Containing Mg ⁺² )). Such salts were derived by incorporating appropriate cations (eg, alkali metal and alkaline earth metal ions or ammonium and quaternary amino ions) and acid anion moieties (typically carboxylic acids). Can be mentioned. Monovalent salts are preferred if water soluble salts are desired.

Metal salts are typically prepared by reacting a metal hydroxide with a compound of the present invention. Examples of metal salts thus prepared include salts containing Li ⁺ , Na ⁺ and K ⁺ . A metal salt with low solubility can be precipitated from a solution of a highly soluble salt by adding a suitable metal compound.

In addition, certain organic and inorganic acids (eg, HCl, HBr, H ₂ SO ₄ , H ₃ PO ₄ or organic sulfonic acids) can be acidified to a base center (typically an amine) or acidic group. From the addition, a salt can be formed. Finally, it is understood that the compositions herein contain the compounds of the invention as hydrates in combination with their zwitterionic forms and stoichiometric amounts of water as well as their non-ionized forms. It should be possible.

  Also within the scope of the invention are salts of the parent compound with one or more amino acids. Any of the above amino acids (especially naturally occurring amino acids found as protein components) are suitable, but typically the amino acid has a side chain with a base or acid group (eg, lysine). , Arginine or glutamic acid) or having a side chain with a neutral group (eg glycine, serine, threonine, alanine, isoleucine or leucine).

(Methods of inhibiting immune regulation)
Another aspect of the present invention relates to a method for inhibiting the activity of at least one immunomodulatory agent, the method comprising the step of treating a sample suspected of containing an immunomodulatory agent with the composition of the present invention. Include.

  The compositions of the invention can act as inhibitors of immunomodulation, as intermediates for such inhibitors, or have other utilities as described below. These inhibitors bind to locations on the surface or in cavities of the immunomodulatory agent that have a profile unique to the immunomodulatory agent. Compositions that bind immunomodulators can bind to varying degrees of reversibility. 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 probes for the detection of immunomodulators. Accordingly, the present invention relates to a method for detecting an immunomodulator in a sample suspected of containing an immunomodulator, the method comprising the following steps: Treating with a composition comprising a compound of the invention bound to a label; and observing the effect of the analyte on the activity of the label. Suitable labels are well known in the diagnostic art and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens. The compounds herein are labeled in the usual manner using functional groups (eg, hydroxyl or amino).

  In the context of the present invention, specimens suspected of containing an immunomodulatory agent include natural or artificial substances (eg, biological organisms; tissues or cell cultures; biological samples (eg, biomaterial samples (eg, Blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.))); laboratory samples; food, water or air samples; biological product samples (eg cell extracts (especially desired glycoproteins) Recombinant cells))) and the like. Typically, this specimen is suspected of containing an immunomodulator. The analyte can be contained in any medium including water and organic solvent / water mixtures. Samples include biological organisms (eg, humans) and artificial materials (eg, cell cultures).

  The processing step of the present invention includes the step of adding the composition of the present invention to the specimen, or the step of adding a precursor of the composition to the specimen. This addition step includes any administration method described above.

  If desired, the activity of the immunomodulator after application of the composition can be observed by any method, including direct and indirect methods of detecting immunomodulator activity. Quantitative, qualitative and semi-quantitative methods for determining immunomodulator activity are all considered. Typically, one of the above screening methods is applied, however, any other method (eg, observing the physiological properties of a biological organism) can also be applied.

  However, it should be noted that in screening for compounds that can inhibit immunomodulators, the results of enzyme assays may not correlate with cell culture assays. Cell-based assays should therefore be the primary screening tool.

(Screen for immunomodulator inhibition)
The compositions of the invention are screened for inhibitory activity against immunomodulators by any of the conventional techniques for assessing enzyme activity. In the context of the present invention, typically compositions are first screened for inhibition of immunomodulatory agents in vitro, and compositions exhibiting inhibitory activity are then screened for activity in vivo. A composition having an in vitro Ki (inhibition constant) of less than about 5 × 10 ⁻⁶ M, typically less than about 1 × 10 ⁻⁷ M, preferably less than about 5 × 10 ⁻⁸ M Preferred for use.

  Useful in vitro screens have been described in detail and will not be described in detail here. However, the examples describe suitable in vitro assays.

(Pharmaceutical formulation)
The compounds of the invention are formulated with conventional carriers and excipients, which are selected according to normal practice. Tablets contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and are generally isotonic when intended for delivery other than by oral administration. All formulations optionally contain excipients such as those described in “Handbook of Pharmaceutical Excipients” (1986). Excipients include ascorbic acid and other antioxidants, chelating agents (eg EDTA), carbohydrates (eg dextrin), hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of these formulations ranges from about 3 to about 11, but is usually about 7-10.

  While it is possible for these active ingredients to be administered alone, it may be preferred to present them as a pharmaceutical formulation. The formulations of the present invention (which are used for both animal and human applications) have at least one active, along with one or more acceptable carriers and optionally other therapeutic ingredients. Contains ingredients (defined above). These carriers must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically benign to the recipient.

  These formulations include those suitable for the aforementioned administration routes. These formulations may conveniently be presented in unit dosage form and prepared by any of the methods well known in pharmacy. Techniques and formulations can be 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 constitutes one or more accessory ingredients. In general, these formulations 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. The

  Formulations of the present invention suitable for oral administration are as discrete units (eg, capsules, cachets or tablets, each containing a predetermined amount of active ingredient); as powders or granules; It can be provided as an aqueous liquid solution or suspension; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered as a bolus, electuary or paste.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are free-flowing form active ingredients (e.g., powders or granules, which may be combined with binders, lubricants, inert diluents, preservatives, if necessary) Can be prepared by compressing) (mixed with a surfactant or dispersant). Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient and a suitable carrier, which is wet with an inert liquid diluent. These tablets can be coated or imprinted as required and are formulated for slow or controlled release of the active ingredient therefrom, if desired.

  For administration to the eyes or other external tissues (eg mouth and skin), these formulations are preferably applied as topical ointments or creams, which contain this active ingredient, eg 0.075- 20% by weight (contains active ingredient in the range between 0.1% and 20% stepwise 0.1% by weight (eg 0.6%, 0.7% by weight, etc.)) , Preferably 0.2 to 15% by weight, most preferably 0.5 to 10% by weight. When formulated in an ointment, these active ingredients can be used in either a paraffin base or a water-miscible ointment base. Alternatively, these active ingredients can be formulated in a cream with an oil-in-water cream base.

  If desired, the aqueous phase of the cream base may contain, for example, at least 30% by weight of a polyhydric alcohol (ie, an alcohol having two or more hydroxyl groups (eg, propylene glycol, butane 1,3-diol, mannitol). Sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof)). These topical formulations may desirably contain 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 simply contain an emulsifier, which is otherwise known as an emission promoter, whereas it desirably comprises at least one emulsifier and a fat or oil or Contains a mixture with both fat and oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier (which acts as a stabilizer). It is also preferred to include both oil and fat. These emulsifiers together with or without stabilizers constitute a so-called emulsifying wax, which together with the oil and fat constitutes a so-called emulsifying ointment base, which is used in these cream formulations To form an oily dispersed phase.

  Discharge enhancers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween® 60, Span® 80, cetyl stearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono Examples include stearate and sodium lauryl sulfate.

  The selection of an appropriate oil or fat for this formulation is based on achieving the desired appearance characteristics. The cream should preferably be a non-oily, non-staining and washable product with adequate fastness to avoid leakage from tubes or other containers. Linear or branched mono- or dibasic alkyl esters (e.g., di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, A blend of branched chain esters known as 2-ethylhexyl palmitate or Crodamol CAP) can be used, the last three being the preferred esters. These can be used alone or in combination depending on the desired properties. Alternatively, lipids with high melting points (eg, white soft paraffin and / or liquid paraffin or other mineral oils) are used.

  The pharmaceutical formulations of the present invention contain one or more compounds of the present invention, along with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. . The pharmaceutical formulation containing the active agent can be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, medicinal drops, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs can be prepared. Compositions for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, such compositions being sweeteners, to provide a palatable formulation One or more agents may be included, including flavoring agents, coloring agents and preservatives. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients include, for example, inert diluents (eg, calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate); granulating agents and disintegrants (E.g. wheat starch or alginic acid); binders (e.g. cellulose, microcrystalline cellulose, starch, gelatin or acacia) and lubricants (e.g. magnesium stearate, stearic acid or talc). These tablets may not be coated or may be coated by known techniques (including microencapsulation) to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period of time. Is obtained. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

  Formulations for oral use include hard gelatin capsules (where the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin), or soft gelatin capsules where the active ingredient Can be provided as water or as an oil medium (eg, mixed with peanut oil, liquid paraffin or olive oil).

  The aqueous suspensions of the present invention contain this active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspensions (eg, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum, and acacia gum); dispersants or wetting agents (eg, naturally occurring phosphatides). (For example, lecithin), condensation products of alkylene oxide and fatty acid (for example, polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohol (for example, heptadecaethyleneoxycetanol), ethylene oxide and fatty acid And condensation products with partial esters derived from hexitol anhydrides (eg, polyoxyethylene sorbitan monooleate) This aqueous suspension may also contain one or more protective agents. An agent (eg, ethyl ester or n-propyl ester of p-hydroxybenzoic acid), one or more colorants, one or more flavoring agents, and one or more sweeteners (eg, Sucrose or saccharin).

  Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (eg, arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (eg, liquid paraffin). This oily suspension may also contain a thickening agent (beeswax, hard paraffin or cetyl alcohol). Sweeteners (eg, listed above) and flavoring agents can be added to provide a palatable oral formulation. These compositions can be preserved by the addition of an antioxidant (eg, ascorbic acid).

  Dispersible powders and granules of the invention suitable for preparing an aqueous suspension by the addition of water contain this active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. To do. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Other excipients such as sweeteners, flavoring agents and coloring agents can also be present.

  The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil (eg, olive oil or peanut oil), a mineral oil (eg, liquid paraffin), or a mixture of these. Suitable emulsifiers include, for example, naturally occurring gums (eg, gum arabic and tragacanth), naturally occurring phosphatides (eg, soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (eg, sorbitan monooles). And a condensation product of the partial ester and ethylene oxide (for example, polyoxyethylene sorbitan monooleate)). The emulsion may also contain sweetening, flavoring and preserving agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative, flavoring or coloring agent.

  The pharmaceutical compositions of the invention may also be in the form of a sterile injectable formulation (eg, a sterile injectable aqueous or oleaginous suspension). This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. This sterile injectable formulation is also a sterile injectable solution or suspension (eg, a solution in 1,3-butanediol) in a nontoxic parenterally acceptable diluent or solvent. Or may be prepared as a lyophilized powder. Among the suitable excipients and solvents that may be used are Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can usually be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used as well for the preparation of injectables.

  The amount of active ingredient that can be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, a time release formulation for oral administration to humans may contain about 1-1000 mg of active substance (which is a suitable and convenient amount of carrier substance, which is about 5 to about 95% (by weight) of the total composition. :) which may vary with weight)). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution for intravenous infusion may contain from about 3 to about 500 μg of active ingredient per milliliter of solution so that a suitable volume of infusion can occur at a rate of about 30 mL / hr.

  Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5 to 20% by weight, advantageously 0.5 to 10% by weight, in particular about 1.5% by weight. is doing.

  Formulations suitable for topical administration in the mouth include medicinal drops (which contain the active ingredient in a seasoning base (usually sucrose and acacia or tragacanth)); pastilles (which are inert groups) Agents (for example, containing the active ingredient in gelatin and glycerin, or sucrose and acacia) and mouthwashes (which contain the active ingredient in a suitable liquid carrier).

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

  Formulations suitable for intrapulmonary or intranasal administration are, for example, 0.1 to 500 microns (particle sizes with an increased number of microns in the range of between 0.1 and 500 microns (eg,. Particle size in the range of 5, 1, 30, 35 microns, etc.), which can be inhaled by rapid inhalation through the nostrils or through the mouth to reach the alveolar sac To be administered. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or anhydrous powder administration can be prepared according to conventional methods and delivered with other therapeutic agents (eg, compounds conventionally used in the treatment or prevention of infections described below). .

  Formulations suitable for intravaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations, which in addition to the active ingredient are suitable as known in the art. Contains a good carrier.

  Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which include antioxidants, buffers, bacteriostats and solutes (this is a recipe for Can be made isotonic with the blood of the ent; and aqueous and non-aqueous sterile suspensions, which may include suspending and thickening agents.

  These formulations can be provided in single-dose or multi-dose containers (eg, sealed ampoules and vials) and stored in a lyophilized state, which is a sterile liquid carrier (eg, injection) immediately prior to use. It is only necessary to add water). Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage forms are those containing a daily dose or unit daily sub-dose of the active ingredient or an appropriate portion thereof, as previously cited herein.

  In addition to the ingredients specifically mentioned above, the formulations of the present invention may contain other agents common in the art for that type of formulation, for example those suitable for oral administration are flavors It should be understood that it may contain a material.

  The present invention further provides a veterinary composition, which, together with its veterinary carrier, contains at least one active ingredient as defined above.

  A veterinary carrier is a substance useful for the purpose of administering the composition, which may be a solid, liquid or gaseous substance, otherwise it is inert or acceptable in the veterinary field, It is compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or by any other desired route.

  The compounds of the present invention may also be formulated to provide sustained release of the active ingredient so as to permit less frequent dosing or improve the pharmacokinetics or toxicity profile of the active ingredient. Accordingly, the present invention also provides compositions containing one or more compounds of the present invention formulated for sustained release.

  The effective dose of the active ingredient depends at least on the nature of the disease to be treated, toxicity, whether the compound is used prophylactically (low dose) or against active infections, delivery methods, and pharmaceutical formulations. And determined by a clinician using routine dose assessment studies. It can be expected to be from about 0.0001 to about 100 mg / kg body weight / day. Typically, from about 0.01 to about 10 mg / kg body weight / day. More typically from about 0.01 to about 5 mg / kg body weight / day. More typically from about 0.05 to about 0.5 mg / kg body weight / day. For example, a daily candidate dose for an adult weighing approximately 70 kg ranges from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of a single dose or multiple doses.

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

(Combination therapy)
The composition of the present invention is also used in combination with other active ingredients. Such combinations are selected based on the disease being treated, the component's interreactivity and the pharmacological properties of the formulation.

  It is also possible to combine any compound of the present invention with one or more other active ingredients in a single dosage form for simultaneous or sequential administration to a patient. This combination therapy can be administered in a simultaneous or sequential regimen. When administered sequentially, the combination can be administered two or more times.

  This combination therapy may provide a “synergistic effect” and “synergistic effect”, ie an effect that is higher than the sum of the effects resulting from the separate use of the compounds when the active ingredients are combined. Synergistic effects can be achieved when these active ingredients are: (1) when formulated together and administered or delivered together in a blended formulation; (2) alternately as separate formulations. Or when delivered in parallel; or (3) by some other regimen. When delivered in alternation therapy, these compounds can be achieved when administered or delivered by different injections sequentially (eg, in separate tablets, pills or capsules) or in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially (ie, sequentially), whereas in combination therapy, effective dosages of two or more active ingredients are administered together. Is done.

(Metabolite of the compound of the present 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 mainly due to 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 period of time sufficient to produce its metabolite. Such products typically prepare a radiolabeled (eg, ¹⁴ C or ³ H) compound of the invention and detect it in an animal (eg, rat, mouse, guinea pig, monkey or human) (E.g., a dose higher than about 0.5 mg / kg) parenterally gives sufficient time (typically about 30 seconds to 30 hours) to cause metabolism, and urine, It is identified by isolating its conversion product from blood or other biological sample. These products are easily isolated because they are labeled (others are isolated by using antibodies that can bind antigenic determinants remaining in the metabolite). The structure of the metabolite is determined by conventional methods (eg, MS or NMR analysis). In general, analysis of metabolites is performed in the same manner as normal drug metabolite studies well known to those skilled in the art. This conversion product is useful in diagnostic assays that therapeutically dose the compounds of the invention, even if they do not have their own immunomodulatory inhibitory activity, unless found in vivo.

  Strategies and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. A compound is defined herein as being stable in the gastrointestinal tract when less than about 50 mole percent of the protecting groups are deprotected in surrogate intestinal fluid or gastric fluid when incubated at 37 ° C. for 1 hour. The Note that just because these compounds are stable in the gastrointestinal tract does not mean they cannot be hydrolyzed in vivo. The phosphonate prodrugs of the invention are typically stable in the digestive system but are substantially hydrolyzed to their parent drug in the gastrointestinal tract, liver or other metabolic organs, or general cells. The

(Representative method for producing the compound of the present invention)
The invention also relates to a method for producing the composition of the invention. These compositions are prepared by any applicable organic synthesis technique. Many such techniques are well known in the art. However, many of these known techniques are described in detail in the following document: “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, Strategy & Efficiency in Modern Organic Chemistry.In 9 Volumes", Barry M. Trost, Editor-in-Chief (printed in Pergamon Press, New York, 1993).

  A number of exemplary methods of preparing the compositions of the present invention are provided below. These methods are to be construed as illustrative of the nature of such preparations and are not to be construed as limiting the scope of the applicable methods.

  In general, reaction conditions such as temperature, reaction time, solvents, work-up procedures, etc. are common in the art for the particular reaction to be performed. The cited materials include a detailed description of such conditions, along with the materials cited herein. Typically, their temperature is -100 to 200 ° C, the solvent is aprotic or protic, and the reaction time is 10 seconds to 10 days. Work-up typically consists of quenching any unreacted reagents followed by partitioning (extraction) between the water / organic layer system and separating the layers containing the product.

  While oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 ° C.), for metal hydride reduction, the temperature is often reduced from 0 ° C. to −100 ° C. The solvent is typically aprotic for reduction and can be either protic or aprotic for oxidation. The reaction time is adjusted to achieve the desired conversion.

  Condensation reactions are typically carried out at temperatures close to room temperature, but lower temperatures (0 ° C. to −100 ° C.) are also common for non-equilibrium and kinetically controlled condensations . The solvent can be either protic (which is common for equilibration reactions) or aprotic (which is common for kinetically controlled reactions).

  Standard synthetic techniques (eg, azeotropic removal of reaction byproducts and use of anhydrous reaction conditions (eg, inert gas environment)) are common in the art and are applied where applicable. Is done.

(Scheme and Examples)
General aspects of these representative methods are described below and in the Examples. Each of the following process products is optionally separated, isolated and / or purified prior to use in subsequent processes.

  In general, reaction conditions such as temperature, reaction time, solvents, work-up procedures, etc. are common in the art for the particular reaction to be performed. The cited materials include a detailed description of such conditions, along with the materials cited herein. Typically, their temperature is -100 to 200 ° C, the solvent is aprotic or protic, and the reaction time is 10 seconds to 10 days. Work-up typically consists of quenching any unreacted reagents followed by partitioning (extraction) between the water / organic layer system and separating the layers containing the product.

  While oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 ° C.), for metal hydride reduction, the temperature is often reduced from 0 ° C. to −100 ° C. The solvent is typically aprotic for reduction and can be either protic or aprotic for oxidation. The reaction time is adjusted to achieve the desired conversion.

  Condensation reactions are typically carried out at temperatures close to room temperature, but lower temperatures (0 ° C. to −100 ° C.) are also common for non-equilibrium and kinetically controlled condensations . The solvent can be either protic (which is common for equilibration reactions) or aprotic (which is common for kinetically controlled reactions).

  Standard synthetic techniques (eg, azeotropic removal of reaction byproducts and use of anhydrous reaction conditions (eg, inert gas environment)) are common in the art and are applied where applicable. Is done.

  The terms “treated”, “treating”, “treatment” and the like are used in connection with chemical synthesis operations to contact, mix, react. Means other terms customary in the art to indicate that contact is made and that one or more chemical elements are processed in a manner that converts them to one or more other chemical elements . This means that “treating compound 1 with compound 2” means “reacting compound 1 with compound 2”, “contacting compound 1 with compound 2”, “reacting compound 1 with compound 2” And the same meaning as other expressions customary in the technical field of organic synthesis, which rationally indicates “treatment”, “react”, “react”, etc., with compound 2. For example, “treating” means the usual rational way of reacting organic chemicals. Unless otherwise stated, normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures (-100 ° C to 250 ° C, typically -78 ° C to 150 ° C, more typically Typically −78 ° C. to 100 ° C., even more typically 0 ° C. to 100 ° C.), reaction vessel (typically glass, plastic, metal), solvent, pressure, atmosphere (typically , Oxygen or water insensitive reactions are intended to be air, or oxygen or water sensitive reactions are nitrogen or argon). Similar reaction knowledge known in the art of organic synthesis is used in selecting conditions and equipment to “treat” in a given process. In particular, one skilled in the art of organic synthesis selects conditions and equipment that are reasonably expected to successfully perform the chemical reactions of the described process, based on knowledge in the art.

  Improvements to each of the exemplary schemes described above and in the examples (hereinafter “representative schemes”) provide various analogs of the specific exemplary materials produced. The above citations describing appropriate methods of organic synthesis are applicable to such modifications.

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

  Other types of separation methods include treating the mixture with reagents selected to bind to the desired products, unreacted starting materials, reaction byproducts, etc., or make them separable. Such reagents include adsorbents or absorbents (eg, activated carbon, molecular sieves, ion exchange media, etc.). Alternatively, these reagents include acids for basic substances, bases for acidic substances, binding reagents (eg, antibodies, binding proteins), selective chelating agents (eg, crown ethers, liquid / liquid ion exchange reagents ( LIX).

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

  Single isomers substantially free of stereoisomers (eg, enantiomers) are obtained by resolution of their racemic mixture using methods such as the formation of diastereomers using optically active resolving agents. Obtainable. ("Stereochemistry of Carbon Compounds" (1962) by EL Liel, McGraw Hill; Lochmuller, CH, (1975) J. Chromatogr., 113: (3) 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) Formation of ionic diastereomeric salts using chiral compounds and fractional crystallization or other Separation by methods, (2) formation of diastereomeric compounds using chiral derivatization reagents, separation of these diastereomers and conversion to pure stereoisomers, and (3) substantial under chiral conditions Direct separation of pure or enriched stereoisomers.

  In method (1), the diastereomeric salt has an enantiomerically pure chiral base (eg, brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), etc.) and an acidic functional group. It can be formed by reaction with asymmetric compounds such as carboxylic acids and sulfonic acids. These diastereomeric salts can be induced to separate by fractional crystallization or ionic chromatography. Addition of chiral carboxylic or sulfonic acids (eg camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid) to separate these optical isomers from amino compounds can form these diastereomeric salts.

  Alternatively, according to method (2), the substrate to be resolved is reacted with an 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 are obtained by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing reagent (eg, a menthyl derivative), followed by separation and hydrolysis of these diastereomers to yield the free enantiomer. It can be formed by obtaining a concentrated xanthene. The method for determining optical purity is in the presence of a base or Mosher ester, a racemic mixture thereof, α-methoxy-α- (trifluoromethyl) phenyl acetate (Jacob III. (1982) J. Org. Chem. 47: 4165). A process for preparing chiral esters (eg, menthyl esters (eg, (-) menthyl chloroformate)) and analyzing for the presence of two atropisomeric diastereomers in an NMR spectrum. . Stable diastereomers of atrop compounds can be separated and isolated by normal phase and reverse phase chromatography followed by separation of the atropisomeric naphthyl-isoquinoline (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) W. J. 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 (eg, optical rotation and circular dichroism).

(Example General section)
Numerous representative methods of preparing the compounds of the present invention are provided herein, for example, in the following examples. These methods are to be construed as illustrative of the nature of such preparations and are not to be construed as limiting the scope of the applicable methods. Certain compounds of the present invention can be used as intermediates for preparing other compounds of the present invention. For example, the interconversion of various phosphonate compounds of the present invention is described below.

(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, in any of the compounds of the invention or their precursors, represents a substructure (ie, the drug “scaffold”), 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. Mol. Org. Chem. , 38: 3224 1973, using chlorotris (triphenylphosphine) rhodium (Wilkinson catalyst) in aqueous ethanol, optionally in the presence of diazabicyclooctane, at reflux. ) 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 the Mitsunobu reaction as described above. The substrate is reacted with the hydroxy compound R ¹ OH in the presence of diethyl azodicarboxylate and 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 1 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.

（ホスホネートカーバメートの調製）
ホスホン酸エステルは、カーバメート連鎖を含有し得る。カーバメートの調製は、Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ，Ａ．Ｒ．Ｋａｔｒｉｔｚｋｙ，ｅｄ．，Ｐｅｒｇａｍｏｎ，１９９５，Ｖｏｌ．６，ｐ．４１６ｆｆおよびＯｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ，ｂｙ Ｓ．Ｒ．Ｓａｎｄｌｅｒ ａｎｄ Ｗ．Ｋａｒｏ，Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９８６，ｐ．２６０ｆｆで記述されている。そのカルバモイル基は、Ｅｌｌｉｓ，ＵＳ ２００２／０１０３３７８ Ａ１ ａｎｄ Ｈａｊｉｍａ，ＵＳ ６０１８０４９の教示を含めて、当該技術分野で公知の方法に従って、水酸基の反応により、形成され得る。

(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 an 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 in 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 conducted 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.

（カルボアルコキシ置換ホスホネートビスアミデート、モノアミデート、ジエステルおよびモノエステルの調製）
ホスホン酸をアミデートおよびエステルに変換する多数の方法が利用可能である。１群の方法では、このホスホン酸は、単離し活性化した中間体（例えば、塩化ホスホリル）に変換されるか、またはアミンまたはヒドロキシ化合物との反応のためにその場で活性化されるか、いずれかである。

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. Org. 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.

この手順の一例は、スキーム３４、例１で示す。この手順では、ホスホン酸ジベンジルＳ３４．１４は、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９５，６０，２９４６で記述されているように、トルエン中にて、還流状態で、ジアザビシクロオクタン（ＤＡＢＣＯ）と反応されて、ホスホン酸モノベンジルＳ３４．１５が得られる。次いで、その生成物は、ピリジン中にて、等モル量のアラニン酸エチルＳ３４．１６およびジシクロヘキシルカルボジイミドと反応されて、アミデート生成物Ｓ３４．１７が得られる。次いで、ベンジル基が、例えば、パラジウム触媒上での水素化分解によって除去されて、モノ酸生成物Ｓ３４．１８が得られ、これは、Ｊ．Ｍｅｄ．Ｃｈｅｍ．（１９９７）４０（２３）：３８４２に従って、不安定にされ得る。次いで、この化合物Ｓ３４．１８は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９５，３８，２７４２で記述されているように、光延反応にて、ロイシン酸エチルＳ３４．１９、トリフェニルホスフィンおよびジエチルアゾジカルボキシレートと反応されて、ビスアミデート生成物Ｓ３４．２０が得られる。

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 diethylazodicarboxylate 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 phosphonic acid S35.2. This transformation procedure 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 amines and phosphonic acids (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.

この方法の例は、スキーム３５、例２および３で示している。例２で示した順序では、ホスホン酸モノベンジルＳ３５．１１は、上記方法の１つを使用して、アラニン酸エチルとの反応により、モノアミデートＳ３５．１２に変換される。そのベンジル基は、次いで、酢酸エチル溶液中にて、炭素上５％触媒で触媒水素化することにより除去されて、ホスホン酸アミデートＳ３５．１３が得られる。その生成物は、次いで、例えば、Ｔｅｔ．Ｌｅｔｔ．，２００１，４２，８８４１で記述されているように、ジクロロメタン溶液中にて、室温で、等モル量の１−（ジメチルアミノプロピル）−３−エチルカルボジイミドおよびトリフルオロエタノールＳ３５．１４と反応されて、アミデートエステルＳ３５．１５が生じる。

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.

スキーム３６は、カルボアルコキシ置換ホスホネートジエステルを調製する方法を図示しており、ここで、それらのエステル基の１個は、カルボアルコキシ置換基を取り込む。

Scheme 36 illustrates a method for 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.

スキーム３７は、ホスホネートジエステルを調製する方法を図示しており、ここで、両方のエステル置換基は、カルボアルコキシ基を取り込む。

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.

２，２−ジメチル−２−アミノエチルホスホン酸中間体は、スキーム５の経路により、調製できる。２−メチル−２−プロパンスルフィンアミドをアセトンで縮合すると、スルフィニルイミンＳ３８．１１が得られる（Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９９９，６４，１２）。Ｓ３８．１１にジメチルメチルホスホン酸リチウムを付加すると、Ｓ３８．１２が得られる。Ｓ３８．１２を酸性メタノール分解すると、アミンＳ３８．１３が得られる。アミンをＣｂｚ基で保護しメチル基を除去すると、ホスホン酸Ｓ３８．１４が生じ、これは、先に報告した方法を使用して、所望のＳ３８．１５（スキーム３８ａ）に変換できる。化合物Ｓ３８．１４の代替的な合成もまた、スキーム３８ｂで示されている。市販の２−アミノ−２−メチル−１−プロパノールは、文献方法（Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９９２，５７，５８１３；Ｓｙｎ．Ｌｅｔｔ．１９９７，８，８９３）に従って、アジリジンＳ３８．１６に変換される。ホスファイトをアジリジン開環すると、Ｓ３８．１７が得られる（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．１９８０，２１，１６２３）。Ｓ３８．１７を再保護すると、Ｓ３８．１４が得られる。

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 provides 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.

本発明は、以下の非限定的な実施例により、ここに例示される。

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

    Example 1

ラパマイシン（化合物１．１であって、ここで、ラパマイシン構造の残りの部分は、示されていない；エベロリムスの合成前駆体）は、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ，１９９５，５，１０３５で報告されたもののような手順に従って、適当なアリールビスマス試薬を使用して、上で示したようにして、Ｏ−アリール化される。３−（ジメチル−ｔ−ブチルシリルオキシ）ブロモベンゼンは、ジエチルエーテル中のマグネシウムで処理されるか、またはテトラヒドロフラン中のブチルリチウムで処理されるか、いずれかであり、得られた有機金属試薬は、三塩化ビスマスと反応されて、トリアリールビスムチンが産生される。１〜１．２当量の過酢酸で処理した後、このビスマス（Ｖ）試薬は、ラパマイシンおよび酢酸銅（ＩＩ）と混合される。その反応は、室温で、もし必要なら、還流状態で、１日間進行し、所望の３−（ジメチル−ｔ−ブチルシリルオキシ）フェニルエーテル１．２が得られる。そのジメチル−ｔ−ブチルシリル保護基を除去した後、Ｏ−アルキル化は、酸化銀の存在下にて、ホスホン酸ジエチル（ブロモメチル）で達成され、所望のエベロリムス類似物（これは、ホスホン酸ジエチル１．３を含有する）が得られる。ヨウ化銀で補助した反応は、ラパマイシンと構造的に類似の免疫抑制性マクロライドでのＯ−アルキル化を媒介するのに使用した：Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９８，４１，１７６４を参照。

Rapamycin (compound 1.1, where the rest of the rapamycin structure is not shown; a synthetic precursor of everolimus) is described in Bioorg. Med. Chem. Following the procedure such as that reported in Lett, 1995, 5, 1035, O-arylation is performed as indicated above using a suitable aryl bismuth reagent. 3- (Dimethyl-t-butylsilyloxy) bromobenzene is either treated with magnesium in diethyl ether or with butyllithium in tetrahydrofuran, and the resulting organometallic reagent is Reacts with bismuth trichloride to produce triarylbismuthine. After treatment with 1-1.2 equivalents of peracetic acid, the bismuth (V) reagent is mixed with rapamycin and copper (II) acetate. The reaction proceeds at room temperature and, if necessary, at reflux for 1 day to give the desired 3- (dimethyl-t-butylsilyloxy) phenyl ether 1.2. After removal of the dimethyl-t-butylsilyl protecting group, O-alkylation is achieved with diethyl phosphonate (bromomethyl) in the presence of silver oxide and the desired everolimus analog (which is diethyl phosphonate 1 .3) is obtained. A silver iodide assisted reaction was used to mediate O-alkylation with an immunosuppressive macrolide structurally similar to rapamycin: Med. Chem. 1998, 41, 1764.

    (Example 2)

エベロリムスインドリルエーテルのホスホネート誘導体は、重要なトリインドリルビスムチン中間体がＪ．Ｏｒｇ．Ｃｈｅｍ．１９９８，６３，６７２１で記述された手順に従って５−ブロモインドールから得られること以外は、実施例１で記述された様式と類似の様式で、ラパマイシン（式２．１であって、ここで、ラパマイシン構造の残りの部分は、示されていない）から調製される。

Everolimus indolyl ether phosphonate derivatives have important triindolyl bismuthine intermediates as described in J. Am. Org. Chem. In a manner similar to that described in Example 1 except that it is obtained from 5-bromoindole according to the procedure described in 1998, 63, 6721, rapamycin (formula 2.1, where rapamycin The rest of the structure is prepared from (not shown).

    (Example 3)

タクロリムス（化合物３．１であって、ここで、タクロリムス分子の残りの部分は、示されていない）は、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ，１９９５，５，１０３５で報告されたもののような手順に従って、適当なアリールビスマス試薬を使用して、上で示したようにして、Ｏ−アリール化される。３−（ジメチル−ｔ−ブチルシリルオキシ）ブロモベンゼンは、ジエチルエーテル中のマグネシウムで処理されるか、またはテトラヒドロフラン中のブチルリチウムで処理されるか、いずれかであり、得られた有機金属試薬は、三塩化ビスマスと反応されて、トリアリールビスムチンが産生される。１〜１．２当量の過酢酸で処理した後、このビスマス（Ｖ）試薬は、タクロリムス３．１および酢酸銅（ＩＩ）と混合される。その反応は、室温で、もし必要なら、還流状態で、１日間進行し、所望の３−（ジメチル−ｔ−ブチルシリルオキシ）フェニルエーテルが得られる。そのジメチル−ｔ−ブチルシリル保護基をＨＦで除去した後、Ｏ−アルキル化は、酸化銀の存在下にて、ホスホン酸ジエチル（ブロモメチル）で達成され、所望のタクロリムス類似物（これは、ホスホン酸ジエチル３８．３を含有する）が得られる。ヨウ化銀で補助した反応は、タクロリムスと構造的に類似の免疫抑制性マクロライドでのＯ−アルキル化を媒介するのに使用した。（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９８，４１，１７６４を参照）。

Tacrolimus (compound 3.1, where the rest of the tacrolimus molecule is not shown) is described in Bioorg. Med. Chem. Following the procedure such as that reported in Lett, 1995, 5, 1035, O-arylation is performed as indicated above using a suitable aryl bismuth reagent. 3- (Dimethyl-t-butylsilyloxy) bromobenzene is either treated with magnesium in diethyl ether or with butyllithium in tetrahydrofuran, and the resulting organometallic reagent is Reacts with bismuth trichloride to produce triarylbismuthine. After treatment with 1-1.2 equivalents of peracetic acid, the bismuth (V) reagent is mixed with tacrolimus 3.1 and copper (II) acetate. The reaction proceeds at room temperature for 1 day at reflux, if necessary, to give the desired 3- (dimethyl-t-butylsilyloxy) phenyl ether. After removal of the dimethyl-t-butylsilyl protecting group with HF, O-alkylation is achieved with diethyl phosphonate (bromomethyl) in the presence of silver oxide and the desired tacrolimus analog (which is phosphonic acid Containing 38.3 diethyl). A silver iodide assisted reaction was used to mediate O-alkylation with an immunosuppressive macrolide structurally similar to tacrolimus. (See J. Med. Chem., 1998, 41, 1764).

    (Example 4)

タクロリムスインドリルエーテル４．３のホスホネート誘導体は、重要なトリインドリルビスムチン中間体がＪ．Ｏｒｇ．Ｃｈｅｍ．１９９８，６３，６７２１で記述された手順に従って５−ブロモインドールから得られること以外は、実施例３で記述された様式と類似の様式で、タクロリムス（化合物４．１であって、ここで、タクロリムス分子の残りの部分は、示されていない）から調製される。

Phosphonate derivatives of tacrolimus indolyl ether 4.3 have important triindolyl bismuthine intermediates as described in J. Am. Org. Chem. In a manner similar to that described in Example 3 except that it was obtained from 5-bromoindole according to the procedure described in 1998, 63, 6721, tacrolimus (compound 4.1, where tacrolimus The rest of the molecule is prepared from (not shown).

(Example 5)
Representative compounds of the present invention are described in Boer et al. Mass Spectrom. 1995, 30, 497-504 and Hoyte et al. Med. Chem. They can be made by procedures such as those described in 2002, 45, 5397-5405; they can also be made according to the following general route.

式５．１および５．２の化合物（ここで、「リンク」は、連結基またはリンカーに対して本明細書中で定義した値のいずれかを有する）は、本発明の代表的な化合物である。

Compounds of formula 5.1 and 5.2 (where “link” has any of the values defined herein for a linking group or linker) are representative compounds of the invention. is there.

    (Example 6)

プレドニゾロン６Ａは、溶媒（例えば、クロロホルム）中で、酸（例えば、濃塩酸）の存在下にて、ホルムアルデヒドで処理される。室温で数時間（好ましくは、７〜１０時間）攪拌した後、層分離され、その有機層が濃縮されて、そのビス−メチレンジオキシ）中間体５．３が得られる（Ｈｉｒｓｃｈｍａｎｎ，Ｒ．ら、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．１９６４，８６，１５２０−１５２７）。この中間体は、溶媒（例えば、ピリジン）中にて、ホスホン酸ジエチル（アミノオキシメチル）で処理されて、そのオキシム５．４が得られる。このオキシムは、酸水溶液で処理されて、そのビス−（メチレンジオキシ）保護基が除去される。例えば、このオキシムは、６０％ギ酸水溶液で処理され、そして９０℃で、１０分間加熱され、冷却され、そしてエタノールの一部を使用して濃縮されて、ギ酸の除去を助ける。その残留物をクロマトグラフィー精製および／または結晶化すると、プレドニゾロンのホスホネートオキシム類似物５．５が得られる。

Prednisolone 6A is treated with formaldehyde in a solvent (eg, chloroform) in the presence of an acid (eg, concentrated hydrochloric acid). After stirring at room temperature for several hours (preferably 7-10 hours), the layers are separated and the organic layer is concentrated to give the bis-methylenedioxy) intermediate 5.3 (Hirschmann, R. et al. J. Am. Chem. Soc. 1964, 86, 1520-1527). This intermediate is treated with diethyl phosphonate (aminooxymethyl) in a solvent (eg pyridine) to give the oxime 5.4. The oxime is treated with an aqueous acid solution to remove its bis- (methylenedioxy) protecting group. For example, the oxime is treated with a 60% aqueous formic acid solution and heated at 90 ° C. for 10 minutes, cooled, and concentrated using a portion of ethanol to help remove formic acid. The residue is chromatographically purified and / or crystallized to give the phosphonate oxime analog 5.5 of prednisolone.

  An important precursor of this synthesis, diethyl phosphonate (aminooxymethyl) can be obtained from diethyl phosphonate (trifluoromethylsulfonyloxymethyl) and N- (t-butoxycarbonyl) -hydroxylamine. Thus, N- (t-butoxycarbonyl) hydroxylamine is dissolved in a solvent (eg, THF) and treated with sodium hydride. When bubbling ceases, diethyl phosphonate (trifluoromethyl-sulfonyloxymethyl), which was prepared according to Tetrahedron Lett., 1986, 27, 1477, is added. After quenching the reaction with aqueous ammonium chloride and extracting the product with an organic solvent (eg, ethyl acetate), the N-Boc protected diethyl phosphonate (aminooxymethyl) is isolated by chromatography. The N-Boc protecting group is then removed by treatment with trialuroacetic acid to give the desired diethyl phosphonate (aminooxymethyl).

    (Example 7)

プレドニゾロン６Ａは、Ｐｒｏｃｏｐｉｏｕ、Ｐ．ら、Ｊ．Ｍｅｄ．Ｃｈｅｍ，２００１，４４，６０２−６１２で報告されたもののような手順に従って、水素下にて、ロジウム触媒（例えば、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ））を使用して、１，２−ジヒドロプレドニゾロン７．１に還元される。次いで、このステロイドのＤ環上のジヒドロキシケトン基は、そのＣ−２位置でのホルミル化の前に、実施例６で記述された方法を使用して、保護される。例えば、このビス−（メチレンジオキシ）中間体７．２は、溶媒（例えば、トルエン）中にて、新たに蒸留したギ酸エチルおよび水素化ナトリウムで処理される。この反応は、弱塩基（例えば、リン酸二水素カリウム）の水溶液でクエンチされる。その粗生成物は、一般的な方法（例えば、結晶化）で精製されて、この２−ホルミル中間体７．３が得られる。この２−ホルミル化合物は、ホスホネート置換フェニルヒドラジンと縮合されて、そのビス−（メチレンジオキシ）保護基を除去した後、プレドニゾロンの所望のホスホネートピラゾール類似物７．４が得られる。

Prednisolone 6A is available from Procopio, P .; Et al. Med. Chem., 2001, 44, 602-612, using a rhodium catalyst (eg, tris (triphenylphosphine) rhodium (I) chloride) under hydrogen using a procedure such as that reported in 1,2- Reduced to dihydroprednisolone 7.1. The dihydroxy ketone group on the D ring of the steroid is then protected using the method described in Example 6 prior to formylation at the C-2 position. For example, the bis- (methylenedioxy) intermediate 7.2 is treated with freshly distilled ethyl formate and sodium hydride in a solvent (eg, toluene). The reaction is quenched with an aqueous solution of a weak base (eg, potassium dihydrogen phosphate). The crude product is purified by conventional methods (eg, crystallization) to give the 2-formyl intermediate 7.3. This 2-formyl compound is condensed with a phosphonate-substituted phenylhydrazine to remove the bis- (methylenedioxy) protecting group to give the desired phosphonate pyrazole analog 7.4 of prednisolone.

  The important precursor 3-[(diethylphosphono) methoxy] phenylhydrazine 7.5 can be prepared starting from phosphonic acid (trifluoromethylsulfonyloxymethyl) diethyl and 3-nitrophenol. 3-Nitrophenol is treated with a base (eg, sodium hydroxide) and then O-alkylated with diethyl phosphonate (trifluoromethylsulfonyloxymethyl). The nitro group is reduced with tin (II) chloride followed by diazotization and sodium sulfite (Chem. Ber., 1960, 93, 540) or tin (II) chloride (J. Med. Chem., 2001, 44,4031) to the aryl hydrazine.

(Examples 8 to 13)
Synthetic methodologies and intermediate compounds that can be used to prepare VX-148 analogs of Formula A, B, or C are described in Examples 8-13. The following compounds are representative examples of compounds of formulas 6, 7 and 8.

（実施例８）

(Example 8)

３，５−二官能化ニトロベンゼン誘導体をアニリン（これは、本発明のＶＸ−１４８類似物を調製するのに使用できる）に変換するのに有用な一般スキームは、上で図示されている。

A general scheme useful for converting 3,5-bifunctionalized nitrobenzene derivatives to anilines, which can be used to prepare VX-148 analogs of the present invention, is illustrated above.

    Example 9

３−ヒドロキシ−５−ニトロ−安息香酸は、塩化チオニル中にて、短時間加熱されて、その酸塩化物が産生される。この酸塩化物は、塩基（例えば、トリエチルアミン）の存在下にて、Ｏ，Ｎ−ジメチル−ヒドロキルアミンと縮合されて、そのＷｅｉｎｒｅｂアミドが生成し、これは、メチルリチウムと反応されると、そのアセトフェノン誘導体が得られる。このアセトフェノン誘導体は、双極性非プロトン性溶媒（例えば、ジメチルホルムアミド）中にて、過剰のＥ−１，４−ジブロモブテンの存在下にて、塩基（例えば、炭酸カリウム）で処理される。この一臭化物は、クロマトグラフィーで単離され、次いで、溶媒（例えば、トルエン）中にて、（または他のＡｒｂｕｚｏｖ反応条件で：Ｅｎｇｅｌ，Ｒ．，「Ｓｙｎｔｈｅｓｉｓ ｏｆ Ｃａｒｂｏｎ−ｐｈｏｓｐｈｏｒｕｓ Ｂｏｎｄｓ」、ＣＲＣ ｐｒｅｓｓ，１９８８を参照）、亜リン酸トリエチルとの処理にかけられて、所望のホスホン酸ジエチルエステルが産生される。その後、このアセトフェノンのカルボニルは、適当なホモキラルオキサザボロジジン（ｈｏｍｏｃｈｉｒａｌ ｏｘａｚａｂｏｒｏｌｉｄｉｎｅ）（例えば、Ｃｏｒｅｙ（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９８７，１０９，５５５１）で記述されたもの）を使用して、エナンチオ選択的に還元され、得られたアルコールは、Ｍｉｔｓｕｎｏｂｕ（Ｂｕｌｌ．Ｃｈｅｍ．Ｓｏｃ．Ｊａｐａｎ．，１９７１，４４，３４２７）で記述されたもののような方法を使用して、アジドで置換される。このアジドは、Ｓｔａｕｄｉｎｇｅｒ条件（Ｈｅｌｖ．Ｃｈｉｍ．Ａｃｔ．，１９１９，２，６３５）下にて、そのアミンに還元され、そして炭酸ｔ−ブチルとして保護される。最後に、このニトロベンゼンのスズ（ＩＩ）媒介還元により、所望のアニリン中間体が産生される。このアニリンは、米国特許第６，０５４，４７２号および米国特許第６，３４４，４６５号で記述されたものと類似のカップリング反応を使用して、式Ａ（また、式６）の化合物に変換される。

3-Hydroxy-5-nitro-benzoic acid is heated briefly in thionyl chloride to produce its acid chloride. The acid chloride is condensed with O, N-dimethyl-hydroxylamine in the presence of a base (eg, triethylamine) to produce the Weinreb amide, which when reacted with methyllithium An acetophenone derivative is obtained. This acetophenone derivative is treated with a base (eg, potassium carbonate) in a dipolar aprotic solvent (eg, dimethylformamide) in the presence of excess E-1,4-dibromobutene. This monobromide is isolated chromatographically and then in a solvent (eg, toluene) (or at other Arbuzov reaction conditions: Engel, R., “Synthesis of Carbon-phosphorus Bonds”, CRC press, 1988) and subjected to treatment with triethyl phosphite to produce the desired phosphonic acid diethyl ester. The carbonyl of the acetophenone is then used using the appropriate homochiral oxazaborodidine (e.g., described in Corey (J. Am. Chem. Soc., 1987, 109, 5551)). The resulting alcohol is substituted with an azide using methods such as those described by Mitsunobu (Bull. Chem. Soc. Japan., 1971, 44, 3427). The azide is reduced to its amine and protected as t-butyl carbonate under Staudinger conditions (Helv. Chim. Act., 1919, 2,635). Finally, the tin (II) mediated reduction of this nitrobenzene produces the desired aniline intermediate. This aniline is converted to a compound of formula A (also formula 6) using a coupling reaction similar to that described in US Pat. No. 6,054,472 and US Pat. No. 6,344,465. Converted.

    (Example 10)

３，４−二官能化ニトロベンゼン誘導体１０．１をアニリン（これは、米国特許第６，０５４，４７２号および米国特許第６，３４４，４６５号で記述されたものと類似のカップリング反応を使用して、式Ｂ（また、式７）の化合物に変換できる）は、上で図示されている。

The 3,4-bifunctionalized nitrobenzene derivative 10.1 is converted to aniline (this uses a coupling reaction similar to that described in US Pat. No. 6,054,472 and US Pat. No. 6,344,465). Formula B (which can also be converted to a compound of Formula 7) is illustrated above.

    (Example 11)

３−置換ニトロベンゼン１１．１を操作すると、アニリン１１．２が得られ、これは、米国特許第６，０５４，４７２号および米国特許第６，３４４，４６５号で記述されたものと類似のカップリング反応を使用して、式Ｃ（また、式８）の化合物に変換できる。

Manipulation of 3-substituted nitrobenzene 11.1 affords aniline 11.2, which is a cup similar to that described in US Pat. No. 6,054,472 and US Pat. No. 6,344,465. A ring reaction can be used to convert to a compound of formula C (also formula 8).

    (Example 12)

３−ニトロベンズアルデヒド１２．１は、グリニャール試薬と反応して、示しているように、保護アルコールを有するテザーが導入され、同時に、ベンジルアルコールが産生される。アルコール１２．２は、実施例９で記述されたものと類似の様式で、アジドで置換される。脱保護後、遊離したアルコールは、塩基（例えば、マグネシウム第三級ブトキシド）を使用して、溶媒（例えば、テトラヒドロフラン）中にて、ホスホノメチルトリフリト酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製される）でアルキル化される。このアジドおよびニトロ基の引き続いた変換は、実施例９で記述されたものと類似の様式で、進行する。Ｂａｔｔ ら、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，１９９５，５，１５４９を参照。

3-Nitrobenzaldehyde 12.1 reacts with a Grignard reagent and, as shown, a tether with a protected alcohol is introduced and, at the same time, benzyl alcohol is produced. Alcohol 12.2 is replaced with an azide in a manner similar to that described in Example 9. After deprotection, the liberated alcohol can be removed from diethyl phosphonomethyltrifritate (which is Tetrahedron Lett., 1986) in a solvent (eg, tetrahydrofuran) using a base (eg, magnesium tertiary butoxide). , 27, 1477). This subsequent conversion of the azide and nitro groups proceeds in a manner similar to that described in Example 9. Batt et al., Bioorg. Med. Chem. Lett. , 1995, 5, 1549.

    (Example 13)

３−第三級ブトキシカルボニルアミン−３−（３−ニトロ−フェニル）−プロピオン酸１３．１（これは、市販されている）は、これは、溶媒（例えば、ジメチルホルムアミド）中で、第二級アミドを形成するのに標準的な試薬（例えば、ジシクロヘキシルカルボジイミド（ＤＣＣ）およびヒドロキシベンゾトリアゾール（ＨＯＢＴ））を使用して、２−アミノエチルホスホン酸ジエチルエステル（これは、市販されている）とカップリングされる。このニトロ基の引き続いた還元は、実施例９で記述されたものと類似の様式で、進行する。

3-Tertiary butoxycarbonylamine-3- (3-nitro-phenyl) -propionic acid 13.1, which is commercially available, is obtained in a solvent (eg dimethylformamide) Standard reagents such as dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) are used to form secondary amides with 2-aminoethylphosphonic acid diethyl ester (which is commercially available) and To be coupled. This subsequent reduction of the nitro group proceeds in a manner similar to that described in Example 9.

    (Example 14)

上記スキームは、式９の化合物を調製するのに使用できる一般経路を図示している。

The above scheme illustrates a general route that can be used to prepare compounds of formula 9.

    (Example 15)

３−ヒドロキシ−５−ニトロ−安息香酸１５．１は、塩化チオニル中にて、短時間加熱されて、その酸塩化物が産生される。次いで、これは、塩基（例えば、トリエチルアミン）の存在下にて、Ｏ，Ｎ−ジメチル−ヒドロキルアミンと縮合されて、そのＷｅｉｎｒｅｂアミドが生成し、これは、メチルリチウムと反応されると、そのアセトフェノン誘導体が得られる。次いで、これは、双極性非プロトン性溶媒（例えば、ジメチルホルムアミド）中にて、過剰のＥ−１，４−ジブロモブテンの存在下にて、塩基（例えば、炭酸カリウム）で処理される。この一臭化物は、クロマトグラフィーで単離され、次いで、溶媒（例えば、トルエン）中にて、（または他のＡｒｂｕｚｏｖ反応条件で：Ｅｎｇｅｌ，Ｒ．，「Ｓｙｎｔｈｅｓｉｓ ｏｆ Ｃａｒｂｏｎ−ｐｈｏｓｐｈｏｒｕｓ Ｂｏｎｄｓ」、ＣＲＣ ｐｒｅｓｓ，１９８８を参照）、亜リン酸トリエチルとの処理にかけられて、所望のホスホン酸ジエチルエステル１５．２が産生される。その後、このアセトフェノンのカルボニルは、適当なホモキラルオキサザボロジジン（ｈｏｍｏｃｈｉｒａｌ ｏｘａｚａｂｏｒｏｌｉｄｉｎｅ）（例えば、Ｃｏｒｅｙ（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９８７，１０９，５５５１）で記述されたもの）を使用して、エナンチオ選択的に還元され、得られたアルコールは、Ｍｉｔｓｕｎｏｂｕ（Ｂｕｌｌ．Ｃｈｅｍ．Ｓｏｃ．Ｊａｐａｎ．，１９７１，４４，３４２７）で記述されたもののような方法を使用して、アジドで置換される。このアジドは、Ｓｔａｕｄｉｎｇｅｒ条件（Ｈｅｌｖ．Ｃｈｉｍ．Ａｃｔ．，１９１９，２，６３５）下にて、そのアミンに還元され、そして炭酸ｔ−ブチルとして保護される。最後に、このニトロベンゼンのスズ（ＩＩ）媒介還元により、所望のアニリン中間体１５．３が産生される。

3-Hydroxy-5-nitro-benzoic acid 15.1 is heated briefly in thionyl chloride to produce its acid chloride. This is then condensed with O, N-dimethyl-hydroxylamine in the presence of a base (eg, triethylamine) to produce the Weinreb amide, which, when reacted with methyllithium, is acetophenone. A derivative is obtained. This is then treated with a base (eg potassium carbonate) in the presence of excess E-1,4-dibromobutene in a dipolar aprotic solvent (eg dimethylformamide). This monobromide is isolated chromatographically and then in a solvent (eg, toluene) (or at other Arbuzov reaction conditions: Engel, R., “Synthesis of Carbon-phosphorus Bonds”, CRC press, 1988) and subjected to treatment with triethyl phosphite to produce the desired phosphonic acid diethyl ester 15.2. The carbonyl of the acetophenone is then used using the appropriate homochiral oxazaborodidine (e.g., described in Corey (J. Am. Chem. Soc., 1987, 109, 5551)). The resulting alcohol is substituted with an azide using methods such as those described by Mitsunobu (Bull. Chem. Soc. Japan., 1971, 44, 3427). The azide is reduced to its amine and protected as t-butyl carbonate under Staudinger conditions (Helv. Chim. Act., 1919, 2,635). Finally, the tin (II) mediated reduction of this nitrobenzene produces the desired aniline intermediate 15.3.

    (Example 16)

式１０の代表的な化合物の合成で使用するのに適当な試薬は、２−ヒドロキシ−５−ニトロ−安息香酸から出発して、実施例１０で図示されたものと類似の経路により、製造され得る。

A suitable reagent for use in the synthesis of a representative compound of formula 10 is prepared by a route analogous to that illustrated in Example 10 starting from 2-hydroxy-5-nitro-benzoic acid. obtain.

    (Example 17)

式１１の代表的な化合物は、上記実施例１１〜１３で図示されているように、調製できる。式１７．２のアニリンの調製は、上記実施例１１〜１３に図示されている。式１７．２のアニリンは、米国特許第６，０５４，４７２号および米国特許第６，３４４，４６５号で記述されたものと類似の手順を使用して、式１１の化合物に変換できる。

Representative compounds of formula 11 can be prepared as illustrated in Examples 11-13 above. The preparation of the aniline of formula 17.2 is illustrated in Examples 11-13 above. The aniline of formula 17.2 can be converted to the compound of formula 11 using procedures similar to those described in US Pat. No. 6,054,472 and US Pat. No. 6,344,465.

(Example 18)
The following are general routes that can be used to prepare compounds of formula 15.

（実施例１９）

Example 19

化合物１９．１および化合物１９．２の初期Ｐｆｉｔｚｉｎｇｅｒ縮合は、示しているように、酸性ワークアップと共に水酸化カリウムを使用して、１段階で達成される。あるいは、この初期アルドール縮合は、エタノール中のジエチルアミンを使用して実行され得、そのキノリン環は、溶媒（例えば、１，４−ジオキサン）中にて、酸（例えば、塩酸）により媒介される第二工程で、形成され得る。そのベンジル保護基を水素化によって除去することに続いて、このフェノールは、溶媒（テトラヒドロフランまたはジメチルホルムアミド）中にて、塩基（例えば、水素化ナトリウム）で処理できる。泡立ちが止まると、ホスホノメチルトリフリト酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）が加えられ、所望のホスホン酸ジエステルが生じる。このカルボキシレートは、エタノール中の水酸化リチウムで処理することにより脱保護されて、化合物１９．４（これは、式１２の化合物である）が得られる。

Initial Pfitzinger condensation of compound 19.1 and compound 19.2 is accomplished in one step using potassium hydroxide with acidic workup, as shown. Alternatively, this initial aldol condensation can be performed using diethylamine in ethanol, the quinoline ring being mediated by an acid (eg, hydrochloric acid) in a solvent (eg, 1,4-dioxane). Can be formed in two steps. Following removal of the benzyl protecting group by hydrogenation, the phenol can be treated with a base (eg, sodium hydride) in a solvent (tetrahydrofuran or dimethylformamide). When bubbling ceases, diethyl phosphonomethyltrifritate (which was prepared according to Tetrahedron Lett., 1986, 27, 1477) is added to give the desired phosphonic diester. The carboxylate is deprotected by treatment with lithium hydroxide in ethanol to give compound 19.4, which is a compound of formula 12.

    (Example 20)

この合成は、このフェノールの脱プロトン化に続いて、Ｅ−１，４−ジブロモブタンが過剰に加えること以外は、実施例１９で描写されたものと類似している。この反応を塩化アンモニウム水溶液でクエンチし、その生成物を有機溶媒（例えば、酢酸エチル）で抽出した後、そのモノアルキル化生成物は、クロマトグラフィーで単離される。得られた臭化物は、溶媒（例えば、トルエン）中にて、亜リン酸トリエチルと共に加熱されて、所望のホスホン酸のジエチルエステルが産生し、そのカルボン酸は、前のように脱保護されて、化合物２０Ａ（これは、式１２の化合物である）が得られる。

This synthesis is similar to that depicted in Example 19 except that an excess of E-1,4-dibromobutane is added following the deprotonation of the phenol. After quenching the reaction with aqueous ammonium chloride and extracting the product with an organic solvent (eg, ethyl acetate), the monoalkylated product is isolated by chromatography. The resulting bromide is heated with triethyl phosphite in a solvent (eg, toluene) to produce the diethyl ester of the desired phosphonic acid, which carboxylic acid is deprotected as before, Compound 20A (which is a compound of formula 12) is obtained.

(Example 21)
The structures of prednisone 21A (US Pat. No. 2,897,464) and representative phosphonates are illustrated below, where the substituent R ¹ is H, alkyl, alkenyl, aryl or aralkyl. is there. These phosphonate compounds incorporate a phosphonate moiety (R ¹ O) ₂ P (O) linked to its nucleus by various linking groups (designated as “links”).

例えば、上記スキームは、保護−脱保護順序を描写しており、ここで、そのステロイド側鎖は、ビスメチレンジオキシ（ＢＭＤ）部分として、保護される。この順序では、プレドニゾン２１Ａは、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、ｂｙ Ｔ．Ｗ．Ｇｒｅｅｎｅ ａｎｄ Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，Ｓｅｃｏｎｄ Ｅｄｉｔｉｏｎ １９９０，ｐ．２２３で記述されているように、パラホルムアルデヒドおよび酸触媒（例えば、塩酸）と反応されて、ＢＭＤ誘導体２１．１が得られる。次いで、そのホスホネート部分は、下記の手順を使用して導入され、ホスホン酸エステル２１．２が生成される。次いで、このＢＭＤ部分は、例えば、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」，ｂｙ Ｔ．Ｗ．Ｇｒｅｅｎｅ ａｎｄ Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，Ｓｅｃｏｎｄ Ｅｄｉｔｉｏｎ １９９０，ｐ．２２３で記述されているように、５０％酢酸水溶液で処理することにより加水分解されて、トリオール２１．３（これは、式２３の化合物である）が得られる。

For example, the above scheme depicts a protection-deprotection sequence, where the steroid side chain is protected as a bismethylenedioxy (BMD) moiety. In this order, prednisone 21A is referred to as “Protective Groups in Organic Synthesis”, by T. B. et al. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. Reacted with paraformaldehyde and an acid catalyst (eg hydrochloric acid) as described in H.223 to give BMD derivative 21.1. The phosphonate moiety is then introduced using the following procedure to produce the phosphonate ester 21.2. This BMD portion is then described in, for example, “Protective Groups in Organic Synthesis”, by T.A. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. Hydrolysis by treatment with 50% aqueous acetic acid as described in H.223 gives triol 21.3 (which is a compound of formula 23).

  If necessary, depending on the nature of the reaction used, the 11-ketone group in BMD compound 21.1 is protected prior to the introduction of the phosphonate group. This ketone is described, for example, in J. Org. Am. Chem. Soc. , 1955, 77, 1904, it is protected as its cyclic ethylene ketal by reaction with ethylene glycol and acid catalyst at reflux temperature in a toluene solution. Deprotection is described in J. Org. Chem. Soc. , Chem. Comm. , 1351, 1987, by reaction with pyridinium tosylate in an aqueous acetone solution.

  Alternatively, the 11-ketone is protected by conversion to its N, N-dimethylhydrazone. This dimethylhydrazone can be obtained from Org. Syn. , 1970, 50, 102, by reacting ketone 21.1 with N, N-dimethylhydrazine in ethanol-acetic acid. This group is described in J. Org. Am. Chem. Soc. , 1979, 101, 5841, by treatment with sodium acetate and acetic acid in aqueous tetrahydrofuran.

  Alternatively, the 11-ketone is protected as the diethylamine adduct. In this procedure, substrate 21.1 is Chem. Soc. , Chem. Comm. , 406, 1983 and reacted with titanium tetrakis (diethylamide) to give this adduct. The ketone is deprotected by reacting with water in an aqueous organic solvent.

The 11-protected BMD compound 21.4 is then converted to the phosphonate 21.5 using the procedure described below. Deprotection then yields 11-ketodiol 21.3.
(Example 22)

ホスホネート２２．３（ここで、このホスホネートは、イミノまたはイミノキシ基および多様な炭素鎖によって、結合されている）の調製は、上で描写している。この手順では、二重保護誘導体２１．４は、アミンまたはヒドロキシルアミン２２．１（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルまたはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールまたはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。

The preparation of phosphonate 22.3, where the phosphonate is linked by imino or iminoxy groups and various carbon chains, is depicted above. In this procedure, the double protected derivative 21.4 is an amine or hydroxylamine 22.1 (where R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally represents a heteroatom O , S or N), or a functional group (such as an amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which is optionally heterogeneous) And X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent).

  For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcohol solvent (eg, ethanol), optionally in the presence of an acid catalyst. This imine or oxime is obtained. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. The protecting group is then removed to give ketodiol 22.3, which is a compound of formula 16.

    (Example 23)

ホスホネートＰ２．１０（ここで、このホスホネートは、イミノキシ基によって、結合されている）の調製は、上で図示している。基質２３．１（式２３．１の化合物であって、ここで、その１１−ケトンは、ジメチルヒドラゾンとして、保護されている）は、ジアルキルホスホノメチルヒドロキシルアミンＰ２．８（これは、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシムＰ２．９が得られ、これは、５０％酢酸水溶液と反応させることにより脱保護されて、ジオールＰ２．１０が得られる。このオキシム形成反応は、典型的には、室温で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。

The preparation of phosphonate P2.10, where the phosphonate is linked by an iminoxy group, is illustrated above. Substrate 23.1 (compound of formula 23.1, where the 11-ketone is protected as dimethylhydrazone) is a dialkylphosphonomethylhydroxylamine P2.8 (which is a phosphonic acid). Reacted with dialkyl trifluoromethylsulfonyloxymethyl (prepared from Tetrahedron Lett., 1986, 27, 1477) and BOC-hydroxylamine) to give oxime P2.9, which is reacted with 50% aqueous acetic acid. To obtain the diol P2.10. This oxime formation reaction is typically carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at room temperature.

The intermediate dialkylphosphonomethylhydroxylamine P2.8 (compound 2.7, where R ² is a bond) can be prepared as follows.

ホスホネートＰ２．４（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミンＰ２．５（Ａｌｄｒｉｃｈ）と反応されて、エーテルＰ２．６が生成される。この反応は、典型的には、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテルＰ２．７が得られる。

Phosphonate P2.4 (where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine P2.5 (Aldrich) to give ether P2.6. Generated. This reaction is typically performed between equimolar amounts of reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine). . Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether P2.7.

    (Example 24)

ジエノン２３．１は、実施例２３で記述されているように、Ｏ−（２−ブロモベンジル）ヒドロキシルアミンＰ２．１１（これは、臭化２−ブロモベンジルから調製した）と反応されて、脱保護後、オキシムＰ２．１２が得られる。次いで、この生成物は、パラジウム触媒の存在下にて、亜リン酸ジアルキルＰ２．１３と反応されて、ホスホネートＰ２．１４ａが得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、典型的には、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。

Dienone 23.1 was reacted with O- (2-bromobenzyl) hydroxylamine P2.11 (prepared from 2-bromobenzyl bromide) as described in Example 23 to remove After protection, the oxime P2.12 is obtained. This product is then reacted with a dialkyl phosphite P2.13 in the presence of a palladium catalyst to give phosphonate P2.14a. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is typically carried out in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0).

  Alternatively, bromo compound P2.12 is coupled with dialkylvinyl phosphonate P2.15 (Aldrich) to give phosphonate P2.16. Coupling of aryl halides and olefins by this Heck reaction is described, for example, in “Advanced Organic Chemistry”, F.M. A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, p. 503ff and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)), optionally in the presence of a base (eg triethylamine or potassium carbonate). Optionally, the styrenoid double bond present in the product P2.16 is reduced, for example by reaction with diimide, to produce the saturated analog P2.17. The reduction of olefinic bonds is described in “Comprehensive Organic Transformations”, by R.C. C. Larock, VCH, 1989, p. It is described in 6ff. This conversion is performed, for example, by catalytic hydrogenation using a palladium on carbon catalyst and hydrogen or hydrogen donor, or by using diimide or diborane.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of benzyloxy reagent P2.11, compounds P2.14, P2.16 and A product similar to P2.17 is obtained.

    (Example 25)

式１６のホスホネート（ここで、このホスホネートは、イミノ基によって、結合されている）の調製は、上で図示している。基質２３．１は、ホスホン酸ジアルキル４−アミノフェニルＰ２．１８（Ｅｐｓｉｌｏｎ）と反応されて、脱保護後、イミン生成物Ｐ２．１９が得られる。この反応は、典型的には、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われる。

The preparation of the phosphonate of formula 16 where the phosphonate is linked by an imino group is illustrated above. Substrate 23.1 is reacted with dialkyl 4-aminophenyl P2.18 (Epsilon) phosphonate to give imine product P2.19 after deprotection. This reaction is typically performed in a hydrocarbon solvent (eg, toluene or xylene) at reflux temperature with a basic catalyst (eg, sodium methoxide) or an acidic catalyst (eg, p-toluenesulfonic acid). In the presence, it is carried out under azeotropic conditions.

    (Example 26)

式１６の代表的なホスホネート（ここで、このホスホネートは、オキシイミノ基およびエーテル連鎖によって、結合されている）の調製は、上で図示している。この手順では、ジエノン２３．１は、Ｏ−（２−ヒドロキシエチル）ヒドロキシルアミンＰ２．２０（Ｊ．Ｃｈｅｍ．Ｓｏｃ．，Ｃｈｅｍ．Ｃｏｍｍ．，１９８６，９０３）と反応されて、オキシムＰ２．２１が生じる。ステロイド性１，４−ジエン−３−オンと置換ヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている。この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物間で実行される。次いで、このオキシムは、光延反応において、ホスホン酸ジアルキル４−ヒドロキシフェニルＰ２．２２（Ｅｐｓｉｌｏｎ）と反応されて、エーテルオキシムＰ２．２３が生じる。光延反応による芳香族エーテルの調製は、例えば、「Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ」、ｂｙ Ｒ．Ｃ．Ｌａｒｏｃｋ，ＶＣＨ，１９８９，ｐ．４４８および「Ａｄｖａｎｃｅｄ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ」、Ｐａｒｔ Ｂ，ｂｙ Ｆ．Ａ．Ｃａｒｅｙ ａｎｄ Ｒ．Ｊ．Ｓｕｎｄｂｅｒｇ，Ｐｌｅｎｕｍ，２００１，ｐ．１５３−４およびＯｒｇ．Ｒｅａｃｔ．，１９９２，４２，３３５で記述されている。このフェノールおよびアルコールまたはチオール成分は、非プロトン性溶媒（例えば、テトラヒドロフラン）中で、アゾジカルボン酸ジアルキルおよび亜リン酸トリアルキルの存在下にて、共に反応されて、それらのエーテルまたはチオエーテル生成物が得られる。この手順もまた、Ｏｒｇ．Ｒｅａｃｔ．，１９９２，４２，３３５−６５６で記述されている。次いで、エーテル生成物Ｐ２．２３は、ケトジオールＰ２．２４（これは、式１６の化合物）に変換される。

The preparation of a representative phosphonate of formula 16 where the phosphonate is linked by an oximino group and an ether linkage is illustrated above. In this procedure, dienone 23.1 is reacted with O- (2-hydroxyethyl) hydroxylamine P2.20 (J. Chem. Soc., Chem. Comm., 1986, 903) to give oxime P2.21. Arise. The reaction of steroidal 1,4-dien-3-one with substituted hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795. This reaction is carried out between equimolar amounts of reactants in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate. This oxime is then reacted in a Mitsunobu reaction with a dialkyl 4-hydroxyphenyl phosphonate P2.22 (Epsilon) to give the ether oxime P2.23. Preparation of aromatic ethers by Mitsunobu reaction is described in, for example, “Comprehensive Organic Transformations”, by R.M. C. Larock, VCH, 1989, p. 448 and “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. The phenol and alcohol or thiol component are reacted together in the presence of a dialkyl azodicarboxylate and a trialkyl phosphite in an aprotic solvent (eg, tetrahydrofuran) to produce their ether or thioether product. can get. This procedure is also described in Org. React. 1992, 42, 335-656. The ether product P2.23 is then converted to ketodiol P2.24, which is a compound of formula 16.

  Using the above procedure, but using a different hydroxy-substituted hydroxylamine and / or a different hydroxy-substituted arylphosphonate aryl instead of hydroxylamine P2.20, a product similar to P2.24 is obtained.

    (Example 27)

式１７および１８のホスホン酸エステル（ここで、そのホスホネート基は、芳香族またはヘテロ芳香族基、ヘテロ原子または多様な炭素鎖によって、そのピラゾール環の１’または２’部分に結合されている）の調製は、上で図示している。この手順では、ＢＭＤ保護ジエノン２１．１は、還元されて、１，２−ジヒドロ生成物Ｐ３．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物Ｐ３．２が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジンＰ３．３（ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応により、異性体２’−および１’−アリールピラゾールＰ３．４およびＰ３．５が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物の間で実行される。次いで、ピラゾールＰ３．４およびＰ３．５は、ＢＭＤ保護中間体Ｐ３．６およびＰ３．７を経由して、ホスホネートＰ３．８およびＰ３．９（これらは、それぞれ、式１７および１８の化合物である）に変換される。

Phosphonate esters of formulas 17 and 18, wherein the phosphonate group is attached to the 1 ′ or 2 ′ portion of the pyrazole ring by an aromatic or heteroaromatic group, heteroatom or various carbon chains The preparation of is illustrated above. In this procedure, BMD protected dienone 21.1 is reduced to give 1,2-dihydro product P3.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. The product is then Am. Chem. Soc. , 1964, 86, 1520, reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product. P3.2 is obtained. This compound is then reacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine P3.3, where substituent X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent. The For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2′- and 1′-arylpyrazoles P3.4 and P3.5. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). The pyrazoles P3.4 and P3.5 are then phosphonates P3.8 and P3.9 via the BMD protected intermediates P3.6 and P3.7, which are compounds of formulas 17 and 18, respectively. ).

    (Example 28)

ホスホネート（ここで、このホスホネートは、フェニル環およびエステルまたはアミド連鎖によって、結合されている）の調製は、上で図示している。ケトアルデヒドＰ３．２は、３−カルボキシフェニルヒドラジンＰ３．１０（Ａｐｉｎ）と反応されて、ピラゾールＰ３．１１およびＰ３．１２が得られる。次いで、２’−置換異性体Ｐ３．１１は、ジクロロメタン溶液中にて、室温で、１モル当量のホスホン酸ジアルキル２−ヒドロキシ−２−メチルプロピルＰ３．１３（仏国特許第２４６２４４０号）およびジシクロヘキシルカルボジイミドと反応されて、エステルＰ３．１４を生じる。次いで、この保護基は除去され、ジオールＰ３．１５（これは、式１８の化合物である）が生じる。

The preparation of phosphonates, where the phosphonate is linked by a phenyl ring and an ester or amide linkage, is illustrated above. Ketoaldehyde P3.2 is reacted with 3-carboxyphenylhydrazine P3.10 (Apin) to give pyrazoles P3.11 and P3.12. The 2′-substituted isomer P3.11 is then obtained in dichloromethane solution at room temperature with 1 molar equivalent of dialkyl 2-hydroxy-2-methylpropyl phosphonate P3.13 (French patent 2462440) and dicyclohexyl. Reacted with carbodiimide to yield ester P3.14. The protecting group is then removed to give the diol P3.15 (which is a compound of formula 18).

  Alternatively, 1'-substituted pyrazole P3.12 is coupled with dialkyl 2-aminoethyl phosphonate P3.17 (Aurora) to give amide P3.18. Preparation of amides from carboxylic acids and derivatives is described, for example, in “Organic Functional Group Preparations”, by S. B. R. Sandler and W.M. Karo, Academic Press, 1968, p. 274 and “Comprehensive Organic Transformations”, by R.C. C. Larock, VCH, 1989, p. 972 ff. The carboxylic acid can be used in the presence of an activator (e.g., dicyclohexylcarbodiimide or diisopropylcarbodiimide), optionally in the presence of, for example, hydroxybenzotriazole, N-hydroxysuccinimide, or N-hydroxypyridone. Reaction with the amine in a protic solvent such as pyridine, DMF or dichloromethane provides the amide.

  Alternatively, the carboxylic acid is first converted to an activated derivative (eg, its acid chloride, anhydride, mixed anhydride, imidazolide, etc.) and then in the presence of an organic base (eg, pyridine) Reaction with an amine gives this amide. Conversion of the carboxylic acid to the corresponding acid chloride can be accomplished by reacting the carboxylic acid in an inert organic solvent (eg, dichloromethane), optionally in the presence of a catalytic amount of dimethylformamide, (eg, Caused by treatment with thionyl chloride or oxalyl chloride). The product P3.18 is then deprotected to give the diol P3.19, which is a compound of formula 17.

  Using the above procedure, but using different amino or hydroxyl substituted phosphonates, and / or different carboxy substituted hydrazines, products similar to P3.15 and P3.19 are obtained. These functionalization procedures can be exchanged between the pyrazole substrates P3.11 and P3.12.

    (Example 29)

式１７および１８のホスホネート（ここで、そのホスホネート基は、フェニル基およびアルコキシまたはアルキルチオ炭素鎖によって、結合されている）の調製は、上で図示されている。この手順では、ケトアルデヒドＰ３．２は、４−ヒドロキシフェニルヒドラジンＰ３．２０（ＥＰ ４３７１０５）と反応されて、ピラゾールＰ３．２１およびＰ３．２２が生成される。１’−置換異性体Ｐ３．２１は、ジメチルホルムアミド溶液中にて、７０°で、ホスホン酸ジアルキルブロモプロピルＰ３．２３（Ｊ．Ａｍｅｒ．Ｃｈｅｍ．Ｓｏｃ．，２０００，１２２，１５５４）および炭酸カリウムと反応されて、ホスホネートＰ３．２４が得られる。次いで、この生成物は、脱保護されて、ジオールＰ３．２５が得られる。

The preparation of phosphonates of formula 17 and 18 wherein the phosphonate group is attached by a phenyl group and an alkoxy or alkylthio carbon chain is illustrated above. In this procedure, ketoaldehyde P3.2 is reacted with 4-hydroxyphenylhydrazine P3.20 (EP 437105) to produce pyrazoles P3.21 and P3.22. The 1′-substituted isomer P3.21 is obtained at 70 ° in a dimethylformamide solution with dialkylbromopropyl phosphonate P3.23 (J. Amer. Chem. Soc., 2000, 122, 1554) and potassium carbonate. Reacted to give phosphonate P3.24. The product is then deprotected to give the diol P3.25.

  Alternatively, the 2′-substituted pyrazole P3.22 is reacted with a dialkyl mercaptoethyl phosphonate P3.26 (Zh. Obschei. Khim., 1973, 43, 2364) as described above in a Mitsunobu reaction to produce a thioether phosphonate. P3.27 is prepared, which is deprotected to give the diol P3.28.

  Using the above procedure, but using different hydroxy substituted aralkyl, aryl or heteroarylalkoxyhydrazines and / or different dialkyl bromo or mercapto substituted phosphonates instead of hydroxyphenyl reagent P3.20, compounds P3.25 and P3 A product similar to .28 is obtained.

    (Example 30)

式１７および１８のホスホン酸エステル（ここで、そのホスホネート基は、多様な炭素連鎖によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒドＰ３．２は、ヒドラジンと反応されて、ピラゾール誘導体Ｐ４．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、室温で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物Ｐ４．２と反応されて、アルキル化生成物Ｐ４．３およびＰ４．４が生成される。置換ピラゾールのアルキル化は、例えば、「Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ」，ｂｙ Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｌｏｎｇｍａｎ，１９９２，ｐ．３０９で記述されている。この反応は、典型的に、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、ジメチルアミノピリジン、リチウムヘキサメチルジシラジドなど）の存在下にて、等モル量のこれらの基質の間で、実行される。生成物Ｐ４．３およびＰ４．４は、Ｘがジアルキルホスホノである場合以外は、本明細書中で記述された手順を使用して、ホスホネートＰ４．５およびＰ４．６に変換される。脱保護すると、ジオールＰ４．７およびＰ４．８（これらは、それぞれ、式１８および１７の化合物である）が得られる。

The preparation of the phosphonate esters of formulas 17 and 18 where the phosphonate group is linked by various carbon linkages is illustrated above. In this procedure, ketoaldehyde P3.2 is reacted with hydrazine to give pyrazole derivative P4.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc, 1964, 86, 1520. This reaction is carried out in acetic acid at room temperature. This pyrazole product is then reacted with bromomethyl compound P4.2 to produce alkylated products P4.3 and P4.4. Alkylation of substituted pyrazoles is described, for example, in “Heterocyclic Chemistry”, by T.W. L. Gilchrist, Longman, 1992, p. 309. This reaction is typically performed in an equimolar amount of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.). In between. Products P4.3 and P4.4 are converted to phosphonates P4.5 and P4.6 using the procedures described herein except when X is a dialkylphosphono. Deprotection yields the diols P4.7 and P4.8, which are compounds of formulas 18 and 17, respectively.

    (Example 31)

上で図示しているように、ピラゾールＰ４．１は、上記は、１モル当量のホスホン酸ジアルキルトリフルオロメタンスルホニルオキシＰ４．９と反応されて、アルキル化ピラゾールＰ４．１０およびＰ４．１１が得られる。脱保護すると、ジオールＰ４．１２およびＰ４．１３（これらは、それぞれ、式１８および１７の化合物である）が生じる。

As illustrated above, pyrazole P4.1 is reacted with 1 molar equivalent of a dialkyltrifluoromethanesulfonyloxyphosphonate phosphonate P4.9 to give alkylated pyrazoles P4.10 and P4.11. . Deprotection yields the diols P4.12 and P4.13, which are compounds of formulas 18 and 17, respectively.

    (Example 32)

上で図示しているように、ピラゾールＰ４．１は、上記のように、１，４−ビス（ブロモメチル）シクロヘキサンＰ４．１４（Ｓａｌｏｒ）と反応されて、ピラゾールＰ４．１５およびＰ４．１６が得られる。生成物Ｐ４．１５は、Ａｒｂｕｚｏｖ反応にかけられ、ここで、そのブロモメチル置換基は、亜リン酸トリアルキルとの反応により、ジアルキルホスホノメチル置換基に変換され、その側鎖の脱保護後、ホスホネートＰ４．１７（これは、式１８の化合物である）が調製される。

As illustrated above, pyrazole P4.1 is reacted with 1,4-bis (bromomethyl) cyclohexane P4.14 (Salor) as described above to give pyrazoles P4.15 and P4.16. It is done. The product P4.15 is subjected to an Arbuzov reaction, where the bromomethyl substituent is converted to a dialkylphosphonomethyl substituent by reaction with a trialkyl phosphite, and after deprotection of the side chain, the phosphonate P4.17, which is a compound of formula 18, is prepared.

  Pyrazole P4.16 is reacted with potassium carbonate and dialkylaminomethyl phosphonate P4.18 (Interchim) in dimethylformamide and after deprotection, aminophosphonate P4.19 (which is a compound of formula 17) ) Is obtained.

  Using the above procedure, but using different dibromides and / or different amino-substituted phosphonates instead of dibromide P4.14, products similar to P4.17 and P4.18 are obtained.

(Example 33)
Representative compounds of the present invention are described in Westwood et al. Med. Chem. 1996, 39, 4608-4621, can be prepared according to the following general route.

適当なアニリン３３．１（ここで、Ｘ^１は、水素、ハロ、トリフルオロメチル、（Ｃ_１〜Ｃ_３）アルキル、シアノまたは（Ｃ_１〜Ｃ_３）アルコキシである）と酸塩化物３３．２とをカップリングすると、化合物３３．３（これは、式１９または２０の代表的な化合物である）が得られる。

A suitable aniline 33.1 (where X ¹ is hydrogen, halo, trifluoromethyl, (C ₁ -C ₃ ) alkyl, cyano or (C ₁ -C ₃ ) alkoxy) and the acid chloride 33. Coupling with 2 gives compound 33.3, which is a representative compound of formula 19 or 20.

  The synthesis of two suitable anilines that can be used in the above reaction is outlined below.

３−ニトロフェノールは、Ｅ−１，４−ジブロモブテンでアルキル化され、得られた一臭化物は、溶媒（例えば、トルエン）中にて、（または他のＡｒｂｕｚｏｖ反応条件で）、亜リン酸トリエチルと共に加熱されて、所望のホスホン酸のジエチルエステル３３．４が産生される。（Ｅｎｇｅｌ，Ｒ．，「Ｓｙｎｔｈｅｓｉｓ ｏｆ ｃａｒｂｏｎ−ｐｈｏｓｐｈｏｒｕｓ ｂｏｎｄｓ」、ＣＲＣ ｐｒｅｓｓ，１９８８を参照）。最後に、このニトロベンゼンのスズ（ＩＩ）媒介還元により、所望のアニリンが産生される。

3-Nitrophenol is alkylated with E-1,4-dibromobutene and the resulting monobromide is triethyl phosphite in a solvent (eg toluene) (or under other Arbuzov reaction conditions). With heating to produce diethyl ester 33.4 of the desired phosphonic acid. (See Engel, R., “Synthesis of carbon-phosphorus bonds”, CRC press, 1988). Finally, the tin (II) mediated reduction of this nitrobenzene produces the desired aniline.

３−ニトロ−４−トリフルオロメチル安息香酸のメチルエステルは、塩化スズ（ＩＩ）で処理されて、対応するアニリンが生成される。この３−ヨード安息香酸は、ジアゾ化およびヨウ化カリウムでの処理により、産生される。ホスホン酸ジエチルエステルは、アセチレンリンカーを介して、パラジウム触媒を使用して結合され、その安息香酸エステルをケン化した後、そのアシルアジドのクルチウス転位により、本発明の代表的なＭＮＡ−７１５類似物に取り込むのに適当なアニリンが得られる。

The methyl ester of 3-nitro-4-trifluoromethylbenzoic acid is treated with tin (II) chloride to produce the corresponding aniline. The 3-iodobenzoic acid is produced by diazotization and treatment with potassium iodide. The phosphonic acid diethyl ester is coupled using a palladium catalyst via an acetylene linker, saponifying the benzoate ester, and then by the Curtius rearrangement of the acyl azide to a representative MNA-715 analog of the present invention. An aniline suitable for incorporation is obtained.

(Example 34)
Representative compounds of formulas 21 and 22 are generally described in Westwood et al, J. MoI. Med. Chem. 1996, 39, 4608-4621, which can be prepared according to the following general route.

適当なアニリン３４．１（ここで、Ｘ^２は、水素、ハロ、トリフルオロメチル、シアノまたはメチルである）と酸塩化物３４．２とのカップリングにより、式２１および２２の代表的な化合物が得られる。実施例３３および本明細書中の他の箇所で記述されているように調製されたアニリンは、この合成に取り込むことができる。

Coupling of a suitable aniline 34.1 (where X ² is hydrogen, halo, trifluoromethyl, cyano or methyl) with an acid chloride 34.2 provides representative compounds of formulas 21 and 22 Is obtained. Aniline prepared as described in Example 33 and elsewhere herein can be incorporated into this synthesis.

  (Example 35)

５−ニトロ−イソベンゾフラン−１，３−ジオン、３５．１（これは、市販されている）は、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，１９９９，９，１６２５で報告された手順に従って、５−アミノ−２−（２，６−ジオキソ−ピペリジン−３−イル）−イソインドール−１，３−ジオン、３５．２に変換される。このアミン中間体は、還元剤（トリアセトキシボロ水素化ナトリウム）の存在下にて、ジエチルホスホノアセトアルデヒド（これは、アリルホスホン酸ジエチルのオゾン分解から得た）で、還元アミノ化にかけられて、所望のアミンリンカー類似物が産生される（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９６，６１，３８４９）。あるいは、このアミンは、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９８２，２５，９６０およびＪ．Ｍｅｄ．Ｃｈｅｍ．，１９８４，２７，６００で報告されたもののような手順に従って、活性化ジエチルホスホノ酢酸でアシル化されて、所望のアミドリンカー化合物が得られる。この活性化ジエチルホスホノ酢酸は、溶媒（例えば、ジメチルホルムアミド）中にて、室温で、カップリング試薬（例えば、シアノホスホン酸ジエチル）および塩基（例えば、ジイソプロピルエチルアミン）で処理することにより、得ることができる。ＸがＣＨ_２である特定の例は、以下で図示している。

5-Nitro-isobenzofuran-1,3-dione, 35.1 (which is commercially available) is available from Bioorg. Med. Chem. Lett. , 1999, 9, 1625, is converted to 5-amino-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione, 35.2. This amine intermediate was subjected to reductive amination with diethylphosphonoacetaldehyde (obtained from ozonolysis of diethyl allylphosphonate) in the presence of a reducing agent (sodium triacetoxyborohydride) The desired amine linker analog is produced (J. Org. Chem., 1996, 61, 3849). Alternatively, the amine is described in J. Org. Med. Chem. , 1982, 25, 960 and J.A. Med. Chem. , 1984, 27, 600, followed by acylation with activated diethylphosphonoacetic acid to give the desired amide linker compound. This activated diethylphosphonoacetic acid is obtained by treatment with a coupling reagent (eg diethyl cyanophosphonate) and a base (eg diisopropylethylamine) in a solvent (eg dimethylformamide) at room temperature. Can do. A specific example where X is CH ₂ is illustrated below.

あるいは、２−（１，３−ジオキソ−１，３−ジヒドロ−イソインドール−２−イル）−ペンタン二酸、３５．４（これは、市販されている）は、溶媒（例えば、アセトニトリル）中にて、トリエチルアミン、１−ヒドロキシベンゾトリアゾール、４−メトキシベンジルアミンおよび１，３−ジシクロヘキシルカルボジイミドで処理される。この反応が完結した後、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００３，４６，３７９３で報告されたもののような手順に従って、この溶媒が除去され、その残留物は、クロマトグラフィーで精製されて、所望の類似物３５．３が得られる。

Alternatively, 2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -pentanedioic acid, 35.4 (which is commercially available) in a solvent (eg, acetonitrile) In triethylamine, 1-hydroxybenzotriazole, 4-methoxybenzylamine and 1,3-dicyclohexylcarbodiimide. After this reaction is complete, J. et al. Med. Chem. , 2003, 46, 3793, the solvent is removed and the residue is purified by chromatography to give the desired analog 35.3.

  (Example 36)

このＢｏｃ−保護（１Ｓ）−１−（９−デアザグアニン−９−イル）−１，４−ジデオキシ−１，４−イミノ−Ｄ−リビトール（化合物３６．３）は、Ｇｒｅｅｎｅ，Ｔ．，「Ｐｒｏｔｅｃｔｉｖｅ ｇｒｏｕｐｓ ｉｎ ｏｒｇａｎｉｃ ｓｙｎｔｈｅｓｉｓ」、Ｗｉｌｅｙ−Ｉｎｔｅｒｓｃｉｅｎｃｅ，１９９９で記述されているように、（１Ｓ）−１−（９−デアザグアニン−９−イル）−１，４−ジデオキシ−１，４−イミノ−Ｄ−リビトール（ＷＯ ９９／１９３３８およびＥｖａｎｓ，Ｇ．Ｂ．ら、Ｔｅｔｒａｈｅｄｒｏｎ，２０００，５６，３０５３；これはまた、Ｅｖａｎｓ，Ｇ．Ｂ．ら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．２００３，４６，３４１２でも報告されている）をＢＯＣ無水物と共に攪拌することにより、調製される。次いで、化合物３６．３は、溶媒（テトラヒドロフランまたはジメチルホルムアミド）中にて、塩基（例えば、水素化ナトリウム）で処理される。泡立ちが止まると、ホスホノメチルトリフルオロメタンスルホン酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）が加えられ、トリフルオロ酢酸（ＴＦＡ）を使用してＢＯＣ基を脱保護した後、所望のホスホン酸ジエステル３６．４が得られる（これは、式２５の化合物である）。

This Boc-protected (1S) -1- (9-deazaguanine-9-yl) -1,4-dideoxy-1,4-imino-D-ribitol (compound 36.3) is described in Greene, T .; , "Protective groups in organic synthesis", Wiley-Interscience, 1999, (1S) -1- (9-deazaguanine-9-yl) -1,4-dideoxy-1,4-imino- D-ribitol (WO 99/19338 and Evans, GB et al., Tetrahedron, 2000, 56, 3053; this is also reported in Evans, GB et al., J. Med. Chem. 2003, 46, 3412. Prepared) with BOC anhydride. Compound 36.3 is then treated with a base (eg, sodium hydride) in a solvent (tetrahydrofuran or dimethylformamide). When bubbling ceased, diethyl phosphonomethyltrifluoromethanesulfonate (prepared according to Tetrahedron Lett., 1986, 27, 1477) was added and the BOC group was deprotected using trifluoroacetic acid (TFA). After that, the desired phosphonic acid diester 36.4 is obtained (this is the compound of formula 25).

  (Example 37)

脱保護化合物３７．１（（１Ｒ）−１−（９−デアザヒポキサンチン−９−イル）−１，２，４−トリデオキシ−１，４−イミノ−Ｄ−エリトロ−ペンチトール；塩酸塩として）は、ジクロロメタン中の二炭酸ジ−ｔ−ブチルを使用して、Ｅｖａｎｓ，Ｇ．Ｂ．ら、Ｔｅｔｒａｈｅｄｒｏｎ，２０００，５６，３０５３で記述されているように、調製される。その５’−ＯＨの酸化に続いて脱離すると、グリカール３７．３が得られる（Ｚｅｍｌｉｃｋａ Ｊ．ら、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９７２，９４，９，３２１３の手順を参照）。セレノエーテル化すると、保護ホスホネート３７．４が得られる（Ｋｉｍ，Ｃ．ら、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９１，５６，２６４２）。このフェニルセレニドを（Ｋｉｍ，Ｃ．ら、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９１，５６，２６４２で記述されているように）酸化脱離し、続いて、立体選択的にジヒドロキシル化すると、所望のジオール３７．６が得られる。最後に、この保護基が除去されて、化合物３７．７（式２６の化合物）が得られる。

Deprotected compound 37.1 ((1R) -1- (9-deazahypoxanthin-9-yl) -1,2,4-trideoxy-1,4-imino-D-erythro-pentitol; as hydrochloride ) Using E-vans, G., et al. Using di-t-butyl dicarbonate in dichloromethane. B. Et al., As described in Tetrahedron, 2000, 56, 3053. Desorption following its 5′-OH oxidation yields glycal 37.3 (see the procedure of Zemlica J. et al., J. Am. Chem. Soc., 1972, 94, 9, 3213). Selenoetherification gives the protected phosphonate 37.4 (Kim, C. et al., J. Org. Chem., 1991, 56, 2642). This phenyl selenide is oxidatively desorbed (as described in Kim, C. et al., J. Org. Chem., 1991, 56, 2642) followed by stereoselective dihydroxylation to give the desired The diol 37.6 is obtained. Finally, the protecting group is removed to give compound 37.7 (compound of formula 26).

  (Example 38)

（１Ｒ）−１−（９−デアザヒポキサンチン−９−イル）−１，２，４−トリデオキシ−１，４−イミノ−Ｄ−エリトロ−ペンチトール（これは、Ｅｖａｎｓ，Ｇ．Ｂ．ら、Ｔｅｔｒａｈｅｄｒｏｎ，２０００，５６，３０５３で記述されているように、そのＨＣｌ塩として調製した）は、まず、保護され、次いで、ＰｔＯ_２で酸化されて、カルボン酸３８．１が得られる。脱炭酸脱離は、高温で、ジメチルホルムアミド中のジメチルホルムアミドジネオペンチルアセタールを使用して、達成される（Ｚｅｍｌｉｃｋａ Ｊ．ら、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９７２，９４，９，３２１３）。セレノエーテル化に続いて、保護グリカールを、ホスホン酸ジエチル（ヒドロキシルメチル）の存在下にて、過塩素酸銀で処理すると（Ｐｈｉｌｌｉｏｎ，Ｄ．ら、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）、ホスホネート３８．３が得られる（Ｋｉｍ，Ｃ．ら、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９１，５６，２６４２）。このセレン化物を酸化脱離するのに続いて、四酸化オスミウムを使用してジヒドロキシル化すると、ジオール３８．５が得られる。Ｇｒｅｅｎｅ，Ｔ．，「Ｐｒｏｔｅｃｔｉｖｅ ｇｒｏｕｐｓ ｉｎ ｏｒｇａｎｉｃ ｓｙｎｔｈｅｓｉｓ」、Ｗｉｌｅｙ−Ｉｎｔｅｒｓｃｉｅｎｃｅ，１９９９の手順に従って、そのアミン保護基を除去すると、化合物３８．６が得られる。

(1R) -1- (9-deazahypoxanthin-9-yl) -1,2,4-trideoxy-1,4-imino-D-erythro-pentitol (this is described by Evans, GB et al. , Prepared as its HCl salt as described in Tetrahedron, 2000, 56, 3053) is first protected and then oxidized with PtO ₂ to give the carboxylic acid 38.1. Decarboxylation elimination is achieved using dimethylformamide dineopentyl acetal in dimethylformamide at high temperature (Zemlicka J. et al., J. Am. Chem. Soc., 1972, 94, 9, 3213). . Following selenoetherification, the protected glycal is treated with silver perchlorate in the presence of diethyl phosphonate (hydroxylmethyl) (Philion, D. et al., Tetrahedron Lett., 1986, 27, 1477). 38.3 is obtained (Kim, C. et al., J. Org. Chem., 1991, 56, 2642). Subsequent oxidative desorption of the selenide followed by dihydroxylation using osmium tetroxide provides the diol 38.5. Greene, T .; , “Protective groups in organic synthesis”, Wiley-Interscience, 1999, removal of the amine protecting group gives compound 38.6.

(Example 39)
Synthetic methodologies and intermediate compounds that can be used to prepare prodrugs of thalidomide analogs are described below.

２−メチル−４−ニトロ安息香酸メチルエステル（これは、市販されている）は、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，１９９９，９，１６２５で報告された手順に従って、３−（５−アミノ−１−オキソ−１，３−ジヒドロ−イソインドール−２−イル）−ピペリジン−２，６−ジオン、３９．１に変換される。このアミン中間体は、還元剤（トリアセトキシボロ水素化ナトリウム）の存在下にて、ジエチルホスホノアセトアルデヒド（これは、アリルホスホン酸ジエチルのオゾン分解から得た）での還元アミノ化にかけられて、所望のアミンリンカー類似物３９．２が産生される（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９６，６１，３８４９）。あるいは、このアミンは、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９８２，２５，９６０およびＪ．Ｍｅｄ．Ｃｈｅｍ．，１９８４，２７，６００で報告されたもののような手順に従って、活性化ジエチルホスホノ酢酸でアシル化されて、所望のアミドリンカー化合物３９．３が得られる。この活性化ジエチルホスホノ酢酸は、溶媒（例えば、ジメチルホルムアミド）中にて、室温で、カップリング試薬（例えば、シアノホスホン酸ジエチル）および塩基（例えば、ジイソプロピルエチルアミン）で処理することにより、得ることができる。

2-Methyl-4-nitrobenzoic acid methyl ester (which is commercially available) is available from Bioorg. Med. Chem. Lett. , 1999, 9, 1625 to 3- (5-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, 39.1 Converted. This amine intermediate was subjected to reductive amination with diethylphosphonoacetaldehyde (obtained from ozonolysis of diethyl allylphosphonate) in the presence of a reducing agent (sodium triacetoxyborohydride) The desired amine linker analog 39.2 is produced (J. Org. Chem., 1996, 61, 3849). Alternatively, the amine is described in J. Org. Med. Chem. , 1982, 25, 960 and J.A. Med. Chem. , 1984, 27, 600 followed by acylation with activated diethylphosphonoacetic acid to give the desired amide linker compound 39.3. This activated diethylphosphonoacetic acid is obtained by treatment with a coupling reagent (eg diethyl cyanophosphonate) and a base (eg diisopropylethylamine) in a solvent (eg dimethylformamide) at room temperature. Can do.

  2-Methyl-3-nitrobenzoic acid methyl ester (which is commercially available) is treated with N-bromosuccinimide under light in a solvent (eg, carbon tetrachloride) to give 2- Bromomethyl-3-nitrobenzoic acid methyl ester 39.4 is produced. This benzylic bromide is obtained in the presence of a base (eg triethylamine) in a solvent (eg dimethylformamide) [2- (3-amino-2,6-dioxo-piperidine-1- Yl) -ethyl] -phosphonic acid diethyl ester (for the preparation of this compound, see Example 40 below). The coupled product is then reduced by hydrogenation (Bioorg. Med. Chem. Lett., 1999, 9, 1625) to give the desired analog.

  (Example 40)

２−メチル−４−ニトロ安息香酸メチルエステル、３９．２（これは、市販されている）は、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，１９９９，９，１６２５で報告された手順に従って、３−（５−アミノ−１−オキソ−１，３−ジヒドロ−イソインドール−２−イル）−ピペリジン−２，６−ジオンに変換される。このアミン中間体は、還元剤（トリアセトキシボロ水素化ナトリウム）の存在下にて、ジエチルホスホノアセトアルデヒド（これは、アリルホスホン酸ジエチルのオゾン分解から得る）で、還元アミノ化にかけられて、所望のアミンリンカー類似物が産生される（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９６，６１，３８４９）。あるいは、このアミンは、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９８２，２５，９６０およびＪ．Ｍｅｄ．Ｃｈｅｍ．，１９８４，２７，６００で報告されたもののような手順に従って、活性化ジエチルホスホノ酢酸でアシル化されて、所望のアミドリンカー化合物が得られる。この活性化ジエチルホスホノ酢酸は、溶媒（例えば、ジメチルホルムアミド）中にて、室温で、カップリング試薬（例えば、シアノホスホン酸ジエチル）および塩基（例えば、ジイソプロピルエチルアミン）で処理することにより、得ることができる。

2-Methyl-4-nitrobenzoic acid methyl ester, 39.2 (which is commercially available) is available from Bioorg. Med. Chem. Lett. , 1999, 9, 1625, and converted to 3- (5-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione. This amine intermediate is subjected to reductive amination with diethylphosphonoacetaldehyde (which is obtained from ozonolysis of diethyl allylphosphonate) in the presence of a reducing agent (sodium triacetoxyborohydride) to give the desired Is produced (J. Org. Chem., 1996, 61, 3849). Alternatively, the amine is described in J. Org. Med. Chem. , 1982, 25, 960 and J.A. Med. Chem. , 1984, 27, 600, followed by acylation with activated diethylphosphonoacetic acid to give the desired amide linker compound. This activated diethylphosphonoacetic acid is obtained by treatment with a coupling reagent (eg diethyl cyanophosphonate) and a base (eg diisopropylethylamine) in a solvent (eg dimethylformamide) at room temperature. Can do.

  (Example 40A)

２−メチル−３−ニトロ安息香酸メチルエステル、３９．２（これは、市販されている）は、溶媒（例えば、四塩化炭素）中で、光の下にて、Ｎ−ブロモスクシンイミドで処理されて、２−ブロモメチル−３−ニトロ安息香酸メチルエステル、３９．４が生成される。このベンジル型臭化物（ｂｅｎｚｙｌｉｃ ｂｒｏｍｉｄｅ）は、溶媒（例えば、ジメチルホルムアミド）中で、塩基（例えば、トリエチルアミン）の存在下にて、［２−（３−アミノ−２，６−ジオキソ−ピペリジン−１−イル）−エチル］−ホスホン酸ジエチルエステル（この化合物の調製については、以下を参照）で処理される。次いで、カップリングされた生成物は、水素化により還元されて（Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，１９９９，９，１６２５）、所望の類似物が得られる。

2-Methyl-3-nitrobenzoic acid methyl ester, 39.2 (which is commercially available) is treated with N-bromosuccinimide in the presence of light in a solvent (eg, carbon tetrachloride). To produce 2-bromomethyl-3-nitrobenzoic acid methyl ester, 39.4. This benzylic bromide is obtained in the presence of a base (eg triethylamine) in a solvent (eg dimethylformamide) [2- (3-amino-2,6-dioxo-piperidine-1- Yl) -ethyl] -phosphonic acid diethyl ester (for the preparation of this compound see below). The coupled product is then reduced by hydrogenation (Bioorg. Med. Chem. Lett., 1999, 9, 1625) to give the desired analog.

  [2- (3-Amino-2,6-dioxo-piperidin-1-yl) -ethyl] -phosphonic acid diethyl ester 40.1 is described in J. Am. Med. Chem. , 2003, 46, 3793. Accordingly, benzyloxycarbonyl protected glutaric acid is treated with triethylamine, 1-hydroxy-benzotriazole, diethyl 2-aminoethyl phosphonate and 1,3-dicyclohexyl-carbodiimide in a solvent (eg, acetonitrile). After the reaction is complete, the solvent is removed and the residue is purified by chromatography to produce the cyclic product, which is exposed to hydrogen in the presence of a palladium catalyst, The desired intermediate is obtained.

  Further manipulations can be performed on this phosphonate moiety prior to final deprotection. These types of transformations are described more extensively herein.

  (Example 41)

ジプロレン４１Ａ（ドイツ特許ＤＥ ２９０５６７４）およびそれらのエステル４１．１〜４１．３の構造は、以下で図示しており、ここで、置換基Ｒ^１は、Ｈ、アルキル、アルケニル、アリールまたはアラルキルである。化合物４１．１〜４１．３は、種々の連結基（添付の構造では、「リンク」として示している）によって、その核に連結されたホスホネート部分（Ｒ^１Ｏ）_２Ｐ（Ｏ）を取り込んでいる。

The structure of diprolene 41A (German Patent DE 2905675) and their esters 41.1 to 41.3 is illustrated below, where the substituent R ¹ is H, alkyl, alkenyl, aryl or aralkyl. . Compounds 41.1-41.3 incorporate phosphonate moieties (R ¹ O) ₂ P (O) linked to their nuclei by various linking groups (shown as “links” in the accompanying structure). It is out.

  (Example 42)

保護−脱保護手順（ここで、このステロイド側鎖は、ビスメチレンジオキシ（ＢＭＤ）部分として、保護される）が上で図示されている。化合物４２．１のプロピオン酸エステル基は、例えば、ジメトキシエタン水溶液中にて、室温で、２モル当量の水酸化リチウムと反応させることにより、加水分解されて、ジオール４２．２が得られる。次いで、この生成物は、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｔ．Ｗ．ＧｒｅｅｎｅおよびＰ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，Ｓｅｃｏｎｄ Ｅｄｉｔｉｏｎ １９９０，ｐ．２２３で記述されているように、パラホルムアルデヒドおよび酸性触媒（例えば、塩酸）と反応されて、ＢＭＤ誘導体４２．３が得られる。次いで、そのホスホネート部分は、下記の手順を使用して導入され、ホスホン酸エステル４２．４が生成される。そのＢＭＤ保護基の加水分解前に、その１１−水酸基が保護される。この保護基は、このＢＭＤ基を除去するのに必要な条件に安定であるように、また、引き続いて導入される１７，２１−ジエステル部分に影響を及ぼすことなく除去可能であるように、選択される。

A protection-deprotection procedure, where the steroid side chain is protected as a bismethylenedioxy (BMD) moiety, is illustrated above. The propionate group of compound 42.1 is hydrolyzed, for example, by reaction with 2 molar equivalents of lithium hydroxide at room temperature in an aqueous dimethoxyethane solution to give diol 42.2. The product is then described in “Protective Groups in Organic Synthesis”, T.M. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. Reacted with paraformaldehyde and an acidic catalyst (eg, hydrochloric acid) to provide BMD derivative 42.3 as described in H.223. The phosphonate moiety is then introduced using the following procedure to produce phosphonate ester 42.4. Prior to hydrolysis of the BMD protecting group, the 11-hydroxyl group is protected. The protecting group is selected so that it is stable to the conditions necessary to remove the BMD group and can be removed without affecting the subsequently introduced 17,21-diester moiety. Is done.

  For example, the 11-hydroxyl group is protected by reaction with 4-azidobutyryl chloride in viridine by conversion to the 4-azidobutyric acid ester. The 11-azidobutyrate group was then transferred to Bull. Soc. Chem. Jpn. , 1986, 59, 1296, is removed from the diester 42.7 by reaction with triphenylphosphine. Alternatively, the 11-hydroxyl group is protected by conversion to 2- (trimethylsilyl) ethyl carbonate by reaction with 2- (trimethylsilyl) ethylcarbonyl chloride and pyridine. This 2- (trimethylsilyl) carbonate is obtained from Tet. Lett. , 1981, 22, 969, from diester 42.7 by reaction with tetrabutylammonium fluoride in tetrahydrofuran at room temperature.

  Alternatively, the 11-hydroxyl group is protected by conversion to trichloroacetyl ester by reaction with trichloroacetyl chloride in dimethylformamide-pyridine. This trichloroacetyl ester is described in Coll. Czech. Chem. Commun. , 1962, 27, 2567, by reaction with ethanolic ammonia at room temperature.

  The BMD moiety in the protected product 42.5 can then be obtained from, for example, Protective Groups in Organic Synthesis, T .; W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. Hydrolysis by treatment with 50% aqueous acetic acid gives diol 42.6 as described in H.223. The diol compound is acylated, for example, by reacting with propionic acid and dicyclohexylcarbodiimide in dimethylformamide at room temperature or by reacting with propionyl chloride and triethylamine in dichloromethane to give dipropionate 42. 7 is generated. The 11-hydroxyl group is then deprotected as described above to give the diester 42.8.

  Alternatively, the 20-ketone group is described in Protective Groups in Organic Synthesis, T .; W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. As described in 219, it is protected as its diethylamine adduct by reaction with titanium tetrakis (diethylamide).

  (Example 43)

ホスホネート（ここで、このホスホネートは、イミノ基またはイミノキシ基および多様な炭素鎖によって、結合されている）の調製は、上で図示している。この手順では、ＢＭＤ保護誘導体４２．３は、アミンまたはヒドロキシルアミン４３．１（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルまたはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールまたはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）である）と反応されて、イミンまたはイミノキシ生成物４３．２が得られる。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）またはアルコール性溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、このイミンまたはオキシムが得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、このＢＭＤ保護化合物４３．２は、上記されているように、ジエステル４３．３に変換される。

The preparation of phosphonates, where the phosphonates are linked by imino or iminoxy groups and various carbon chains, is illustrated above. In this procedure, the BMD protected derivative 42.3 is converted to an amine or hydroxylamine 43.1 where R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally represents a heteroatom O, S or N), or a functional group (such as an amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O, S or N)) to give the imine or iminoxy product 43.2. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcoholic solvent (eg, ethanol), optionally in the presence of an acid catalyst. This imine or oxime is obtained. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. This BMD protected compound 43.2 is then converted to the diester 43.3 as described above.

ホスホネート基を含むヒドロキシルアミンエーテルの調製は、上で図示している。この手順では、ホスホネート４３．４（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン４３．５（Ａｌｄｒｉｃｈ）と反応されて、エーテル４３．６が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われて、生成物４３．６が得られる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル４３．７が得られる。

The preparation of hydroxylamine ethers containing phosphonate groups is illustrated above. In this procedure, a phosphonate 43.4 (where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 43.5 (Aldrich) to give an ether 43.6 is generated. This reaction is performed between equimolar amounts of reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine) to give product 43 .6 is obtained. Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 43.7.

  (Example 44)

ホスホネート（ここで、このホスホネートは、イミノキシ基によって、結合されている）の調製は、上で図示している。この手順では、基質４２．３は、ジアルキルホスホノメチルヒドロキシルアミン４４．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製する）と反応されて、脱保護および側鎖アシル化後、オキシムエーテル４４．２が得られる。このオキシム形成反応は、室温で、ピリジン溶液中にて、等モル量の反応物間で実行される。

The preparation of phosphonates, where the phosphonate is linked by an iminoxy group, is illustrated above. In this procedure, the substrate 42.3 is a dialkylphosphonomethylhydroxylamine 44.1 (which, as described above, is a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett., 1986, 27, 1477) and BOC. -Prepared from hydroxylamine) to give the oxime ether 44.2 after deprotection and side chain acylation. This oxime formation reaction is carried out between equimolar amounts of reactants in a pyridine solution at room temperature.

  Using the above procedure, but replacing oxime ether 44.1 with a different oxime ether 43.7 gives the corresponding product 43.3.

  (Example 45)

基質４２．３とＯ−２−（５−ブロモ−２−チエニル）エトキシヒドロキシルアミン４５．１（これは、上記のように、臭化２−（５−ブロモ−２−チエニル）エチルから調製した）との間の反応によるイミノキシ基を含むホスホネートの調製（Ｊ．Ｃｈｅｍ．Ｓｏｃ．，Ｐｅｒｋｉｎ Ｔｒａｎｓ．Ｐｈｙｓ．Ｏｒｇ．Ｃｈｅｍ．，１９７５，８２１）は、上で図示している。得られたオキシムエーテルは、脱保護および側鎖アシル化により、化合物４５．２に変換され、これは、次いで、パラジウム触媒の存在下にて、亜リン酸ジアルキル４５．３と反応されて、ホスホネート４５．４が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。

Substrate 42.3 and O-2- (5-bromo-2-thienyl) ethoxyhydroxylamine 45.1 (prepared from 2- (5-bromo-2-thienyl) ethyl bromide as described above. The preparation of phosphonates containing iminoxy groups by reaction with (J. Chem. Soc., Perkin Trans. Phys. Org. Chem., 1975, 821) is illustrated above. The resulting oxime ether is converted to compound 45.2 by deprotection and side chain acylation, which is then reacted with a dialkyl phosphite 45.3 in the presence of a palladium catalyst to give the phosphonate. 45.4 is obtained. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0).

  Alternatively, the bromo substituted product 45.2 is coupled by a palladium catalyzed Heck reaction with a dialkylpropenyl phosphonate 45.5 (Acros) to give the unsaturated phosphonate 45.6. Coupling of aryl halides and olefins by this Heck reaction is described, for example, in “Advanced Organic Chemistry”, F.R. A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, p. 503ff and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)), optionally in the presence of a base (eg triethylamine or potassium carbonate).

  Optionally, the styrenoid double bond present in the product 45.6 is reduced, for example by reaction with diimide, to produce the saturated analog 45.7. Reduction of olefinic bonds is described in “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. It is described in 6ff. This conversion is performed, for example, by catalytic hydrogenation using a palladium on carbon catalyst and hydrogen or a hydrogen donor, or by using diimide or diborane.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromothienyl reagent 45.1, compounds 45.4, 45.6 and 45 A product similar to .7 is obtained.

  (Example 46)

ホスホネート（ここで、このホスホネートは、イミノ基によって、結合されている）の調製は、上で図示している。この手順では、基質４２．３は、ホスホン酸ジアルキル２−アミノフェニル４６．１（Ａｕｒｏｒａ）と反応されて、脱保護および側鎖アシル化後、イミン生成物４６．２が得られる。この反応は、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われ、生成物４６．２が得られる。

The preparation of phosphonates, where the phosphonate is linked by an imino group, is illustrated above. In this procedure, substrate 42.3 is reacted with dialkyl 2-aminophenyl 46.1 phosphonate (Aurora) to give imine product 46.2 after deprotection and side chain acylation. This reaction is carried out in a hydrocarbon solvent (eg toluene or xylene) at reflux temperature in the presence of a basic catalyst (eg sodium methoxide) or an acidic catalyst (eg p-toluenesulfonic acid). Performed under azeotropic conditions to give product 46.2.

  Using the above procedure, but using a different amino substituted aryl phosphonate or heteroaryl amino substituted phosphonate instead of 2-aminophenyl 46.1 phosphonate, a product similar to 46.2 is obtained.

  (Example 47)

ホスホネート（ここで、このホスホネートは、オキシイミノ基によって、結合されている）を調製する代替方法は、上で図示している。この手順では、ジエノン４２．３は、Ｏ−（カルボキシメチル）ヒドロキシルアミン４７．１（Ｉｎｔｅｒｃｈｉｍ）と反応されて、脱保護および側鎖アシル化後、オキシム４７．２が生じる。ステロイド性１，４−ジエン−３−オンとヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている。この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物間で実行される。次いで、オキシム４７．２は、光延反応において、ホスホン酸ジアルキル３−ヒドロキシフェニル４７．３（Ｅｐｓｉｌｏｎ）と反応されて、置換オキシム４７．４が生じる。光延反応による芳香族エーテルおよび芳香族チオエーテルの調製は、例えば、「Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ」、Ｒ．Ｃ．Ｌａｒｏｃｋ，ＶＣＨ，１９８９，ｐ．４４８および「Ａｄｖａｎｃｅｄ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ」、Ｐａｒｔ Ｂ，Ｆ．Ａ．ＣａｒｅｙおよびＲ．Ｊ．Ｓｕｎｄｂｅｒｇ，Ｐｌｅｎｕｍ，２００１，ｐ．１５３−４およびＯｒｇ．Ｒｅａｃｔ．，１９９２，４２，３３５で記述されている。このフェノールおよびヒドロキシ成分またはメルカプト成分は、非プロトン性溶媒（例えば、テトラヒドロフラン）中で、アゾジカルボン酸ジアルキルおよびトリアリールホスフィンの存在下にて、共に反応されて、それらのエーテル生成物またはチオエーテル生成物が得られる。この手順もまた、Ｏｒｇ．Ｒｅａｃｔ．，１９９２，４２，３３５−６５６で記述されている。次いで、生成物４７．４は、脱保護およびアシル化により、ジエステル４７．５に変換される。

An alternative method for preparing phosphonates, where the phosphonate is linked by an oxyimino group, is illustrated above. In this procedure, dienone 42.3 is reacted with O- (carboxymethyl) hydroxylamine 47.1 (Interchim) to yield oxime 47.2 after deprotection and side chain acylation. The reaction of steroidal 1,4-dien-3-one with hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795. This reaction is carried out between equimolar amounts of reactants in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate. The oxime 47.2 is then reacted with a dialkyl 3-hydroxyphenyl 47.3 phosphonate (Epsilon) in a Mitsunobu reaction to give the substituted oxime 47.4. Preparation of aromatic ethers and aromatic thioethers by Mitsunobu reaction is described, for example, in “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. 448 and "Advanced Organic Chemistry", Part B, F.M. A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, p. 153-4 and Org. React. 1992, 42, 335. The phenol and hydroxy or mercapto components are reacted together in the presence of a dialkyl azodicarboxylate and a triarylphosphine in an aprotic solvent (eg, tetrahydrofuran) to produce their ether or thioether product. Is obtained. This procedure is also described in Org. React. 1992, 42, 335-656. The product 47.4 is then converted to the diester 47.5 by deprotection and acylation.

  Using the above procedure, but using a different dialkylhydroxy substituted aryl phosphonate or heteroalkyl dialkylhydroxy substituted phosphonate heteroaryl instead of phosphonate 47.3, a product similar to 47.5 is obtained.

  (Example 48)

ホスホン酸エステル（ここで、そのホスホネート基は、芳香族基またはヘテロ芳香族基、ヘテロ原子および多様な炭素鎖によって、そのピラゾール環の１’位または２’位に結合されている）の調製は、上で図示している。この手順では、ジプロレン４１Ａは、還元されて、１，２−ジヒドロ生成物４８．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、オーストラリア国特許出願２７５９５０４０９で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物４８．３が得られる。

Preparation of the phosphonate ester, where the phosphonate group is attached to the 1 'or 2' position of the pyrazole ring by an aromatic or heteroaromatic group, a heteroatom and various carbon chains This is illustrated above. In this procedure, diprolene 41A is reduced to give 1,2-dihydro product 48.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. This product is then reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) as described in Australian Patent Application 2759950409. 2-formyl product 48.3 is obtained.

  If necessary, the substrate 41A can be prepared by, for example, Am. Chem. Soc. , 1964, 86, 1520 is protected prior to this formylation reaction as described in Example 42 above. The formylation product is then reacted with an aryl hydrazine or heteroaryl hydrazine 48.3, where substituent X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent. The For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2'-arylpyrazole 48.4 and 1'-arylpyrazole and 48.5. This ring formation reaction is described in J. Org. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). Pyrazole 48.4 and 48.5 are then converted to phosphonates 48.6 and 48.7, respectively, for example, by the procedure described in Examples 49-50.

  (Example 49)

ホスホネート（ここで、このホスホネートは、フェニル基によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド４８．２は、上記のように、２−ブロモフェニルヒドラジン４９．１（Ｆｌｕｋａ）と反応されて、異性体ピラゾール生成物４９．２および４９．３が得られる。次いで、これらの生成物は、ここで記述されているように、亜リン酸ジアルキルＨＰ（Ｏ）（ＯＲ^１）_２およびパラジウム触媒と反応されて、それぞれ、ホスホネート４９．４および４９．５が得られる。上記手順を使用するが、２−ブロモフェニルヒドラジンに代えて、異なるブロモアリールヒドラジンまたはブロモヘテロアリールヒドラジン４８．３を使用して、生成物４８．６および４８．７が得られる。

The preparation of phosphonates, where the phosphonate is linked by a phenyl group, is illustrated above. In this procedure, ketoaldehyde 48.2 is reacted with 2-bromophenylhydrazine 49.1 (Fluka) as described above to give isomeric pyrazole products 49.2 and 49.3. These products are then reacted with a dialkyl phosphite HP (O) (OR ¹ ) ₂ and a palladium catalyst as described herein to give phosphonates 49.4 and 49.5, respectively. It is done. Using the above procedure, but using a different bromoaryl hydrazine or bromoheteroaryl hydrazine 48.3 in place of 2-bromophenylhydrazine gives products 48.6 and 48.7.

  (Example 50)

ホスホネート（ここで、このホスホネートは、芳香族基またはヘテロ芳香族基、および飽和または不飽和アルキル鎖によって、結合されている）の調製は、上で図示している。この手順では、ブロモフェニル置換ピラゾール４９．２は、上記のように、Ｈｅｃｋ反応で、例えば、ホスホン酸ジアルキルブテニル５０．１（Ｏｒｇ．Ｌｅｔｔ．，２００１，３，２１７）とカップリングされて、不飽和ホスホネート生成物５０．２が得られる。必要に応じて、この生成物は、上記のように、還元されて、飽和類似物５０．３が得られる。上記手順を異性体ブロモフェニルピラゾール４９．３に適用すると、５０．２および５０．３と異性体である生成物が得られる。上記手順を使用するが、ホスホネート５０．１に代えて、異なるホスホン酸ジアルキルアルケニル、および／または異なるブロモアリールピラゾールまたはブロモヘテロアリールピラゾール４８．４または４８．５を使用して、５０．２および５０．３に類似した生成物が得られる。

The preparation of phosphonates, where the phosphonate is linked by an aromatic or heteroaromatic group, and a saturated or unsaturated alkyl chain, is illustrated above. In this procedure, bromophenyl substituted pyrazole 49.2 is coupled with, for example, dialkylbutenyl phosphonate 50.1 (Org. Lett., 2001, 3, 217) in a Heck reaction, as described above, The unsaturated phosphonate product 50.2 is obtained. If necessary, the product is reduced as described above to give the saturated analog 50.3. Applying the above procedure to the isomer bromophenylpyrazole 49.3 gives products that are isomers of 50.2 and 50.3. Using the above procedure, but instead of phosphonate 50.1, using a different dialkylalkenyl phosphonate and / or a different bromoarylpyrazole or bromoheteroarylpyrazole 48.4 or 48.5, 50.2 and 50 A product similar to .3 is obtained.

  (Example 51)

ホスホネート５１．５および５１．６（ここで、このホスホネートは、アリール基またはヘテロアリール基およびアルコキシ鎖によって、結合されている）の調製は、上で図示している。この手順では、４−アミノチオフェノール５１．１は、ジメチルホルムアミド溶液中にて、室温で、ホスホン酸ジアルキルトリフルオロメタンスルホニルオキシメチル５１．２（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）および炭酸カリウムと反応されて、チオエーテル５１．３が得られる。次いで、この生成物は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，４０３１で記述されているように、エタノール性塩酸水溶液中でのジアゾ化に続いて、そのジアゾニウムクロライドを塩化スズ（ＩＩ）で還元することにより、対応するヒドラジン５１．４に変換される。次いで、このヒドラジンは、上記のように、ケトアルデヒド４８．２と反応されて、異性体ピラゾール５１．５および５１．６が得られる。

The preparation of phosphonates 51.5 and 51.6, where the phosphonate is linked by an aryl or heteroaryl group and an alkoxy chain, is illustrated above. In this procedure, 4-aminothiophenol 51.1 is reacted with dialkyl trifluoromethanesulfonyloxymethyl phosphonate 51.2 (Tetrahedron Lett., 1986, 27, 1477) and potassium carbonate in dimethylformamide solution at room temperature. The reaction gives thioether 51.3. The product is then Med. Chem. , 2001, 44, 4031, followed by diazotization in aqueous ethanolic hydrochloric acid followed by reduction of the diazonium chloride with tin (II) chloride to the corresponding hydrazine 51.4. Is done. This hydrazine is then reacted with ketoaldehyde 48.2 as described above to give the isomeric pyrazoles 51.5 and 51.6.

  The above procedure is used, but instead of trifluoromethanesulfonic acid 51.2, a different dialkylphosphonoalkyl bromide or trifluoromethanesulfonic acid and / or a different aromatic or heteroaromatic mercapto or heteroaromatic hydroxyamine is used. A product similar to 51.5 and 51.6 is obtained.

  (Example 52)

ホスホネート（ここで、このホスホネートは、ピリジル基およびヘテロ原子および多様な炭素鎖によって、結合されている）の調製は、上で図示している。この手順では、３−アミノ−５−ヒドロキシピリジン５２．１は、無水酢酸との反応により、ジアセチル類似物５２．２に変換される。次いで、この生成物は、上記のように、ジアゾ化および還元により、ヒドラジン５２．３に変換される。次いで、このヒドラジン５２．３は、ケトアルデヒド４８．２と反応されて、異性体ピラゾール５２．４および５２．５が得られる。２’−ピリジル生成物５２．４は、光延反応で、上記のように、ホスホン酸ジアルキルヒドロキシエチル５２．６と反応されて（Ｚｈ．Ｏｂｓｃｈｅｉ．Ｋｈｉｍ．，１９７３，４３，２３６４）、エーテル５２．７が得られる。この手順を異性体フェノール５２．５に適用すると、化合物５２．７の異性体である生成物が得られる。

The preparation of phosphonates, where the phosphonates are linked by pyridyl groups and heteroatoms and various carbon chains, is illustrated above. In this procedure, 3-amino-5-hydroxypyridine 52.1 is converted to the diacetyl analog 52.2 by reaction with acetic anhydride. This product is then converted to hydrazine 52.3 by diazotization and reduction as described above. This hydrazine 52.3 is then reacted with ketoaldehyde 48.2 to give the isomeric pyrazoles 52.4 and 52.5. The 2′-pyridyl product 52.4 is reacted with dialkylhydroxyethyl phosphonate 52.6 (Zh. Obschei. Khim., 1973, 43, 2364) in the Mitsunobu reaction as described above. 7 is obtained. Applying this procedure to the isomer phenol 52.5 gives a product that is an isomer of compound 52.7.

  Alternatively, the isomeric phenol 52.5 can be obtained in a dimethylformamide solution at about 80 ° C. with 1 molar equivalent of dialkyl bromopropynyl phosphonate 52.8 (Bioorg. Med. Chem. Lett., 1994, 4, 273). And reacted with cesium carbonate to prepare phosphonate 52.9. Applying this procedure to the isomer phenol 52.4 yields a product that is an isomer of compound 52.4. Use the above procedure, but instead of carbinol 52.6 or bromide 52.8, different thiols, alcohols or bromides, and / or different phenols 48.4 or 48.5 (where X is OH) ) Is used to obtain the corresponding products similar to 52.27 and 52.9.

  (Example 53)

ホスホン酸エステル（ここで、そのホスホネート基は、多様な炭素結合によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド４８．２は、ヒドラジンと反応されて、ピラゾール誘導体５３．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、室温で実行される。次いで、得られたピラゾールは、ホスホン酸ジアルキルブロモメチル５３．２（ここで、Ｒ^２は、上で定義したとおりである）と反応されて、それぞれ、異性体２’アルキル化生成物５３．３および異性体１’アルキル化生成物５３．４が生成される。置換ピラゾールのアルキル化は、例えば、Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ，Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｌｏｎｇｍａｎ，１９９２，ｐ．３０９で記述されている。

The preparation of phosphonates, where the phosphonate group is attached by various carbon bonds, is illustrated above. In this procedure, ketoaldehyde 48.2 is reacted with hydrazine to give pyrazole derivative 53.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc, 1964, 86, 1520. This reaction is carried out in acetic acid at room temperature. The resulting pyrazole is then reacted with a dialkylbromomethyl phosphonate 53.2 (where R ² is as defined above) to give the isomer 2 ′ alkylation product 53.3, respectively. And the isomer 1 ′ alkylated product 53.4 is produced. Alkylation of substituted pyrazoles is described, for example, in Heterocyclic Chemistry, T .; L. Gilchrist, Longman, 1992, p. 309.

  (Example 54)

ピラゾール５３．１は、ジメチルホルムアミド溶液中にて、約９０℃で、ホスホン酸ジアルキルブロモプロピル５４．１（Ａｌｄｒｉｃｈ）および塩基（例えば、ジメチルアミノピリジンまたはリチウムヘキサメチルジシラジド）と反応されて、異性体アルキル化生成物５４．２および５４．３が生じる。

Pyrazole 53.1 is reacted with a dialkyl bromopropyl 54.1 (Aldrich) phosphonate and a base (eg dimethylaminopyridine or lithium hexamethyldisilazide) in a dimethylformamide solution at about 90 ° C. The isomeric alkylated products 54.2 and 54.3 are produced.

  In Scheme 54A, pyrazole 53.1 is reacted with 1 molar equivalent of 1,4-dibromobut-2-yne 54.4 (Narchem) and potassium carbonate in a dimethylformamide solution at room temperature to produce an alkylated product. The products 54.5 and 54.6 are obtained. These products are then heated in an Arbuzov reaction at 120 ° C. with a trialkyl phosphite to give phosphonates 54.7 and 54.8. This Arbuzov reaction is described in Handb. Organophosphorus Chem. 1992, 115-72. Using the above procedure, but using a different alkyl dibromide, alkenyl dibromide or alkynyl dibromide instead of dibromide 54.4, products similar to 54.7 and 54.8 were obtained. It is done.

(Example 55)
The structure of acromethasone dipropionate 55 / A (J. Med. Chem., 1980, 23, 430; U.S. Pat. No. 4,124,707) and their esters 55A-55C is illustrated below, where And the substituent R ¹ is H, alkyl, alkenyl, aryl or aralkyl. Compounds 55A-55C incorporate a phosphonate moiety (R ¹ O) ₂ P (O) linked to its nucleus by various linking groups (shown as “links” in the accompanying structure).

このステロイド側鎖は、スキーム５５Ａで図示されているように、ビスメチレンジオキシ（ＢＭＤ）部分として、保護される。この手順では、それらのプロピオン酸エステルは、例えば、ジメトキシエタン水溶液中にて、室温で、２モル当量の水酸化リチウムと反応させることにより、加水分解されて、ジオール５５．１が得られる。次いで、この生成物は、Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ，Ｔ．Ｗ．ＧｒｅｅｎｅおよびＰ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，Ｓｅｃｏｎｄ Ｅｄｉｔｉｏｎ １９９０，ｐ．２２３で記述されているように、パラホルムアルデヒドおよび酸性触媒（例えば、塩酸）と反応されて、ＢＭＤ誘導体５５．２が得られる。次いで、そのホスホネート部分は、下記の手順を使用して導入され、ホスホン酸エステル５５．３が生成される。そのＢＭＤ保護基の加水分解前に、その１１−水酸基が保護される。この保護基は、このＢＭＤ基を除去するのに必要な条件に安定であるように、また、引き続いて導入される１７，２１−ジエステル部分に影響を及ぼすことなく除去可能であるように、選択される。例えば、この１１−水酸基は、ビリジン中で４−アジドブチリルクロライドと反応させることにより、その４−アジド酪酸エステルに変換することにより、保護される。次いで、この１１−水酸基は、Ｂｕｌｌ．Ｓｏｃ．Ｃｈｅｍ．Ｊｐｎ．，１９８６，５９，１２９６で記述されているように、トリフェニルホスフィンと反応させることにより、ジエステル５５．７から除去される。あるいは、この１１−水酸基は、塩化２−（トリメチルシリル）エチルカルボニルおよびピリミジンと反応することによって、２−（トリメチルシリル）エチルカーボネートへと変換されることによって、保護される。この２−（トリメチルシリル）カーボネートは、Ｔｅｔ．Ｌｅｔｔ．，１９８１，２２，９６９で記述されているように、テトラヒドロフラン中にて、室温で、フッ化テトラブチルアンモニウムと反応させることにより、ジエステル５５．６から除去される。

This steroid side chain is protected as a bismethylenedioxy (BMD) moiety as illustrated in Scheme 55A. In this procedure, the propionic acid esters are hydrolyzed to give the diol 55.1, for example, by reaction with 2 molar equivalents of lithium hydroxide in aqueous dimethoxyethane at room temperature. The product was then obtained from Protective Groups in Organic Synthesis, T .; W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. Reacted with paraformaldehyde and an acidic catalyst (eg, hydrochloric acid) to provide BMD derivative 55.2 as described in H.223. The phosphonate moiety is then introduced using the following procedure to produce phosphonate ester 55.3. Prior to hydrolysis of the BMD protecting group, the 11-hydroxyl group is protected. The protecting group is selected so that it is stable to the conditions necessary to remove the BMD group and can be removed without affecting the subsequently introduced 17,21-diester moiety. Is done. For example, the 11-hydroxyl group is protected by reacting with 4-azidobutyryl chloride in viridine to convert to its 4-azidobutyric acid ester. The 11-hydroxyl group is then converted to Bull. Soc. Chem. Jpn. , 1986, 59, 1296, is removed from the diester 55.7 by reaction with triphenylphosphine. Alternatively, the 11-hydroxyl group is protected by conversion to 2- (trimethylsilyl) ethyl carbonate by reaction with 2- (trimethylsilyl) ethylcarbonyl chloride and pyrimidine. This 2- (trimethylsilyl) carbonate is obtained from Tet. Lett. , 1981, 22, 969, from diester 55.6 by reaction with tetrabutylammonium fluoride in tetrahydrofuran at room temperature.

  Alternatively, the 11-hydroxyl group is protected by conversion to trichloroacetyl ester by reaction with trichloroacetyl chloride in dimethylformamide pyridine. This trichloroacetyl ester is described in Coll. Czech. Chem. Commun. , 1962, 27, 2567, by reaction with ethanolic ammonia at room temperature. The BMD moiety in the protected product 55.6 can then be obtained, for example, from “Protective Groups in Organic Synthesis”, T.M. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. Hydrolysis by treatment with 50% aqueous acetic acid as described in H.223 gives diol 55.5; diol 55.5 is then obtained, for example, in dimethylformamide at room temperature. Acylation by reaction with propionic acid and dicyclohexylcarbodiimide or in dichloromethane with propionyl chloride and triethylamine yields 55.6 dipropionate. The 11-hydroxyl group is then deprotected as described above to give the diester 55.7.

  Alternatively, the 20-ketone group is described in “Protective Groups in Organic Synthesis”, T.W. W. Greene and P.M. G. M Wuts, Wiley, Second Edition 1990, p. As described in 219, it is protected as its diethylamine adduct by reaction with titanium tetrakis (diethylamide).

  (Example 56)

ホスホネート（ここで、このホスホネートは、イミノ基またはイミノキシ基および多様な炭素鎖によって、結合されている）の調製は、上で図示している。この手順では、ＢＭＤ保護誘導体５５．２は、アミンまたはヒドロキシルアミン５６．１（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルまたはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールまたはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）である）と反応されて、イミン生成物またはイミノキシ生成物５６．２が得られる。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）またはアルコール性溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、このイミンまたはオキシムが得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、このＢＭＤ保護側鎖化合物５６．２は、ジエステル５６．３に変換される。

The preparation of phosphonates, where the phosphonates are linked by imino or iminoxy groups and various carbon chains, is illustrated above. In this procedure, the BMD protected derivative 55.2 is converted to an amine or hydroxylamine 56.1 (where R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (optionally a heteroatom O, S or N), or a functional group (such as an amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom Containing O, S or N) to give an imine or iminoxy product 56.2. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcoholic solvent (eg, ethanol), optionally in the presence of an acid catalyst. This imine or oxime is obtained. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. This BMD protected side chain compound 56.2 is then converted to the diester 56.3.

  (Example 56A)

ホスホネート基を含むヒドロキシルアミンエーテルの調製もまた、上で図示している。ホスホネート５６．４（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン５６．５（Ａｌｄｒｉｃｈ）と反応されて、エーテル５６．６が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われて、生成物５６．６が得られる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル５６．７が得られる。

The preparation of hydroxylamine ethers containing phosphonate groups is also illustrated above. Phosphonate 56.4 (where Lv is a leaving group (eg bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 56.5 (Aldrich) to give ether 56.6. Generated. This reaction is performed between equimolar amounts of reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine) to give product 56 .6 is obtained. Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 56.7.

  (Example 56B)

ホスホネート（ここで、このホスホネートは、イミノキシ基によって、結合されている）の調製は、上で図示している。この手順では、基質５５．２は、ジアルキルホスホノメチルヒドロキシルアミン５６．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、脱保護および側鎖アシル化後、オキシムエーテル５６．２が得られる。このオキシム形成反応は、室温で、ピリジン溶液中にて、等モル量の反応物間で実行される。

The preparation of phosphonates, where the phosphonate is linked by an iminoxy group, is illustrated above. In this procedure, the substrate 55.2 is a dialkylphosphonomethylhydroxylamine 56.1 (which, as described above, is a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett., 1986, 27, 1477) and BOC. -Prepared from hydroxylamine) to give the oxime ether 56.2 after deprotection and side chain acylation. This oxime formation reaction is carried out between equimolar amounts of reactants in a pyridine solution at room temperature.

  Using the above procedure, but using a different oxime ether 56.7 instead of the oxime ether 56.1, the corresponding product 56.2 is obtained.

  (Example 57)

基質５５．２とＯ−２−（３−ブロモフェニル）エチルヒドロキシルアミン５７．１（これは、上記のように、それぞれ、化合物５５．１および臭化２−（３−ブロモフェニル）エチルから調製した）との間の反応によるイミノキシ基を含むホスホネートの調製は、上で図示している。得られたオキシムエーテルは、脱保護および側鎖アシル化により、化合物５７．２に変換され、これは、次いで、パラジウム触媒の存在下にて、亜リン酸ジアルキル５７．３と反応されて、ホスホネート５７．４が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。

Substrate 55.2 and O-2- (3-bromophenyl) ethylhydroxylamine 57.1 (prepared from compound 55.1 and 2- (3-bromophenyl) ethyl bromide, respectively, as described above. The preparation of phosphonates containing iminoxy groups by reaction with The resulting oxime ether is converted to compound 57.2 by deprotection and side chain acylation, which is then reacted with a dialkyl phosphite 57.3 in the presence of a palladium catalyst to give the phosphonate. 57.4 is obtained. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0).

あるいは、ブロモ置換生成物５７．２は、ホスホン酸ジアルキルビニル５７．５（Ａｌｄｒｉｃｈ）とのパラジウム触媒Ｈｅｃｋ反応によりカップリングされて、不飽和ホスホネート５７．６が得られる。このＨｅｃｋ反応によるハロゲン化アリールとオレフィンとのカップリングは、例えば、「Ａｄｖａｎｃｅｄ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ」、Ｆ．Ａ．ＣａｒｅｙおよびＲ．Ｊ．Ｓｕｎｄｂｅｒｇ，Ｐｌｅｎｕｍ，２００１，ｐ．５０３ｆｆおよびＡｃｃ．Ｃｈｅｍ．Ｒｅｓ．，１２，１４６，１９７９で記述されている。この臭化アリールおよびオレフィンは、極性溶媒（例えば、ジメチルホルムアミドまたはジオキサン）中で、パラジウム（０）触媒（例えば、テトラキス（トリフェニルホスフィン）パラジウム（０））またはパラジウム（ＩＩ）触媒（例えば、酢酸パラジウム（ＩＩ））の存在下にて、必要に応じて、塩基（例えば、トリエチルアミンまたは炭酸カリウム）の存在下にて、カップリングされる。必要に応じて、生成物５７．６で存在しているスチレノイド二重結合は、例えば、ジイミドと反応させることにより還元されて、飽和類似物５７．７が生成される。オレフィン性結合の還元は、「Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ」、Ｒ．Ｃ．Ｌａｒｏｃｋ，ＶＣＨ，１９８９，ｐ．６ｆｆで記述されている。この変換は、例えば、炭素担持パラジウム触媒、および水素または水素ドナーを使用して、またはジイミドまたはジボランを使用することにより、触媒水素化によって、行われる。

Alternatively, the bromo substituted product 57.2 is coupled by a palladium catalyzed Heck reaction with a dialkyl vinyl phosphonate 57.5 (Aldrich) to give the unsaturated phosphonate 57.6. Coupling of aryl halides and olefins by this Heck reaction is described, for example, in “Advanced Organic Chemistry”, F.C. A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, p. 503ff and Acc. Chem. Res. 12, 146, 1979. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)), optionally in the presence of a base (eg triethylamine or potassium carbonate). Optionally, the styrenoid double bond present in the product 57.6 is reduced, for example by reaction with diimide, to produce the saturated analog 57.7. Reduction of olefinic bonds is described in “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. It is described in 6ff. This conversion is performed, for example, by catalytic hydrogenation using a carbon-supported palladium catalyst and hydrogen or a hydrogen donor, or by using diimide or diborane.

  Using the above procedure, but using a different bromo-substituted arylalkoxyhydroxylamine or bromo-substituted heteroarylalkoxyhydroxylamine and / or different dialkylalkenyl phosphonates instead of bromophenyl reagent 57.1, compound 57.4 , 57.6 and 57.7 are obtained.

  (Example 58)

ホスホネート（ここで、このホスホネートは、イミノ基によって、結合されている）は、上で図示している。この手順では、基質５５．２は、ホスホン酸ジアルキル３−アミノフェニル５８．１（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９８４，２７，６５４）と反応されて、脱保護および側鎖アシル化後、イミン生成物５８．２が得られる。この反応は、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われ、生成物５８．２が得られる。

The phosphonate, where the phosphonate is linked by an imino group, is illustrated above. In this procedure, substrate 55.2 is reacted with dialkyl 3-aminophenyl 58.1 phosphonate (J. Med. Chem., 1984, 27, 654) to generate imine after deprotection and side chain acylation. Product 58.2 is obtained. This reaction is carried out in a hydrocarbon solvent (eg toluene or xylene) at reflux temperature in the presence of a basic catalyst (eg sodium methoxide) or an acidic catalyst (eg p-toluenesulfonic acid). Performed under azeotropic conditions to give product 58.2.

  Using the above procedure, but using a different amino substituted aryl phosphonate or heteroaryl amino substituted phosphonate heteroaryl instead of 58.1 phosphonate 3-aminophenyl, a product similar to 58.2 is obtained.

  An alternative method of preparing phosphonate 58.3, where the phosphonate is linked by an oxyimino group, starts with dienone 55.2 and is illustrated above. This dienone is reacted with hydroxylamine to give oxime 58.3 after deprotection and side chain acylation. The reaction of steroidal 1,4-dien-3-one with hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795. This reaction is carried out between equimolar amounts of reactants in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate. This oxime is then reacted in a Mitsunobu reaction with dialkyl 3-hydroxyphenyl phosphonate 58.4 (Epsilon) to give the substituted oxime 58.5. Preparation of aromatic ethers and aromatic thioethers by Mitsunobu reaction is described, for example, in “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. 448 and “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. The phenol and hydroxy or mercapto components are reacted together in the presence of a dialkyl azodicarboxylate and a trialkylphosphine in an aprotic solvent (eg, tetrahydrofuran) to give their ether or thioether product. . This procedure is also described in Org. React. 1992, 42, 335-656.

  Using the above procedure, but using a different diarylhydroxy substituted aryl phosphonate or heteroaryl diaryl hydroxy substituted phosphonate instead of phosphonate 58.4, a product similar to 58.5 is obtained.

  (Example 59)

ホスホン酸エステル（ここで、そのホスホネート基は、芳香族基またはヘテロ芳香族基、ヘテロ原子および多様な炭素鎖によって、そのピラゾール環の１’位または２’位に結合されている）の調製は、上で図示している。この手順では、二プロピオン酸アクロメタゾン５９Ａは、還元されて、１，２−ジヒドロ生成物５９．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、オーストラリア国特許出願２７５９５０４０９で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物５９．２が得られる。必要に応じて、基質５９Ａは、例えば、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、このホルミル化反応の前に、実施例５５で記述されているように、保護される。次いで、その２−ホルミル生成物は、アリールヒドラジンまたはヘテロアリールヒドラジン５９．３（ここで、置換基Ｘは、ホスホネート基、または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応により、異性体２’−アリールピラゾール５９．４および１’−アリールピラゾール５９．５が生じる。この環形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物間で実行される。次いで、ピラゾール５９．４および５９．５は、例えば、実施例６０〜６５で記述されているように、それぞれ、ホスホネート５９．６および５９．７に変換される。

Preparation of the phosphonate ester, where the phosphonate group is attached to the 1 'or 2' position of the pyrazole ring by an aromatic or heteroaromatic group, a heteroatom and various carbon chains This is illustrated above. In this procedure, acromethasone dipropionate 59A is reduced to give the 1,2-dihydro product 59.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. This product is then reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) as described in Australian Patent Application 2759950409. 2-formyl product 59.2 is obtained. If necessary, the substrate 59A can be prepared, for example, as described in J. Org. Am. Chem. Soc. , 1964, 86, 1520, prior to this formylation reaction, as described in Example 55. The 2-formyl product is then the aryl hydrazine or heteroaryl hydrazine 59.3 (wherein the substituent X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). Reacted. For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2'-arylpyrazole 59.4 and 1'-arylpyrazole 59.5. This ring formation reaction is described in J. Org. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). Pyrazole 59.4 and 59.5 are then converted to phosphonates 59.6 and 59.7, respectively, as described, for example, in Examples 60-65.

  (Example 60)

ホスホネート（ここで、このホスホネートは、フェニル基によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド５９．２は、上記のように、３−ブロモフェニルヒドラジン６０．１（Ｆｌｕｋａ）と反応されて、異性体ピラゾール生成物６０．２および６０．３が得られる。次いで、これらの生成物は、上記のように、亜リン酸ジアルキルＨＰ（Ｏ）（ＯＲ^１）_２およびパラジウム触媒と反応されて、それぞれ、ホスホネート６０．４および６０．５が得られる。上記手順を使用するが、３−ブロモフェニルヒドラジンに代えて、異なるブロモアリールヒドラジンまたはブロモヘテロアリールヒドラジン５９．３を使用して、対応する生成物５９．６および５９．７が得られる。

The preparation of phosphonates, where the phosphonate is linked by a phenyl group, is illustrated above. In this procedure, ketoaldehyde 59.2 is reacted with 3-bromophenylhydrazine 60.1 (Fluka) as described above to give isomeric pyrazole products 60.2 and 60.3. These products are then reacted with a dialkyl phosphite HP (O) (OR ¹ ) ₂ and a palladium catalyst as described above to give phosphonates 60.4 and 60.5, respectively. Using the above procedure, but using different bromoaryl hydrazines or bromoheteroaryl hydrazines 59.3 instead of 3-bromophenylhydrazines, the corresponding products 59.6 and 59.7 are obtained.

  (Example 60A)

ホスホネート（ここで、このホスホネートは、芳香族基またはヘテロ芳香族基、および飽和アルキル鎖または不飽和アルキル鎖によって、結合されている）の調製は、上で図示している。この手順では、ブロモフェニル置換ピラゾール６０．２は、上記のように、Ｈｅｃｋ反応で、例えば、ホスホン酸ジアルキルビニル６０．６（Ａｌｄｒｉｃｈ）とカップリングされて、不飽和ホスホネート生成物６０．７が得られる。必要に応じて、この生成物は、上記のように、還元されて、飽和類似物６０．８が得られる。上記手順を異性体ブロモフェニルピラゾール６０．３に適用すると、６０．７および６０．８と異性体である生成物が得られる。

The preparation of phosphonates, where the phosphonate is linked by an aromatic or heteroaromatic group, and a saturated or unsaturated alkyl chain, is illustrated above. In this procedure, bromophenyl substituted pyrazole 60.2 is coupled with, for example, a dialkyl vinyl phosphonate 60.6 (Aldrich) in the Heck reaction as described above to give the unsaturated phosphonate product 60.7. It is done. If necessary, the product is reduced as described above to give the saturated analog 60.8. Applying the above procedure to the isomer bromophenylpyrazole 60.3 gives products that are isomers of 60.7 and 60.8.

  Using the above procedure, but instead of phosphonate 60.6, using a different dialkylalkenyl phosphonate and / or a different bromoarylpyrazole 59.4 or bromoheteroarylpyrazole 59.5 (X = Br) Products similar to .7 and 60.8 are obtained.

  (Example 61)

ホスホネート（ここで、このホスホネートは、アリール基またはヘテロアリール基およびアルコキシ鎖によって、結合されている）の調製は、上で図示している。この手順では、４−アミノフェノール６１．１は、ジメチルホルムアミド溶液中にて、室温で、ホスホン酸ジアルキルトリフルオロメタンスルホニルオキシメチル６１．２（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）および炭酸カリウムと反応されて、エーテル６１．３が得られる。次いで、この生成物は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，４０３１で記述されているように、エタノール性塩酸水溶液中でのジアゾ化に続いて、そのジアゾニウムクロライドを塩化スズ（ＩＩ）で還元することにより、対応するヒドラジン６１．４に変換される。次いで、このヒドラジンは、上記のように、ケトアルデヒド５９．２と反応されて、異性体ピラゾール６１．５および６１．６が得られる。

The preparation of phosphonates, where the phosphonate is linked by an aryl or heteroaryl group and an alkoxy chain, is illustrated above. In this procedure, 4-aminophenol 61.1 is reacted with dialkyl trifluoromethanesulfonyloxymethyl phosphonate 61.2 (Tetrahedron Lett., 1986, 27, 1477) and potassium carbonate in dimethylformamide solution at room temperature. As a result, ether 61.3 is obtained. The product is then Med. Chem. , 2001, 44, 4031, followed by diazotization in aqueous ethanolic hydrochloric acid followed by reduction of the diazonium chloride with tin (II) chloride to the corresponding hydrazine 61.4. Is done. This hydrazine is then reacted with ketoaldehyde 59.2 as described above to give the isomers pyrazoles 61.5 and 61.6.

  Using the above procedure, but instead of trifluoromethanesulfonic acid 61.2, using a different dialkylphosphonoalkyl bromide or trifluoromethanesulfonic acid, and / or a different aromatic or heteroaromatic hydroxyamine, 61 Products similar to .5 and 61.6 are obtained.

  (Example 62)

ホスホネート（ここで、このホスホネートは、ピリジル基およびヘテロ原子および多様な炭素鎖によって、結合されている）の調製は、上で図示している。この手順では、３−アミノ−５−ヒドロキシピリジン６２．１は、無水酢酸との反応により、ジアセチル類似物６２．２に変換される。次いで、この生成物は、上記のように、ジアゾ化および還元により、ヒドラジン６２．３に変換される。

The preparation of phosphonates, where the phosphonates are linked by pyridyl groups and heteroatoms and various carbon chains, is illustrated above. In this procedure, 3-amino-5-hydroxypyridine 62.1 is converted to the diacetyl analog 62.2 by reaction with acetic anhydride. This product is then converted to hydrazine 62.3 by diazotization and reduction as described above.

次いで、ヒドラジン６２．３は、ケトアルデヒド５９．２と反応されて、異性体ピラゾール６２．４および６２．５が得られる。２’−ピリジル生成物６２．４は、光延反応で、上記のように、ホスホン酸ジアルキルメルカプトエチル６２．６と反応されて（Ｚｈ．Ｏｂｓｃｈｅｉ．Ｋｈｉｍ．，１９７３，４３，２３６４）、チオエーテル６２．７が得られる。この手順を異性体フェノール６２．５に適用すると、６２．７と異性体である生成物が得られる。

Hydrazine 62.3 is then reacted with ketoaldehyde 59.2 to give the isomeric pyrazoles 62.4 and 62.5. The 2′-pyridyl product 62.4 is reacted with a dialkyl mercaptoethyl phosphonate 62.6 as described above in a Mitsunobu reaction (Zh. Obschei. Khim., 1973, 43, 2364). 7 is obtained. Applying this procedure to the isomeric phenol 62.5 gives a product that is an isomer of 62.7.

  Alternatively, the isomeric phenol 62.5 can be obtained in a dimethylformamide solution at about 80 ° C. with 1 molar equivalent of dialkyl bromobutenyl phosphonate 62.8 (J. Med. Chem., 1992, 35, 1371) and Reacted with cesium carbonate to prepare phosphonate 62.9. Applying this procedure to isomeric phenol 62.4 yields a product that is an isomer of 62.9.

  The above procedure is used, but instead of thiol 62.6 or bromide 62.8, a different thiol, alcohol or bromide, and / or different phenol 59.4 or 59.5 (where X is OH) Are used to obtain the corresponding products similar to 62.7 and 62.9.

  (Example 63)

ホスホン酸エステル（ここで、そのホスホネート基は、多様な炭素結合によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド５９．２は、ヒドラジンと反応されて、ピラゾール誘導体６３．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、室温で実行される。次いで、得られたピラゾールは、ホスホン酸ジアルキルブロモメチル６３．２（ここで、Ｒ^２は、上で定義したとおりである）と反応されて、それぞれ、異性体２’アルキル化生成物６３．３および異性体１’アルキル化生成物６３．４が生成される。置換ピラゾールのアルキル化は、例えば、「Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ」、Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｌｏｎｇｍａｎ，１９９２，ｐ．３０９で記述されている。

The preparation of phosphonates, where the phosphonate group is attached by various carbon bonds, is illustrated above. In this procedure, ketoaldehyde 59.2 is reacted with hydrazine to give pyrazole derivative 63.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc, 1964, 86, 1520. This reaction is carried out in acetic acid at room temperature. The resulting pyrazole is then reacted with a dialkyl bromomethyl 63.2 phosphonate, where R ² is as defined above, to give each of the isomeric 2 ′ alkylated products 63.3. And the isomer 1 ′ alkylated product 63.4 is produced. Alkylation of substituted pyrazoles is described, for example, in “Heterocyclic Chemistry”, T.W. L. Gilchrist, Longman, 1992, p. 309.

  (Example 64)

ピラゾール６３．１は、ジメチルホルムアミド溶液中にて、約９０℃で、ホスホン酸ジアルキルブロモプロピル６４．１（Ａｌｄｒｉｃｈ）および塩基（例えば、ジメチルアミノピリジンまたはリチウムヘキサメチルジシラジド）と反応されて、異性体アルキル化生成物６４．２および６４．３が生じる。

Pyrazole 63.1 is reacted with a dialkyl bromopropyl 64.1 (Aldrich) phosphonate and a base (eg dimethylaminopyridine or lithium hexamethyldisilazide) in a dimethylformamide solution at about 90 ° C. Isomeric alkylation products 64.2 and 64.3 are produced.

(Example 65)
Pyrazole 63.1 is reacted with dialkyl 4-bromomethylbenzyl 65.1 (Tet. 1998, 54, 9341) phosphonate as described above to give products 65.2 and 65.3.

（実施例６６）
ヒドロコルチゾン６６Ａ（米国特許第２，６０２，７６９号）およびそれらのホスホン酸エステルの構造は、以下で図示しており、ここで、置換基Ｒ^１は、Ｈ、アルキル、アルケニル、アリールまたはアラルキルである。これらの化合物は、種々の連結基（添付の構造では、「リンク」として示している）によって、その核に連結されたホスホネート部分（Ｒ^１Ｏ）_２Ｐ（Ｏ）を取り込んでいる。そのステロイド側鎖がビス−メチレンジオキシ（ＢＭＤ）部分として保護される一般的な保護−脱保護手順は、以下で図示している。

Example 66
The structures of hydrocortisone 66A (US Pat. No. 2,602,769) and their phosphonates are illustrated below, where the substituent R ¹ is H, alkyl, alkenyl, aryl or aralkyl. . These compounds incorporate a phosphonate moiety (R ¹ O) ₂ P (O) linked to its nucleus by various linking groups (shown as “links” in the accompanying structure). A general protection-deprotection procedure in which the steroid side chain is protected as a bis-methylenedioxy (BMD) moiety is illustrated below.

ヒドロコルチゾン６６Ａは、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｔ．Ｗ．ＧｒｅｅｎｅおよびＰ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，Ｓｅｃｏｎｄ Ｅｄｉｔｉｏｎ １９９０，ｐ．２２３で記述されているように、パラホルムアルデヒドおよび触媒（例えば、塩酸）と反応されて、ＢＭＤ誘導体６６．１が得られる。次いで、そのホスホネート部分は、下記の手順を使用して導入され、ホスホン酸エステル６６．２が生成される。次いで、このＢＭＤ部分は、例えば、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｔ．Ｗ．ＧｒｅｅｎｅおよびＰ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，Ｓｅｃｏｎｄ Ｅｄｉｔｉｏｎ １９９０，ｐ．２２３で記述されているように、５０％酢酸水溶液で処理することにより加水分解されて、トリオール６６．３が得られる。

Hydrocortisone 66A is described in “Protective Groups in Organic Synthesis”, T.M. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. Reacted with paraformaldehyde and a catalyst (eg hydrochloric acid) as described in H.223 to give BMD derivative 66.1. The phosphonate moiety is then introduced using the following procedure to produce phosphonate ester 66.2. This BMD portion is then described in, for example, “Protective Groups in Organic Synthesis”, T.M. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. Hydrolysis by treatment with 50% aqueous acetic acid gives triol 66.3 as described in H.223.

  (Example 66A)

ＢＭＤ保護誘導体６６．１は、アミンまたはヒドロキシルアミン６６．４（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルまたはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールまたはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基、または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）またはアルコール性溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、イミンまたはオキシム６６．５が得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。Ｘがジアルキルホスホノではない場合、置換基Ｘは、下記の方法を使用して、ホスホネート含有置換基に変換される；次いで、このＢＭＤ保護側鎖は、除去されて、トリオール６６．６が得られる。

The BMD protected derivative 66.1 is an amine or hydroxylamine 66.4 (wherein R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally contains a heteroatom O, S or N). Or a functional group (such as amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O, S or And N is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcoholic solvent (eg, ethanol), optionally in the presence of an acid catalyst. To give imine or oxime 66.5. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. If X is not a dialkylphosphono, the substituent X is converted to a phosphonate-containing substituent using the following method; the BMD protected side chain is then removed to give the triol 66.6. It is done.

  (Example 66B)

ホスホネート基を含むヒドロキシルアミンエーテルの調製は、上で図示している。この手順では、ホスホネート６６．７（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン６６．８（Ａｌｄｒｉｃｈ）と反応されて、６６．９が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたは字メチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル６６．１０が得られる。

The preparation of hydroxylamine ethers containing phosphonate groups is illustrated above. In this procedure, the phosphonate 66.7, where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy) is reacted with BOC-hydroxylamine 66.8 (Aldrich) to give 66 .9 is generated. This reaction is performed between equimolar amounts of the reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or methylaminopyridine). Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 66.10.

  (Example 67)

基質６６．１は、ジアルキルホスホノメチルヒドロキシルアミン６７．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシム６７．２が得られ、これは、脱保護されて、トリオール６７．３が得られる。このオキシム形成反応は、室温で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。上記手順を使用するが、ヒドロキシルアミンエーテル６７．１に代えて、異なるオキシムエーテル６７．１０を使用して、対応する生成物６６．６が得られる。

Substrate 66.1 is derived from dialkylphosphonomethylhydroxylamine 67.1 (as described above from dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett., 1986, 27, 1477) and BOC-hydroxylamine. Prepared) to give the oxime 67.2, which is deprotected to give the triol 67.3. This oxime formation reaction is carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at room temperature. Using the above procedure, but using a different oxime ether 67.10 instead of hydroxylamine ether 67.1, the corresponding product 66.6 is obtained.

  (Example 68)

化合物（ここで、そのホスホネート基は、フェニルエトキシ基によって、結合されている）の調製は、上で図示している。この手順では、エノン６６．１は、上記のように、Ｏ−（３−ブロモフェニル）エチルヒドロキシルアミン６８．１（これは、臭化２−（３−ブロモフェニル）エチルから調製した（フランス国特許ＦＲ １，４８１，０５２））と反応されて、その側鎖の脱保護後、オキシム６８．２が得られる。次いで、この生成物は、パラジウム触媒の存在下にて、亜リン酸ジアルキル６８．３と反応されて、ホスホネート６８．４が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。

The preparation of the compound, where the phosphonate group is linked by a phenylethoxy group, is illustrated above. In this procedure, enone 66.1 was prepared as described above from O- (3-bromophenyl) ethylhydroxylamine 68.1 (which was 2- (3-bromophenyl) ethyl bromide (France). Reacting with patent FR 1,481,052)), after deprotection of the side chain, oxime 68.2 is obtained. This product is then reacted with a dialkyl phosphite 68.3 in the presence of a palladium catalyst to give the phosphonate 68.4. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0).

  (Example 68A)

あるいは、ブロモ生成物６８．２は、ホスホン酸ジアルキルビニル６８．５（Ａｌｄｒｉｃｈ）とカップリングされて、ホスホネート６８．６が得られる。このＨｅｃｋ反応によるハロゲン化アリールとオレフィンとのカップリングは、例えば、「Ａｄｖａｎｃｅｄ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ」、Ｆ．Ａ．ＣａｒｅｙおよびＲ．Ｊ．Ｓｕｎｄｂｅｒｇ，Ｐｌｅｎｕｍ，２００１，ｐ．５０３ｆｆおよびＡｃｃ．Ｃｈｅｍ．Ｒｅｓ．，１２，１４６，１９７９で記述されている。この臭化アリールおよびオレフィンは、極性溶媒（例えば、ジメチルホルムアミドまたはジオキサン）中で、パラジウム（０）触媒（例えば、テトラキス（トリフェニルホスフィン）パラジウム（０））またはパラジウム（ＩＩ）触媒（例えば、酢酸パラジウム（ＩＩ））の存在下にて、必要に応じて、塩基（例えば、トリエチルアミンまたは炭酸カリウム）の存在下にて、カップリングされる。必要に応じて、生成物６８．６で存在しているスチレノイド二重結合は、例えば、ジイミドと反応させることにより還元されて、飽和類似物６８．７が生成される。オレフィン性結合の還元は、「Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ」、Ｒ．Ｃ．Ｌａｒｏｃｋ，ＶＣＨ，１９８９，ｐ．６ｆｆで記述されている。この変換は、例えば、炭素担持パラジウム触媒、および水素または水素ドナーを使用して、またはジイミドまたはジボランを使用することにより、触媒水素化によって、行われる。

Alternatively, the bromo product 68.2 is coupled with dialkyl vinyl phosphonate 68.5 (Aldrich) to give phosphonate 68.6. Coupling of aryl halides and olefins by this Heck reaction is described, for example, in “Advanced Organic Chemistry”, F.C. A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, p. 503ff and Acc. Chem. Res. 12, 146, 1979. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)), optionally in the presence of a base (eg triethylamine or potassium carbonate). Optionally, the styrenoid double bond present in the product 68.6 is reduced, for example by reaction with diimide, to produce the saturated analog 68.7. Reduction of olefinic bonds is described in “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. It is described in 6ff. This conversion is performed, for example, by catalytic hydrogenation using a carbon-supported palladium catalyst and hydrogen or a hydrogen donor, or by using diimide or diborane.

  Using the above procedure, but using different bromo-substituted arylalkoxyhydroxylamines or bromo-substituted heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromophenylethoxy reagent 68.1, compound 68. Products similar to 4, 68.6 and 68.7 are obtained.

  (Example 69)

エノン６６．１は、Ｏ−（２−アミノエチル）ヒドロキシルアミン６９．１（Ｐｏｌ．Ｊ．Ｃｈｅｍ．，１９８１，５５，１１６３）と反応されて、オキシム６９．２が生じる。ステロイド性１，４−ジエン−３−オンと置換ヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている。この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物間で実行される。次いで、このオキシムは、ホスホン酸ジアルキル４−カルボキシフェニル６９．３（Ｅｐｓｉｌｏｎ）とカップリングされて、アミドオキシム６９．４が生じる。カルボン酸および誘導体からのアミドの調製は、例えば、Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ，Ｓ．Ｒ．Ｓａｎｄｌｅｒ ａｎｄ Ｗ．Ｋａｒｏ，Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９６８，ｐ．２７４およびＣｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ、Ｒ．Ｃ．Ｌａｒｏｃｋ，ＶＣＨ，１９８９，ｐ．９７２ｆｆで記述されている。このカルボン酸は、活性化剤（例えば、ジシクロヘキシルカルボジイミドまたはジイソプロピルカルボジイミド）の存在下にて、必要に応じて、例えば、ヒドロキシベンゾトリアゾール、Ｎ−ヒドロキシスクシンイミドまたはＮ−ヒドロキシピリドンの存在下にて、非プロトン性溶媒（例えば、ピリジン、ＤＭＦまたはジクロロメタン）中で、このアミンと反応されて、このアミドが得られる。

Enone 66.1 is reacted with O- (2-aminoethyl) hydroxylamine 69.1 (Pol. J. Chem., 1981, 55, 1163) to give oxime 69.2. The reaction of steroidal 1,4-dien-3-one with substituted hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795. This reaction is carried out between equimolar amounts of reactants in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate. This oxime is then coupled with a dialkyl 4-carboxyphenyl phosphonate 69.3 (Epsilon) to give the amide oxime 69.4. Preparation of amides from carboxylic acids and derivatives is described, for example, in Organic Functional Group Preparations, S.A. R. Sandler and W.M. Karo, Academic Press, 1968, p. 274 and Comprehensive Organic Transformations, R.A. C. Larock, VCH, 1989, p. 972 ff. The carboxylic acid can be used in the presence of an activator (e.g., dicyclohexylcarbodiimide or diisopropylcarbodiimide), optionally in the presence of, for example, hydroxybenzotriazole, N-hydroxysuccinimide, or N-hydroxypyridone. Reaction with the amine in a protic solvent such as pyridine, DMF or dichloromethane provides the amide.

  Alternatively, the carboxylic acid (eg, dialkyl 4-carboxyphenyl phosphonate 69.3) is first converted to an activated derivative (eg, its acid chloride, anhydride, mixed anhydride, imidazolide, etc.) and then Reaction with the amine in the presence of an organic base (eg pyridine) provides the amide. Conversion of the carboxylic acid to the corresponding acid chloride can be accomplished by reacting the carboxylic acid in an inert organic solvent (eg, dichloromethane), optionally in the presence of a catalytic amount of dimethylformamide, (eg, Caused by treatment with thionyl chloride or oxalyl chloride). The amide product 69.4 is then converted to the triol 69.5 as described herein.

  Using the above procedure, but using a different amino-substituted hydroxylamine and / or a different carboxy-substituted phosphonate instead of hydroxylamine 69.1, a product similar to 69.5 is obtained.

  (Example 70)

ホスホン酸エステル（ここで、そのホスホネート基は、多様な炭素鎖によって、そのピラゾール環の１’位または２’位に結合されている）の調製は、上で図示している。この手順では、ＢＭＤ保護エノン６６．１は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物７０．１が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジン７０．２（Ｒ^２は、アルキル、アラルキル、アリールまたはヘテロアリールであり、ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応により、異性体２’−および１’−アリールピラゾール７０．３および７０．４が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物間で実行される。次いで、ピラゾール７０．３および７０．４は、例えば、本明細書中で記述された手順を使用して、ＢＭＤ保護中間体７０．５および７０．６を経由して、ホスホネート７０．７および７０．８に変換される。

The preparation of phosphonates, where the phosphonate group is attached to the 1 ′ or 2 ′ position of the pyrazole ring by various carbon chains, is illustrated above. In this procedure, BMD protected enone 66.1 is Am. Chem. Soc. , 1964, 86, 1520, reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product. 70.1 is obtained. This compound is then alkyl, aralkyl, aryl or heteroaryl hydrazine 70.2 (R ² is alkyl, aralkyl, aryl or heteroaryl, where substituent X is a phosphonate group or subsequently a phosphonate containing substituent Any of the groups converted to groups). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2'- and 1'-arylpyrazoles 70.3 and 70.4. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). The pyrazoles 70.3 and 70.4 are then converted to the phosphonates 70.7 and 70 via the BMD protected intermediates 70.5 and 70.6 using, for example, the procedures described herein. .8.

  (Example 71)

ホスホネート（ここで、このホスホネート部分は、フェニル環およびアミド連鎖によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド７０．１は、３−カルボメトキシフェニルヒドラジン７１．１（Ａｐｉｎ）と反応されて、ピラゾール７１．２および７１．３が得られる。次いで、２’−置換異性体７１．２は、ジメトキシエタン水溶液中にて、１モル当量の水酸化リチウムと反応されて、カルボン酸７１．４が生成される。次いで、この酸は、上記のように、ホスホン酸ジアルキルアミノメチル７１．５（Ｉｎｔｅｒｃｈｉｍ）とカップリングされて、アミド７１．６が得られ、次いで、脱保護すると、トリオール７１．７が得られる。あるいは、１’−置換ピラゾール７１．３は、上記のように、カルボン酸７１．８に加水分解される。次いで、この生成物は、ホスホン酸ジアルキル３−アミノフェニル７１．９（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９８４，２７，６５４）とカップリングされて、脱保護後、トリオールアミド７１．１０が生じる。

The preparation of phosphonates, where the phosphonate moiety is linked by a phenyl ring and an amide linkage, is illustrated above. In this procedure, ketoaldehyde 70.1 is reacted with 3-carbomethoxyphenylhydrazine 71.1 (Apin) to give pyrazoles 71.2 and 71.3. The 2'-substituted isomer 71.2 is then reacted with 1 molar equivalent of lithium hydroxide in aqueous dimethoxyethane to produce the carboxylic acid 71.4. This acid is then coupled with dialkylaminomethyl phosphonate 71.5 (Interchim) as described above to give amide 71.6, followed by deprotection to give triol 71.7. Alternatively, 1′-substituted pyrazole 71.3 is hydrolyzed to carboxylic acid 71.8 as described above. This product is then coupled with dialkyl 3-aminophenyl 71.9 phosphonate (J. Med. Chem., 1984, 27, 654) to yield triolamide 71.10 after deprotection.

  Using the above procedure, but using different carbomethoxy substituted aralkyl, aryl or heteroarylalkoxyhydrazines, and / or different amino-substituted dialkyl phosphonates instead of carbomethoxyhydrazine 71.1, compounds 71.7 and 71 A product similar to 10 is obtained.

  (Example 72)

ホスホン酸エステル（ここで、そのホスホネート基は、多様な炭素鎖によって、結合している）は、上で図示している。この手順では、ケトアルデヒド７０．１は、上記のように、４−ブロモフェニルヒドラジン７２．１（Ｊ．Ｏｒｇａｎｏｍｅｔ．Ｃｈｅｍ．，１９９９，６２，５８１）と反応されて、ピラゾール７２．２および７２．３が生成される。１’−置換異性体７２．２は、ここで記述されているように、パラジウム触媒の存在下にて、ホスホン酸ジアルキルブテニル７２．４（Ｏｒｇ．Ｌｅｔｔ．，２００１，３，２１７）と反応されて、ホスホネート７２．５が得られる。次いで、この生成物は、脱保護されて、トリオール７２．６が得られる。必要に応じて、生成物７２．６に存在しているスチレノイド二重結合は、上記のように、還元されて、飽和類似物７２．７が生成される。

Phosphonate esters, where the phosphonate groups are linked by various carbon chains, are illustrated above. In this procedure, ketoaldehyde 70.1 is reacted with 4-bromophenylhydrazine 72.1 (J. Organomet. Chem., 1999, 62, 581) as described above to give pyrazoles 72.2 and 72. 3 is generated. The 1′-substituted isomer 72.2 is reacted with dialkylbutenyl 72.4 phosphonate (Org. Lett., 2001, 3, 217) in the presence of a palladium catalyst as described herein. To give phosphonate 72.5. The product is then deprotected to give triol 72.6. Optionally, the styrenoid double bond present in product 72.6 is reduced as described above to produce saturated analog 72.7.

  Alternatively, 2′-substituted pyrazole 72.3 is coupled with dialkyl phosphite in the presence of a palladium catalyst to prepare phosphonate 72.8, which is deprotected to give triol 72.9. Is prepared. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is carried out in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and tetrakis (triphenylphosphine) -palladium (0).

  Using the above procedure, but using, instead of bromophenylhydrazine 72.1, different bromo-substituted aralkyl, aryl or heteroarylalkoxyhydrazine, and / or different dialkylalkenyl phosphonates, compounds 72.6, 72.7 And a product similar to 72.9 is obtained.

  (Example 73)

ホスホン酸エステル（ここで、そのホスホネート基は、多様な炭素連鎖によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド７０．１は、ヒドラジンと反応されて、ピラゾール誘導体７３．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ，１９６４，８６，１５２０で記述されている。この反応は、エタノール中にて、還流温度で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物７３．２（ここで、Ｒ^２およびＸは、上で定義したとおりである）と反応されて、アルキル化生成物７３．３および７３．４が生成される。置換ピラゾールのアルキル化は、例えば、「Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ」、Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｌｏｎｇｍａｎ，１９９２，ｐ．３０９で記述されている。

The preparation of phosphonates, where the phosphonate group is linked by various carbon linkages, is illustrated above. In this procedure, ketoaldehyde 70.1 is reacted with hydrazine to give pyrazole derivative 73.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc, 1964, 86, 1520. This reaction is carried out in ethanol at reflux temperature. This pyrazole product is then reacted with bromomethyl compound 73.2 (where R ² and X are as defined above) to produce alkylated products 73.3 and 73.4. The Alkylation of substituted pyrazoles is described, for example, in “Heterocyclic Chemistry”, T.W. L. Gilchrist, Longman, 1992, p. 309.

  This reaction is carried out between equimolar amounts of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.) Executed. Products 73.3 and 73.4 are converted to phosphonates 73.5 and 73.6 using the procedures described herein except when X is a dialkylphosphono. Deprotection gives triols 73.7 and 73.8.

  (Example 74)

ピラゾール７３．１は、上記のように、１モル当量のホスホン酸ジアルキル４−（ブロモメチル）フェニル７４．１（ＷＯ ２００３／０４２１５０）と反応されて、アルキル化ピラゾール７４．２および７４．３が得られる。次いで、脱保護すると、トリオール７４．４および７４．５が生じる。

Pyrazole 73.1 is reacted with 1 molar equivalent of dialkyl 4- (bromomethyl) phenyl phosphonate 74.1 (WO 2003/042150) as described above to give alkylated pyrazoles 74.2 and 74.3. It is done. Deprotection then yields triols 74.4 and 74.5.

  (Example 75)

ピラゾール７３．１は、上記のように、２，５−ビス（ブロモメチル）チオフェン７５．１（Ｔｅｔ．１９９９，５５，４７０９）と反応されて、ピラゾール７５．２および７５．３が得られる。これらの生成物は、Ａｒｂｕｚｏｖ反応にかけられ、ここで、そのブロモメチル置換基は、１２０°での亜リン酸トリアルキルとの反応により、ジアルキルホスホノメチル置換基に変換されて、その側鎖の脱保護後、ホスホネート７５．４および７５．５が調製される。このＡｒｂｕｚｏｖ反応は、Ｈａｎｄｂ．Ｏｒｇａｎｏｐｈｏｓｐｈｏｒｕｓ Ｃｈｅｍ．，１９９２，１１５−７２で記述されている。この手順では、その基質は、６０°〜約１６０°で、５〜５０倍モル過剰の亜リン酸トリアルキルと共に加熱される。

Pyrazole 73.1 is reacted with 2,5-bis (bromomethyl) thiophene 75.1 (Tet. 1999, 55, 4709) as described above to give pyrazoles 75.2 and 75.3. These products are subjected to an Arbuzov reaction, where the bromomethyl substituent is converted to a dialkylphosphonomethyl substituent by reaction with a trialkyl phosphite at 120 ° to remove the side chain. After protection, phosphonates 75.4 and 75.5 are prepared. This Arbuzov reaction is described in Handb. Organophosphorus Chem. 1992, 115-72. In this procedure, the substrate is heated from 60 ° to about 160 ° with a 5-50 fold molar excess of trialkyl phosphite.

  Using the above procedure, but using different dibromides instead of dibromide 75.1, products similar to 75.4 and 75.5 are obtained.

(Example 76)
Dexamethasone 76A (US Pat. No. 3,007,923) analog (wherein the substituent R ¹ is H, alkyl, alkenyl, aryl or aralkyl) is prepared by the following procedure. Compounds 76.1-76.3 incorporate phosphonate moieties (R ¹ O) ₂ P (O) linked to their nuclei by various linking groups (shown as “links” in the accompanying structure). It is out.

  (Scheme M1)

デキサメタゾン７６Ａは、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｔ．Ｗ．Ｇｒｅｅｎｅ ａｎｄ Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，Ｓｅｃｏｎｄ Ｅｄｉｔｉｏｎ １９９０，ｐ．２２３で記述されているように、パラホルムアルデヒドおよび触媒（例えば、塩酸）と反応されて、ＢＭＤ誘導体７６．１が得られる。次いで、そのホスホネート部分は、下記の手順を使用して導入され、ホスホン酸エステル７６．２が生成される。次いで、このＢＭＤ部分は、例えば、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｔ．Ｗ．Ｇｒｅｅｎｅ ａｎｄ Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，Ｓｅｃｏｎｄ Ｅｄｉｔｉｏｎ １９９０，ｐ．２２３で記述されているように、５０％酢酸水溶液で処理することにより加水分解されて、トリオール７６．３が得られる。

Dexamethasone 76A is described in “Protective Groups in Organic Synthesis”, T.M. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. Reacted with paraformaldehyde and a catalyst (eg, hydrochloric acid) as described in H.223 to give BMD derivative 76.1. The phosphonate moiety is then introduced using the following procedure to produce the phosphonate ester 76.2. This BMD portion is then described in, for example, “Protective Groups in Organic Synthesis”, T.M. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. Hydrolysis by treatment with 50% aqueous acetic acid gives triol 76.3 as described in H.223.

  (Example 77)

ホスホネート（ここで、このホスホネートは、イミノまたはイミノキシ基および多様な炭素鎖によって、結合されている）の調製は、上で図示している。この手順では、ＢＭＤ保護誘導体７６．１は、アミンまたはヒドロキシルアミン７７．１（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルまたはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールまたはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）または含アルコール溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、このイミンまたはオキシムが得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、このＢＭＤ保護側鎖化合物７７．２は、実施例７６のスキームＭ１で記述されているように、トリオール７７．３に変換される。

The preparation of phosphonates, where the phosphonates are linked by imino or iminoxy groups and various carbon chains, is illustrated above. In this procedure, the BMD protected derivative 76.1 is converted to an amine or hydroxylamine 77.1 (where R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally represents a heteroatom O, S or N), or a functional group (such as an amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O and S or N), and X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcohol-containing solvent (eg, ethanol), optionally in the presence of an acid catalyst. This imine or oxime is obtained. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. This BMD protected side chain compound 77.2 is then converted to the triol 77.3 as described in Scheme M1 of Example 76.

  (Example 77A)

ホスホネート基を含むヒドロキシルアミンエーテルの調製は、上で図示している。この手順では、ホスホネート７７．４（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン７７．５（Ａｌｄｒｉｃｈ）と反応されて、エーテル７７．６が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル７７．７が得られる。

The preparation of hydroxylamine ethers containing phosphonate groups is illustrated above. In this procedure, a phosphonate 77.4 (where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 77.5 (Aldrich) to give an ether 77.6 is generated. This reaction is performed between equimolar amounts of the reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine). Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 77.7.

  (Example 78)

ホスホネート（ここで、このホスホネートは、イミノキシ基によって、結合されている）の調製は、上で図示している。この手順では、基質７６．１は、ジアルキルホスホノメチルヒドロキシルアミン７８．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシム７８．２が得られ、これは、脱保護されて、トリオール７８．３が得られる。このオキシム形成反応は、室温で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。

The preparation of phosphonates, where the phosphonate is linked by an iminoxy group, is illustrated above. In this procedure, the substrate 76.1 is a dialkylphosphonomethylhydroxylamine 78.1 (which, as described above, is a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett., 1986, 27, 1477) and BOC. -Prepared from hydroxylamine) to give oxime 78.2, which is deprotected to give triol 78.3. This oxime formation reaction is carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at room temperature.

  Using the above procedure, but using a different oxime ether 77.1 instead of hydroxylamine ether 78.1, the corresponding product 77.3 is obtained.

  (Example 79)

化合物（ここで、そのホスホネート基は、ピリジルメトキシ基によって、結合されている）の調製は、上で図示している。この手順では、ジエノン７６．１は、上記のように、Ｏ−（３−ブロモ−５−ピリジルメチル）ヒドロキシルアミン７９．１（これは、３−ブロモ−５−ブロモメチルピリジンから調製した（ＷＯ ９５／２８４００））と反応されて、その側鎖の脱保護後、オキシム７９．２が得られる。次いで、この生成物は、パラジウム触媒の存在下にて、亜リン酸ジアルキル７９．３と反応されて、ホスホネート７９．４が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。

The preparation of compounds (wherein the phosphonate group is linked by a pyridylmethoxy group) is illustrated above. In this procedure, dienone 76.1 was prepared as described above from O- (3-bromo-5-pyridylmethyl) hydroxylamine 79.1 (which was prepared from 3-bromo-5-bromomethylpyridine (WO 95/28400)) to give the oxime 79.2 after deprotection of its side chain. This product is then reacted with a dialkyl phosphite 79.3 in the presence of a palladium catalyst to give the phosphonate 79.4. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0).

  Alternatively, the bromo product 79.2 is coupled with dialkyl vinyl phosphonate 79.15 (Aldrich) to give phosphonate 79.6. Coupling of aryl halides and olefins by this Heck reaction is described, for example, in “Advanced Organic Chemistry”, F.R. A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, p. 503ff and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)), optionally in the presence of a base (eg triethylamine or potassium carbonate). Optionally, the styrenoid double bond present in the product 79.6 is reduced, for example by reaction with diimide, to produce the saturated analog 79.7. Reduction of olefinic bonds is described in “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. It is described in 6ff. This conversion is performed, for example, by catalytic hydrogenation using a palladium on carbon catalyst and hydrogen or hydrogen donor, or by using diimide or diborane.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromopyridyloxy reagent 79.1, compounds 79.4, 79.6 And a product similar to 79.7 is obtained.

  (Example 80)

ホスホネート（ここで、このホスホネートは、イミノ基によって、結合されている）の調製は、上で図示している。この手順では、基質７６．１は、ホスホン酸ジアルキル２−アミノフェニル８０．１（Ｓｙｎ．，１９９９，１３６８）と反応されて、脱保護後、イミン生成物８０．２が得られる。この反応は、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われる。

The preparation of phosphonates, where the phosphonate is linked by an imino group, is illustrated above. In this procedure, substrate 76.1 is reacted with dialkyl 2-aminophenyl 80.1 phosphonate (Syn., 1999, 1368) to give imine product 80.2 after deprotection. This reaction is carried out in a hydrocarbon solvent (eg toluene or xylene) at reflux temperature in the presence of a basic catalyst (eg sodium methoxide) or an acidic catalyst (eg p-toluenesulfonic acid). Performed under azeotropic conditions.

  Using the above procedure, but using a different amino-substituted aryl or heteroaryl phosphonate instead of 2-aminophenyl phosphonate 80.1, a product similar to 80.2 is obtained.

  (Example 81)

ホスホネート（ここで、このホスホネートは、オキシイミノ基およびアミド連鎖によって、結合されている）の調製は、上で図示している。この手順では、ジエノン７６．２は、Ｏ−（２−カルボキシエチル）ヒドロキシルアミン８１．１（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９０，３３，１４２３）と反応されて、オキシム８１．２が生じる。ステロイド性１，４−ジエン−３−オンと置換ヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている；この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物間で実行される。次いで、このオキシムは、ホスホン酸ジアルキルメチルアミノメチル８１．３と反応されて、アミドオキシム８１．２３が生じる。カルボン酸および誘導体からのアミドの調製は、例えば、「Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ」、Ｓ．Ｒ．Ｓａｎｄｌｅｒ ａｎｄ Ｗ．Ｋａｒｏ，Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９６８，ｐ．２７４および「Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ」、Ｒ．Ｃ．Ｌａｒｏｃｋ，ＶＣＨ，１９８９，ｐ．９７２ｆｆで記述されている。このカルボン酸は、活性化剤（例えば、ジシクロヘキシルカルボジイミドまたはジイソプロピルカルボジイミド）の存在下にて、必要に応じて、例えば、ヒドロキシベンゾトリアゾール、Ｎ−ヒドロキシスクシンイミドまたはＮ−ヒドロキシピリドンの存在下にて、非プロトン性溶媒（例えば、ピリジン、ＤＭＦまたはジクロロメタン）中で、このアミンと反応されて、このアミドが得られる。

The preparation of phosphonates, where the phosphonate is linked by an oximino group and an amide linkage, is illustrated above. In this procedure, dienone 76.2 is reacted with O- (2-carboxyethyl) hydroxylamine 81.1 (J. Med. Chem., 1990, 33, 1423) to give oxime 81.2. The reaction of steroidal 1,4-dien-3-one with substituted hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795; this reaction is carried out in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate, and equimolar amounts of the reactants. Executed between. This oxime is then reacted with dialkylmethylaminomethyl 81.3 phosphonate to give the amide oxime 81.23. Preparation of amides from carboxylic acids and derivatives is described, for example, in “Organic Functional Group Preparations”, S.M. R. Sandler and W.M. Karo, Academic Press, 1968, p. 274 and “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. 972 ff. The carboxylic acid can be used in the presence of an activator (e.g., dicyclohexylcarbodiimide or diisopropylcarbodiimide), optionally in the presence of, for example, hydroxybenzotriazole, N-hydroxysuccinimide, or N-hydroxypyridone. Reaction with the amine in a protic solvent such as pyridine, DMF or dichloromethane provides the amide.

  Alternatively, the carboxylic acid is first converted to an activated derivative (eg, its acid chloride, anhydride, mixed anhydride, imidazolide, etc.) and then in the presence of an organic base (eg, pyridine) Reaction with an amine gives this amide. Conversion of the carboxylic acid to the corresponding acid chloride can be accomplished by reacting the carboxylic acid in an inert organic solvent (eg, dichloromethane), optionally in the presence of a catalytic amount of dimethylformamide, (eg, Caused by treatment with thionyl chloride or oxalyl chloride).

  The amide product 81.4 is then converted to the triol 81.5 as described herein.

  Using the above procedure, but using a different carboxy-substituted hydroxylamine and / or a different amino-substituted phosphonate instead of hydroxylamine 81.3, a product similar to 81.5 is obtained.

  (Example 82)

ホスホン酸エステル（ここで、そのホスホネート基は、芳香族またはヘテロ芳香族基、ヘテロ原子または多様な炭素鎖によって、そのピラゾール環の１’位または２’位に結合されている）の調製は、上で図示している。この手順では、ＢＭＤ保護ジエノン７６．１は、還元されて、１，２−ジヒドロ生成物８２．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物８２．２が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジン８２．３（ここで、Ｒ^２は、アルキル、アラルキル、アリールまたはヘテロアリールであり、ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応により、異性体２’−アリールピラゾール８２．４および１’−アリールピラゾール８２．５が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物間で実行される。次いで、ピラゾール８２．４および８２．５は、例えば、本明細書中で記述された手順により、ＢＭＤ保護中間体８２．６および８２．７を経由して、ホスホネート８２．８および８２．９に変換される。

The preparation of a phosphonate ester, wherein the phosphonate group is attached to the 1 ′ or 2 ′ position of the pyrazole ring by an aromatic or heteroaromatic group, a heteroatom or various carbon chains, Illustrated above. In this procedure, BMD protected dienone 76.1 is reduced to give 1,2-dihydro product 82.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. The product is then Am. Chem. Soc. , 1964, 86, 1520, reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product. 82.2 is obtained. The compound is then alkyl, aralkyl, aryl or heteroaryl hydrazine 82.3 (wherein R ² is alkyl, aralkyl, aryl or heteroaryl, wherein substituent X is a phosphonate group or subsequently Any of the groups that are converted to phosphonate-containing substituents). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2'-arylpyrazole 82.4 and 1'-arylpyrazole 82.5. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). The pyrazoles 82.4 and 82.5 are then converted to the phosphonates 82.8 and 82.9 via the BMD protected intermediates 82.6 and 82.7, for example, according to the procedure described herein. Converted.

  (Example 83)

ホスホネート（ここで、このホスホネートは、フェニル環およびアルコキシまたはアセチレン連鎖によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド８２．２は、上記のように、３−ヒドロキシフェニル−ヒドラジン８３．１（日本特許第ＪＰ ０３０１１０８１号）と反応されて、ピラゾール８３．２および８３．３が得られる。次いで、２’−置換異性体８３．２は、ジクロロメタン溶液中にて、室温で、１モル当量の塩化トリフルオロメチルスルホニルおよびジメチルアミノピリジンと反応されて、トリフレート８３．４が生じる。次いで、この生成物は、トルエン溶液中にて、ホスホン酸ジアルキルプロピニル８３．５（Ｓｙｎ １９９９，２０２７）、トリエチルアミンおよび触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）と反応されて、アセチレン性生成物８３．６が得られる。トリフリト酸アリールと末端アセチレンとのパラジウム触媒カップリング反応は、ＷＯ ０２／３０９３０で記述されている。次いで、そのＢＭＤ保護基は、除去されて、トリオール８３．７が生じる。

The preparation of phosphonates, where the phosphonate is linked by a phenyl ring and an alkoxy or acetylene linkage, is illustrated above. In this procedure, ketoaldehyde 82.2 is reacted with 3-hydroxyphenyl-hydrazine 83.1 (Japanese Patent JP 03011081) as described above to give pyrazoles 83.2 and 83.3. The 2'-substituted isomer 83.2 is then reacted with 1 molar equivalent of trifluoromethylsulfonyl chloride and dimethylaminopyridine in dichloromethane solution at room temperature to give the triflate 83.4. This product is then reacted with a dialkylpropynyl phosphonate 83.5 (Syn 1999, 2027), triethylamine and a catalytic amount of tetrakis (triphenylphosphine) palladium (0) in a toluene solution to produce an acetylenic product. Product 83.6 is obtained. The palladium-catalyzed coupling reaction of aryl triflate with terminal acetylene is described in WO 02/30930. The BMD protecting group is then removed to yield the triol 83.7.

  Alternatively, 1'-substituted pyrazole 83.3 is reacted with dialkylhydroxyethyl phosphonate 83.8 (Epsilon) in a Mitsunobu reaction to give ether 83.9. Preparation of aromatic ethers by this Mitsunobu reaction is described in, for example, “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. 448 and “Advanced Organic Chemistry”, Part B, F.M. A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, p. 153-4 and Org. React. 1992, 42, 335. The phenol and alcohol components are reacted together in the presence of a dialkyl azodicarboxylate and a triaryl phosphite in an aprotic solvent (eg, tetrahydrofuran) to give their ether or thioether product. . This procedure is also described in Org. React. 1992, 42, 335-656. The product 83.9 is then deprotected to give the triol 83.10.

  Using the above procedure, but using different acetylenic or hydroxy substituted phosphonates, products similar to 83.7 and 83.10. Are obtained. These functionalization procedures are interchangeable between pyrazole substrates 83.2 and 83.3.

  (Example 84)

これらのホスホネート（ここで、そのホスホネート基は、ベンジル基および飽和または不飽和炭素鎖によって、結合している）の調製は、上で図示している。この手順では、ケトアルデヒド８２．２は、上記のように、３−ブロモベンジルヒドラジン８４．１（米国特許第４，３７０，３３９号）と反応されて、ピラゾール８４．２および８４．３が生成される。１’−置換異性体８４．２は、パラジウム触媒の存在下にて、ホスホン酸ジアルキルビニル８４．４（Ａｌｄｒｉｃｈ）と反応されて、ホスホネート８４．５が得られる。次いで、この生成物は、脱保護されて、トリオール８４．６が得られる。必要に応じて、生成物８４．６に存在しているスチレノイド二重結合は、上記のように、還元されて、飽和類似物８４．７が生成される。

The preparation of these phosphonates, where the phosphonate group is attached by a benzyl group and a saturated or unsaturated carbon chain, is illustrated above. In this procedure, ketoaldehyde 82.2 is reacted with 3-bromobenzylhydrazine 84.1 (US Pat. No. 4,370,339) as described above to produce pyrazoles 84.2 and 84.3. Is done. The 1′-substituted isomer 84.2 is reacted with dialkyl vinyl phosphonate 84.4 (Aldrich) in the presence of a palladium catalyst to give phosphonate 84.5. The product is then deprotected to give triol 84.6. If necessary, the styrenoid double bond present in the product 84.6 is reduced as described above to produce the saturated analog 84.7.

  Alternatively, 2′-substituted pyrazole 84.3 is coupled with dialkyl phosphite in the presence of a palladium catalyst to prepare phosphonate 84.8, which is deprotected to give triol 84.9. Is prepared. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is carried out in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and tetrakis (triphenylphosphine) palladium (0).

  Using the above procedure, but using different bromo-substituted aralkyl, aryl or heteroarylalkoxyhydrazines and / or different dialkylalkenyl phosphonates instead of bromobenzyl reagent 84.1, compounds 84.6, 84.7 And a product similar to 84.9 is obtained.

  (Example 85)

ホスホン酸エステル８５．７および８５．８（ここで、そのホスホネート基は、多様な炭素連鎖によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド８２．２は、ヒドラジンと反応されて、ピラゾール誘導体８５．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、室温で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物８５．２（ここで、Ｒ^２およびＸは、上で定義したとおりである）と反応されて、アルキル化生成物８５．３および８５．４が生成される。置換ピラゾールのアルキル化は、例えば、「Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ」、Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｌｏｎｇｍａｎ，１９９２，ｐ．３０９で記述されている。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、ジメチルアミノピリジン、リチウムヘキサメチルジシラジドなど）の存在下にて、等モル量のこれらの基質の間で、実行される。生成物８５．３および８５．４は、Ｘがジアルキルホスホノである場合以外は、本明細書中で記述された手順を使用して、ホスホネート８５．５および８５．６に変換され、次いで、脱保護すると、トリオール８５．７および８５．８が得られる。

The preparation of phosphonate esters 85.7 and 85.8, where the phosphonate groups are linked by various carbon linkages, is illustrated above. In this procedure, ketoaldehyde 82.2 is reacted with hydrazine to give pyrazole derivative 85.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc, 1964, 86, 1520. This reaction is carried out in acetic acid at room temperature. This pyrazole product is then reacted with bromomethyl compound 85.2 (where R ² and X are as defined above) to produce alkylated products 85.3 and 85.4. The Alkylation of substituted pyrazoles is described, for example, in “Heterocyclic Chemistry”, T.W. L. Gilchrist, Longman, 1992, p. 309. This reaction is carried out between equimolar amounts of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.) Executed. Products 85.3 and 85.4 are converted to phosphonates 85.5 and 85.6 using the procedures described herein, except when X is a dialkylphosphono, then Deprotection yields triols 85.7 and 85.8.

  (Example 86)

ピラゾール８５．１は、上記のように、１モル当量のホスホン酸ジアルキルブロモアセトニル８６．１（Ｔｅｔ．，１９７８，３４，６４９）と反応されて、アルキル化ピラゾール８６．２および８６．３が得られる。次いで、脱保護すると、トリオール８６．４および８６．５が生じる。

Pyrazole 85.1 was reacted with 1 molar equivalent of dialkyl bromoacetonyl phosphonate 86.1 (Tet., 1978, 34, 649) as described above to give alkylated pyrazoles 86.2 and 86.3. can get. Deprotection then yields triols 86.4 and 86.5.

  (Example 87)

ピラゾール８５．１は、上記のように、１，４−ビス（ブロモメチル）ベンゼン８７．１と反応されて、ピラゾール８７．２および８７．３が得られる。これらの生成物は、Ａｒｂｕｚｏｖ反応にかけられ、ここで、そのブロモメチル置換基は、１２０°での亜リン酸トリアルキルとの反応により、ジアルキルホスホノメチル置換基に変換され、その側鎖の脱保護後、ホスホネート８７．４および８７．５が調製される。このＡｒｂｕｚｏｖ反応は、Ｈａｎｄｂ．Ｏｒｇａｎｏｐｈｏｓｐｈｏｒｕｓ Ｃｈｅｍ．，１９９２，１１５−７２で記述されている。この手順では、その基質は、６０°〜約１６０°で、５〜５０倍モル過剰の亜リン酸トリアルキルと共に加熱される。

Pyrazole 85.1 is reacted with 1,4-bis (bromomethyl) benzene 87.1 as described above to give pyrazoles 87.2 and 87.3. These products are subjected to an Arbuzov reaction, where the bromomethyl substituent is converted to a dialkylphosphonomethyl substituent by reaction with a trialkyl phosphite at 120 ° to deprotect the side chain. Later, phosphonates 87.4 and 87.5 are prepared. This Arbuzov reaction is described in Handb. Organophosphorus Chem. 1992, 115-72. In this procedure, the substrate is heated from 60 ° to about 160 ° with a 5-50 fold molar excess of trialkyl phosphite.

  Using the above procedure, but using a different dibromide instead of the dibromide 87.1, products similar to 87.4 and 87.5 are obtained.

(Example 88)
Synthetic methodologies for preparing phosphonate compounds of Formulas 88.1 and 88.2 are described in Westwood et al., J. Mol. Med. Chem. 1996, 39, 4608-4621.

（実施例８９）
ホスホネート基を有する本発明の化合物およびそれらの合成に有用な中間体化合物の調製は、以下で図示している。

Example 89
The preparation of compounds of the present invention having phosphonate groups and intermediate compounds useful for their synthesis are illustrated below.

（実施例９０）
ホスホネート基を有する本発明の化合物およびそれらの合成に有用な中間体化合物の調製は、以下で図示している。

(Example 90)
The preparation of compounds of the present invention having phosphonate groups and intermediate compounds useful for their synthesis are illustrated below.

（実施例９１）

(Example 91)

スレプタン酸メチルプレゾニゾロン９１Ａ（ＷＯ ８９／００５５８）およびそれらのホスホン酸エステル９１．１〜９１．３の構造は、実施例９１において上で図示しており、ここで、置換基Ｒ^１は、Ｈ、アルキル、アルケニル、アリールまたはアラルキルである。化合物９１．１〜９１．３は、種々の連結基（添付の構造では、「リンク」として示している）によって、その核に連結されたホスホネート部分（Ｒ^１Ｏ）_２Ｐ（Ｏ）を取り込んでいる。本発明のホスホネート化合物９１．１〜９１．３およびそれらの合成に必要な中間体化合物の合成は、以下で述べる。

The structure of streptanoic acid methylprezonisolone 91A (WO 89/00558) and their phosphonic acid esters 91.1 to 91.3 is illustrated above in Example 91, where the substituent R ¹ is H, alkyl, alkenyl, aryl or aralkyl. Compound 91.1 to 91.3 (in the structure of the attachment, and are shown as "links") Various linking groups by incorporating linked phosphonate moiety to the nucleus _{^{(R 1 O) 2 P (}} O) It is out. The synthesis of the phosphonate compounds 91.1 to 91.3 of the present invention and intermediate compounds necessary for their synthesis are described below.

  Methylprezonizolone 91.4 is described in “Protective Groups in Organic Synthesis”, T.M. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. Reacted with paraformaldehyde and a catalyst (eg, hydrochloric acid) as described in H.223 to give BMD derivative 91.5. The phosphonate moiety is then introduced using the following procedure to produce the phosphonate ester 91.6. This BMD portion is then described in, for example, “Protective Groups in Organic Synthesis”, T.M. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. As described in H.223, it is hydrolyzed by treatment with 50% aqueous acetic acid to give triol 91.7. This triol is then converted to its 21-streptanoic acid ester as described in WO 89/00558. In this procedure, a mixed anhydride prepared by reacting streptanoic acid with pivaloyl chloride in the presence of a base (eg, triethylamine) is reacted with 21-hydroxysteroid 91.7 to give 21-sleptane. The acid ester 91.8 is prepared.

  (Example 92)

ホスホネート（ここで、このホスホネートは、イミノまたはイミノキシ基および多様な炭素鎖によって、結合されている）の調製は、上で図示している。この手順では、ＢＭＤ保護誘導体９１．５は、アミンまたはヒドロキシルアミン９２．１（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルまたはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールまたはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）または含アルコール溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、このイミンまたはオキシムが得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、このＢＭＤ保護側鎖化合物９２．２は、実施例６１で上で記述されているように、トリオール９２．３に変換され、次いで、スレプタネート９２．４に変換される。

The preparation of phosphonates, where the phosphonates are linked by imino or iminoxy groups and various carbon chains, is illustrated above. In this procedure, the BMD protected derivative 91.5 is an amine or hydroxylamine 92.1 (where R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally represents a heteroatom O, S or N), or a functional group (such as an amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O and S or N), and X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcohol-containing solvent (eg, ethanol), optionally in the presence of an acid catalyst. This imine or oxime is obtained. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. This BMD protected side chain compound 92.2 is then converted to the triol 92.3 and then converted to the streptinate 92.4 as described above in Example 61.

  (Example 92A)

ホスホネート基を含むヒドロキシルアミンエーテルの調製は、上で図示している。この手順では、ホスホネート９２．５（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン９２．６（Ａｌｄｒｉｃｈ）と反応されて、９２．７が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル９２．８が得られる。

The preparation of hydroxylamine ethers containing phosphonate groups is illustrated above. In this procedure, phosphonate 92.5 (where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 92.6 (Aldrich) to yield 92 .7 is generated. This reaction is performed between equimolar amounts of the reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine). Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 92.8.

  (Example 93)

ホスホネート（ここで、このホスホネートは、イミノキシ基によって、結合されている）の調製は、上で図示している。この手順では、基質９１．５は、ジアルキルホスホノメチルヒドロキシルアミン９３．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシム９３．４が得られ、これは、脱保護されて、トリオール９３．５が得られ、このトリオール９３．５からスレプタン酸エステル９３．６が調製される。このオキシム形成反応は、室温で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。

The preparation of phosphonates, where the phosphonate is linked by an iminoxy group, is illustrated above. In this procedure, the substrate 91.5 is dialkylphosphonomethylhydroxylamine 93.1 (as described above, dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett., 1986, 27, 1477) and BOC). -Prepared from hydroxylamine) to give oxime 93.4, which is deprotected to give the triol 93.5, from which the streptanoic acid ester 93.6 is prepared. Is done. This oxime formation reaction is carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at room temperature.

  Using the above procedure, but using a different oxime ether 92.1 instead of hydroxylamine ether 93.1, the corresponding product 92.4 is obtained.

  (Example 94)

化合物（ここで、そのホスホネート基は、フェノキシエトキシオキシム基によって、結合されている）の調製は、上で図示している。この手順では、ジエノン９１．５は、上記のように、Ｏ−（３−ブロモフェノキシエチル）ヒドロキシルアミン９４．１（これは、上記のように、臭化３−ブロモフェノキシエチルおよびＢＯＣ−保護ヒドロキシルアミンから調製した（ＦＲ １，４８１，０５２））と反応されて、その側鎖の脱保護後、オキシム９４．２が得られる。次いで、この生成物は、パラジウム触媒の存在下にて、亜リン酸ジアルキル９４．３と反応されて、ホスホネート９４．４が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。次いで、この２１−水酸基は、２１−スレプタネート生成物９４．５に変換される。

The preparation of the compound, where the phosphonate group is linked by a phenoxyethoxyoxime group, is illustrated above. In this procedure, dienone 91.5 was converted to O- (3-bromophenoxyethyl) hydroxylamine 94.1 as described above (which was 3-bromophenoxyethyl bromide and BOC-protected hydroxyl as described above. Reaction with (FR 1,481,052) prepared from amine to give oxime 94.2 after deprotection of its side chain. This product is then reacted with a dialkyl phosphite 94.3 in the presence of a palladium catalyst to give the phosphonate 94.4. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0). This 21-hydroxyl group is then converted to the 21-streptanate product 94.5.

  Alternatively, bromo product 94.2 is coupled with dialkylpropenyl phosphonate 94.15 (Aldrich) to give phosphonate 94.7. Coupling of aryl halides and olefins by this Heck reaction is described, for example, in “Advanced Organic Chemistry”, F.R. A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, p. 503ff and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)), optionally in the presence of a base (eg triethylamine or potassium carbonate). Optionally, the styrenoid double bond present in product 94.7 is reduced, for example by reaction with diimide, to produce saturated analog 94.9. Reduction of olefinic bonds is described in “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. It is described in 6ff. This conversion is performed, for example, by catalytic hydrogenation using a palladium on carbon catalyst and hydrogen or hydrogen donor, or by using diimide or diborane. Products 94.7 and 94.9 are then converted to streptanoic acid esters 94.8 and 94.10.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromophenoxyethoxy reagent 94.1, compounds 94.5, 94.8 And a product similar to 94.10 is obtained.

  (Example 95)

ホスホネート（ここで、このホスホネートは、イミノ基によって、結合されている）の調製は、上で図示している。この手順では、化合物９１．５は、ホスホン酸ジアルキル４−アミノフェニル９５．１（Ｅｐｓｉｌｏｎ）と反応されて、脱保護後、イミン生成物９５．２が得られる。この反応は、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われる。次いで、この生成物は、スレプタン酸エステル９５．３に変換される。

The preparation of phosphonates, where the phosphonate is linked by an imino group, is illustrated above. In this procedure, compound 91.5 is reacted with dialkyl 4-aminophenyl 95.1 (Epsilon) phosphonate to give imine product 95.2 after deprotection. This reaction is carried out in a hydrocarbon solvent (eg toluene or xylene) at reflux temperature in the presence of a basic catalyst (eg sodium methoxide) or an acidic catalyst (eg p-toluenesulfonic acid). Performed under azeotropic conditions. This product is then converted to the streptanoic acid ester 95.3.

  Using the above procedure, but using a different amino-substituted aryl phosphonate or heteroaryl instead of 4-aminophenyl phosphonate 95.1, a product similar to 95.3 is obtained.

  Example 96

ホスホネート（ここで、このホスホネートは、オキシイミノ基およびアミド連鎖によって、結合されている）の調製は、上で図示している。この手順では、ジエノン９１．５は、Ｏ−（４−アミノブチル）ヒドロキシルアミン９６．１（Ｐｏｌ．Ｊ．Ｃｈｅｍ．，１９８１，５５，１１６３）と反応されて、オキシム９６．２が生じる。ステロイド性１，４−ジエン−３−オンと置換ヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている。この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物の間で実行される。次いで、このオキシムは、ホスホノ酢酸ジアルキル９６．３（Ａｌｄｒｉｃｈ）とカップリングされて、アミドオキシム９６．４が生じる。カルボン酸および誘導体からのアミドの調製は、例えば、「Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ」、Ｓ．Ｒ．Ｓａｎｄｌｅｒ ａｎｄ Ｗ．Ｋａｒｏ，Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９６８，ｐ．２７４およびＣｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ，ｂｙ Ｒ．Ｃ．Ｌａｒｏｃｋ，ＶＣＨ，１９８９，ｐ．９７２ｆｆで記述されている。このカルボン酸は、活性化剤（例えば、ジシクロヘキシルカルボジイミドまたはジイソプロピルカルボジイミド）の存在下にて、必要に応じて、例えば、ヒドロキシベンゾトリアゾール、Ｎ−ヒドロキシスクシンイミドまたはＮ−ヒドロキシピリドンの存在下にて、非プロトン性溶媒（例えば、ピリジン、ＤＭＦまたはジクロロメタン）中で、このアミンと反応されて、このアミドが得られる。

The preparation of phosphonates, where the phosphonate is linked by an oximino group and an amide linkage, is illustrated above. In this procedure, dienone 91.5 is reacted with O- (4-aminobutyl) hydroxylamine 96.1 (Pol. J. Chem., 1981, 55, 1163) to give oxime 96.2. The reaction of steroidal 1,4-dien-3-one with substituted hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795. This reaction is carried out between equimolar amounts of the reactants in a polar organic solvent such as pyridine or methanol, optionally in the presence of acetic acid or sodium acetate. This oxime is then coupled with dialkyl phosphonoacetate 96.3 (Aldrich) to give the amide oxime 96.4. Preparation of amides from carboxylic acids and derivatives is described, for example, in “Organic Functional Group Preparations”, S.M. R. Sandler and W.M. Karo, Academic Press, 1968, p. 274 and Comprehensive Organic Transformations, by R.C. C. Larock, VCH, 1989, p. 972 ff. The carboxylic acid can be used in the presence of an activator (e.g., dicyclohexylcarbodiimide or diisopropylcarbodiimide), optionally in the presence of, for example, hydroxybenzotriazole, N-hydroxysuccinimide, or N-hydroxypyridone. Reaction with the amine in a protic solvent such as pyridine, DMF or dichloromethane provides the amide.

  Alternatively, the carboxylic acid is first converted to an activated derivative (eg, its acid chloride, anhydride, mixed anhydride, imidazolide, etc.) and then in the presence of an organic base (eg, pyridine) Reaction with an amine gives this amide. Conversion of the carboxylic acid to the corresponding acid chloride can be accomplished by reacting the carboxylic acid in an inert organic solvent (eg, dichloromethane), optionally in the presence of a catalytic amount of dimethylformamide, (eg, Caused by treatment with thionyl chloride or oxalyl chloride).

  The amide product 96.4 is then converted to the streptate 96.6 as described herein.

  Using the above procedure, but using a different amino-substituted hydroxylamine and / or a different carboxy-substituted phosphonate instead of hydroxylamine 96.1, a product similar to 96.6 is obtained.

  (Example 97)

ホスホン酸エステル（ここで、そのホスホネート基は、芳香族またはヘテロ芳香族基、ヘテロ原子または多様な炭素鎖によって、そのピラゾール環の１’位または２’位に結合されている）の調製は、上で図示している。この手順では、ＢＭＤ保護ジエノン９１．５は、還元されて、１，２−ジヒドロ生成物９７．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物９７．２が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジン９７．３（Ｒ^２は、アルキル、アラルキル、アリールまたはヘテロアリールであり、ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応により、異性体２’−および１’−アリールピラゾール９７．４および９７．５が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物の間で実行される。次いで、ピラゾール９７．４および９７．５は、例えば、実施例９８および９９で記述された手順により、ＢＭＤ保護中間体９７．６および９７．７を経由して、ホスホネートスレプタネート９７．９および９７．１１に変換される。

The preparation of a phosphonate ester, wherein the phosphonate group is attached to the 1 ′ or 2 ′ position of the pyrazole ring by an aromatic or heteroaromatic group, a heteroatom or various carbon chains, Illustrated above. In this procedure, BMD protected dienone 91.5 is reduced to give 1,2-dihydro product 97.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. The product is then Am. Chem. Soc. , 1964, 86, 1520, reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product. 97.2 is obtained. This compound is then alkyl, aralkyl, aryl or heteroaryl hydrazine 97.3 (R ² is alkyl, aralkyl, aryl or heteroaryl, where substituent X is a phosphonate group or subsequently a phosphonate containing substituent. Any of the groups converted to groups). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2'- and 1'-arylpyrazoles 97.4 and 97.5. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). The pyrazoles 97.4 and 97.5 are then converted to the phosphonate streptinate 97.9 and via the BMD protected intermediates 97.6 and 97.7, for example by the procedure described in Examples 98 and 99. Converted to 97.11.

  (Example 98)

ホスホネート（ここで、このホスホネートは、フェニル環およびアルコキシまたはアルケニル連鎖によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド９７．２は、上記のように、４−ヒドロキシフェニルヒドラジン９８．１（Ｅｐｓｉｌｏｎ）と反応されて、ピラゾール９８．２および９８．３が得られる。次いで、２’−置換異性体９８．２は、ジメチルホルムアミド溶液中にて、室温で、１モル当量の１，４−ジブロモブタ−２−エンおよびジメチルアミノピリジンと反応されて、ブロモエーテル９８．４が生じる。次いで、この生成物は、１２０°で、Ａｒｂｕｚｏｖ反応において、亜リン酸トリアルキル９８．５と反応されて、ホスホネート生成物９８．６が得られる。このＡｒｂｕｚｏｖ反応（ここで、臭化アルキルは、亜リン酸トリアルキルと共に、６０°〜約１５０°まで加熱することにより、対応するホスホネートに変換される）は、Ｈａｎｄｂ．Ｏｒｇａｎｏｐｈｏｓｐｈｏｒｕｓ Ｃｈｅｍ．，１９９２，１１５−７２で記述されている。次いで、このＢＭＤ保護基は、除去され、その生成物は、アシル化されて、スレプタン酸エステルトリオール９８．８が生じる。

The preparation of phosphonates, where the phosphonate is linked by a phenyl ring and an alkoxy or alkenyl linkage, is illustrated above. In this procedure, ketoaldehyde 97.2 is reacted with 4-hydroxyphenylhydrazine 98.1 (Epsilon) as described above to give pyrazoles 98.2 and 98.3. The 2'-substituted isomer 98.2 is then reacted with 1 molar equivalent of 1,4-dibromobut-2-ene and dimethylaminopyridine in a dimethylformamide solution at room temperature to give 98.4 bromoether. Occurs. This product is then reacted with a trialkyl phosphite 98.5 in an Arbuzov reaction at 120 ° to give the phosphonate product 98.6. This Arbuzov reaction (wherein the alkyl bromide is converted to the corresponding phosphonate by heating to 60 ° to about 150 ° with trialkyl phosphite) is described in Handb. Organophosphorus Chem. 1992, 115-72. The BMD protecting group is then removed and the product is acylated to yield the streptanoic ester triol 98.8.

  Alternatively, 1'-substituted pyrazole 98.3 is reacted with dialkylhydroxymethyl phosphonate 98.9 (Aldrich) in Mitsunobu reaction to give ether 98.10. Preparation of aromatic ethers by this Mitsunobu reaction is described in, for example, “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. 448 and “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. The phenol and alcohol or thiol components are reacted together in the presence of a dialkyl azodicarboxylate and a triaryl phosphite in an aprotic solvent (eg, tetrahydrofuran) to give their ether or thioether product. can get. This procedure is also described in Org. React. 1992, 42, 335. The product 98.10 is then deprotected to give the triol 98.11 and the latter compound is acylated to give the streptate 98.12.

  Using the above procedure, but using different dibromides or hydroxy substituted phosphonates, products similar to 98.8 and 98.12. Are obtained. These functionalization procedures are interchangeable between pyrazole substrates 98.2 and 98.3.

  Example 99

これらのホスホネート（ここで、そのホスホネート基は、フェニル基またはフェニル基および飽和または不飽和炭素鎖によって、結合している）の調製は、上で図示している。この手順では、ケトアルデヒド９７．２は、上記のように、４−ブロモフェニルヒドラジン９９．１（Ｊ．Ｏｒｇａｎｏｍｅｔ．Ｃｈｅｍ．，１９９９，６２，５８１）と反応されて、ピラゾール９９．２および９９．３が生成される。１’−置換異性体９９．２は、パラジウム触媒の存在下にて、ホスホン酸ジアルキルビニル９９．４（Ａｌｄｒｉｃｈ）と反応されて、ホスホネート９９．４ａが得られる。次いで、この生成物は、脱保護されて、トリオール９９．５が得られ、これは、スレプタネート９９．６に変換される。必要に応じて、生成物９９．６に存在しているスチレノイド二重結合は、上記のように、還元されて、飽和類似物９９．８が生成される。

The preparation of these phosphonates, where the phosphonate group is linked by a phenyl group or phenyl group and a saturated or unsaturated carbon chain, is illustrated above. In this procedure, ketoaldehyde 97.2 is reacted with 4-bromophenylhydrazine 99.1 (J. Organomet. Chem., 1999, 62, 581) as described above to give pyrazoles 99.2 and 99. 3 is generated. The 1′-substituted isomer 99.2 is reacted with a dialkyl vinyl phosphonate 99.4 (Aldrich) in the presence of a palladium catalyst to give the phosphonate 99.4a. The product is then deprotected to give triol 99.5, which is converted to streptinate 99.6. Optionally, the styrenoid double bond present in the product 99.6 is reduced as described above to produce the saturated analog 99.8.

  Alternatively, 2'-substituted pyrazole 99.3 is coupled with dialkyl phosphite in the presence of a palladium catalyst to prepare phosphonate 99.9, which is deprotected and the product is Acylation affords the streptanoic acid ester 99.11. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is carried out in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and tetrakis (triphenylphosphine) -palladium (0).

  Using the above procedure, but using different bromo-substituted aralkyl, aryl or heteroarylalkoxyhydrazine, and / or different dialkylalkenyl phosphonates instead of bromophenylhydrazine 99.1, compounds 99.6, 99.8 And a product similar to 99.11 is obtained.

  (Example 100)

これらのホスホン酸エステル（ここで、そのホスホネート基は、多様な炭素連鎖によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド９７．２は、ヒドラジンと反応されて、ピラゾール誘導体１００．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、室温で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物１００．２（ここで、Ｒ^２およびＸは、上で定義したとおりである）と反応されて、アルキル化生成物１００．３および１００．４が生成される。置換ピラゾールのアルキル化は、例えば、「Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ」、Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｌｏｎｇｍａｎ，１９９２，ｐ．３０９で記述されている。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、ジメチルアミノピリジン、リチウムヘキサメチルジシラジドなど）の存在下にて、等モル量のこれらの基質の間で、実行される。生成物１００．３および１００．４は、Ｘがジアルキルホスホノである場合以外は、本明細書中で記述された手順を使用して、ホスホネート１００．５および１００．６に変換され、次いで、脱保護／アシル化すると、スレプタン酸エステル１００．８および１００．１０が得られる。

The preparation of these phosphonate esters, where the phosphonate groups are linked by various carbon linkages, is illustrated above. In this procedure, ketoaldehyde 97.2 is reacted with hydrazine to give pyrazole derivative 100.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc, 1964, 86, 1520. This reaction is carried out in acetic acid at room temperature. Then, the pyrazole product, bromomethyl compound 100.2 (wherein, ^{R 2} and X are as defined above) is reacted with, alkylation products 100.3 and 100.4 are produced The Alkylation of substituted pyrazoles is described, for example, in “Heterocyclic Chemistry”, T.W. L. Gilchrist, Longman, 1992, p. 309. This reaction is carried out between equimolar amounts of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.) Executed. Products 100.3 and 100.4 are converted to phosphonates 100.5 and 100.6 using the procedures described herein except when X is a dialkylphosphono, then Deprotection / acylation yields the streptanoic acid esters 100.8 and 100.10.

  (Example 101)

ピラゾール１００．１は、テトラヒドロフラン溶液にて、上記のように、１モル当量のホスホン酸ジアルキルブロモブチル１０１．１（Ｓｙｎｔｈｅｓｉｓ，１９９４，９，９０９）およびリチウムヘキサメチルジシラザンと反応されて、アルキル化ピラゾール１０１．２および１０１．３が得られる。次いで、脱保護／アシル化すると、スレプタネート１０１．５および１０１．７が生じる。

Pyrazole 100.1 is reacted with 1 molar equivalent of dialkyl bromobutyl phosphonate 101.1 (Synthesis, 1994, 9, 909) and lithium hexamethyldisilazane in tetrahydrofuran solution as described above to alkylate. Pyrazoles 101.2 and 101.3 are obtained. Deprotection / acylation then yields the streptanates 101.5 and 101.7.

  (Example 102)

ピラゾール１００．１は、テトラヒドロフラン溶液中にて、上記のように、１，２−ビス（ブロモメチル）シクロプロパン１０２．１（Ｔｅｔ．，１９９７，５３，１０４５９）と反応されて、ピラゾール１０２．２および１０２．３が得られる。これらの生成物は、Ａｒｂｕｚｏｖ反応にかけられ、ここで、そのブロモメチル置換基は、１２０°での亜リン酸トリアルキルとの反応によりジアルキルホスホノメチル置換基に変換し、その側鎖の脱保護およびアシル化後、スレプタネートホスホネート１０２．５および１０２．７が調製される。このＡｒｂｕｚｏｖ反応は、Ｈａｎｄｂ．Ｏｒｇａｎｏｐｈｏｓｐｈｏｒｕｓ Ｃｈｅｍ．，１９９２，１１５−７２で記述されている。この手順では、その基質は、６０°〜約１６０°で、５〜５０倍モル過剰の亜リン酸トリアルキルと共に加熱される。

Pyrazole 100.1 is reacted with 1,2-bis (bromomethyl) cyclopropane 102.1 (Tet., 1997, 53, 10459) as described above in tetrahydrofuran solution to give pyrazole 102.2 and 102.3 is obtained. These products are subjected to an Arbuzov reaction, where the bromomethyl substituent is converted to a dialkylphosphonomethyl substituent by reaction with a trialkyl phosphite at 120 ° to remove the side chain deprotection and After acylation, streptate phosphonates 102.5 and 102.7 are prepared. This Arbuzov reaction is described in Handb. Organophosphorus Chem. 1992, 115-72. In this procedure, the substrate is heated from 60 ° to about 160 ° with a 5-50 fold molar excess of trialkyl phosphite.

  Using the above procedure, but using different dibromides instead of dibromide 102.1, products similar to 102.5 and 102.7 are obtained.

  (Example 103)

クロベタゾール１０３Ａ（米国特許第３，７２１，６８７号）およびそれらのホスホン酸エステル１０３．１〜１０３．３の構造は、上で図示している。化合物１０３．１〜１０３．３は、種々の連結基（添付の構造では、「リンク」として示している）によって、その核に連結されたホスホネート部分（Ｒ^１Ｏ）_２Ｐ（Ｏ）を取り込んでいる。

The structures of clobetasol 103A (US Pat. No. 3,721,687) and their phosphonates 103.1-103.3 are illustrated above. Compounds 103.1-103.3 incorporate phosphonate moieties (R ¹ O) ₂ P (O) linked to their nuclei by various linking groups (shown as “links” in the accompanying structure). It is out.

このステロイド側鎖がビス−メチレンジオキシ（ＢＭＤ）部分として保護される保護−脱保護手順は、上で図示している。この手順では、９α−フルオロ−１６β−メチル−１１β，１７α，２１−トリヒドロキシプレグナ−１，４−ジエン−３，２１−ジオン１０３．４（米国特許３，７２１，６８７）は、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｔ．Ｗ．Ｇｒｅｅｎｅ ａｎｄ Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，Ｓｅｃｏｎｄ Ｅｄｉｔｉｏｎ １９９０，ｐ．２２３で記述されているように、パラホルムアルデヒドおよび酸触媒（例えば、塩酸）と反応されて、ＢＭＤ誘導体１０３．５が生じる。次いで、このホスホネート部分は、下記の手順を使用して導入され、ホスホン酸エステル１０３．６が生成される。次いで、このＢＭＤ部分は、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｔ．Ｗ．Ｇｒｅｅｎｅ ａｎｄ Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，Ｓｅｃｏｎｄ Ｅｄｉｔｉｏｎ １９９０，ｐ．２２３で記述されているように、例えば、５０％酢酸水溶液で処理することにより加水分解されて、トリオール１０３．７が得られる。次いで、その２１−水酸基は、米国特許第３，７２１，６８７号、Ｃｈｉｍｉａ，１９９２，４６，３３８またはＪ．Ｍｅｄ．Ｃｈｅｍ．，１９８７，３０，１５８１で記述されているように、２１−クロロ基に変換される。この手順では、２１−ヒドロキシ基質は、約０°で、塩基性溶媒（例えば、ピリジン）中にて、１モル当量の塩化メタンスルホニルと反応されて、２１−メシレート１０３．８が得られる。次いで、この生成物は、ジメチルホルムアミド溶液中にて、約７０°で、約５モル当量の塩化リチウムと反応されて、２１−クロロ生成物１０３．９が生じる。

A protection-deprotection procedure in which this steroid side chain is protected as a bis-methylenedioxy (BMD) moiety is illustrated above. In this procedure, 9α-fluoro-16β-methyl-11β, 17α, 21-trihydroxypregna-1,4-diene-3,21-dione 103.4 (U.S. Pat. No. 3,721,687) is described as “Protective”. Groups in Organic Synthesis, "T. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. As described in H.223, it is reacted with paraformaldehyde and an acid catalyst (eg hydrochloric acid) to yield the BMD derivative 103.5. This phosphonate moiety is then introduced using the following procedure to produce the phosphonate ester 103.6. This BMD portion is then described in “Protective Groups in Organic Synthesis”, T.M. W. Greene and P.M. G. M.M. Wuts, Wiley, Second Edition 1990, p. As described in H.223, the triol 103.7 is obtained by hydrolysis, for example by treatment with 50% aqueous acetic acid. The 21-hydroxyl group is then described in U.S. Pat. No. 3,721,687, Chimia, 1992, 46,338 or J. Am. Med. Chem. , 1987, 30, 1581, converted to the 21-chloro group. In this procedure, the 21-hydroxy substrate is reacted with 1 molar equivalent of methanesulfonyl chloride in a basic solvent (eg, pyridine) at about 0 ° to give 21-mesylate 103.8. This product is then reacted with about 5 molar equivalents of lithium chloride in a dimethylformamide solution at about 70 ° to yield the 21-chloro product 103.9.

  (Example 104)

ホスホネート（ここで、このホスホネートは、イミノまたはイミノキシ基および多様な炭素鎖によって、結合されている）の調製は、本明細書中で記述している。この手順では、ＢＭＤ保護誘導体１０３．１は、アミンまたはヒドロキシルアミン１０４．１（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルまたはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールまたはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）または含アルコール溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、このイミンまたはオキシムが得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、このＢＭＤ保護側鎖化合物１０４．２は、トリオール１０４．３に変換され、本明細書に記載されるように、次いで、２１−クロロ生成物１０４．４に変換される。

The preparation of phosphonates, where the phosphonates are linked by imino or iminoxy groups and various carbon chains, is described herein. In this procedure, BMD protected derivatives 103.1, amine or hydroxylamine 104.1 (wherein, ^{R 2} is alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally, heteroatoms O, S or N), or a functional group (such as an amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O and S or N), and X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcohol-containing solvent (eg, ethanol), optionally in the presence of an acid catalyst. This imine or oxime is obtained. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. This BMD protected side chain compound 104.2 is then converted to the triol 104.3 and then converted to the 21-chloro product 104.4 as described herein.

  (Example 104A)

ホスホネート基を含むヒドロキシルアミンエーテルの調製は、上で図示している。この手順では、ホスホネート１０４．５（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン１０４．６（Ａｌｄｒｉｃｈ）と反応されて、エーテル１０４．７が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル１０４．８が得られる。

The preparation of hydroxylamine ethers containing phosphonate groups is illustrated above. In this procedure, phosphonate 104.5 (where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 104.6 (Aldrich) to give ether. 104.7 is generated. This reaction is performed between equimolar amounts of the reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine). Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 104.8.

  (Example 105)

ホスホネート（ここで、このホスホネートは、イミノキシ基によって、結合されている）の調製は、上で図示している。この手順では、基質１０３．１は、ジアルキルホスホノメチルヒドロキシルアミン１０５．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔｒａｈｅｒｄｏｎ．Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシム１０５．２が得られる。次いで、脱保護すると、トリオール１０５．３が得られ、そこから、２１−クロロ化合物１０５．４が調製される。このオキシム形成反応は、室温で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。上記手順を使用するが、ヒドロキシルアミンエーテル１０５．１に代えて、異なるオキシムエーテル１０４．１を使用して、対応する生成物１０５．４が得られる。

The preparation of phosphonates, where the phosphonate is linked by an iminoxy group, is illustrated above. In this procedure, the substrate 103.1 is dialkylphosphonomethylhydroxylamine 105.1 (as described above, dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Teteraherdon. Lett., 1986, 27, 1477) and Prepared from BOC-hydroxylamine) to give oxime 105.2. Deprotection then yields the triol 105.3, from which the 21-chloro compound 105.4 is prepared. This oxime formation reaction is carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at room temperature. Using the above procedure, but replacing the hydroxylamine ether 105.1 with a different oxime ether 104.1 gives the corresponding product 105.4.

  (Example 106)

化合物（ここで、そのホスホネート基は、３−ピリジルメトキシオキシム基によって、結合されている）の調製は、本明細書中で記述している。この手順では、ジエノン１０３．１は、上記のように、Ｏ−（５−ブロモ−３−ピリジルメトキシ）ヒドロキシルアミン１０６．１（これは、上記のように、５−ブロモ−３−ブロモメチルピリジンおよびＢＯＣ−保護ヒドロキシルアミンから調製した（ＷＯ ９５／２８４００））と反応されて、その側鎖の脱保護後、オキシム１０６．２が得られる。次いで、この生成物は、パラジウム触媒の存在下にて、亜リン酸ジアルキル１０６．３と反応されて、ホスホネート１０６．４が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。次いで、この２１−水酸基は、２１−クロロ誘導体１０６．５に変換される。

The preparation of compounds where the phosphonate group is linked by a 3-pyridylmethoxyoxime group is described herein. In this procedure, the dienone 103.1 is converted to O- (5-bromo-3-pyridylmethoxy) hydroxylamine 106.1 as described above (which is 5-bromo-3-bromomethylpyridine as described above). And prepared from BOC-protected hydroxylamine (WO 95/28400)) to yield oxime 106.2 after deprotection of its side chain. This product is then reacted with a dialkyl phosphite 106.3 in the presence of a palladium catalyst to give the phosphonate 106.4. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0). This 21-hydroxyl group is then converted to the 21-chloro derivative 106.5.

  Alternatively, bromo product 106.2 is coupled with dialkyl 4-vinylphenyl phosphonate 106.6 (Macromolecules, 1998, 31, 2918) to give phosphonate 106.7. Coupling of aryl halides and olefins by this Heck reaction is described, for example, in “Advanced Organic Chemistry”, F.R. A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, p. 503ff and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)), optionally in the presence of a base (eg triethylamine or potassium carbonate). Optionally, the styrenoid double bond present in the product 106.7 is reduced, for example by reaction with diimide, to produce the saturated analog 106.6. Reduction of olefinic bonds is described in “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. It is described in 6ff. This conversion is performed, for example, by catalytic hydrogenation using a palladium on carbon catalyst and hydrogen or hydrogen donor, or by using diimide or diborane. Products 106.7 and 106.9 are then converted to 21-chloro analogs 106.8 and 106.10. Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromopyridylmethoxy reagent 106.1, compounds 106.5, 106.8 And a product similar to 106.10 is obtained.

  (Example 107)

ホスホネート（ここで、このホスホネートは、イミノ基によって、結合されている）の調製は、上で図示している。この手順では、基質１０３．１は、ホスホン酸ジアルキル４−アミノベンジル１０７．１（Ｆｌｕｋａ）と反応されて、脱保護後、イミン生成物１０７．２が得られる。この反応は、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われる。次いで、この生成物は、２１−クロロ化合物１０７．３に変換される。

The preparation of phosphonates, where the phosphonate is linked by an imino group, is illustrated above. In this procedure, the substrate 103.1 is reacted with a dialkyl 4-aminobenzyl 107.1 (Fluka) phosphonate to give, after deprotection, the imine product 107.2. This reaction is carried out in a hydrocarbon solvent (eg toluene or xylene) at reflux temperature in the presence of a basic catalyst (eg sodium methoxide) or an acidic catalyst (eg p-toluenesulfonic acid). Performed under azeotropic conditions. This product is then converted to the 21-chloro compound 107.3.

  Using the above procedure, but using a different amino-substituted aryl or heteroaryl phosphonate instead of 4-aminobenzyl phosphonate 107.1, a product similar to 107.3 is obtained.

  (Example 108)

ホスホネート（ここで、このホスホネートは、オキシイミノ基およびチオエーテル連鎖によって、結合されている）の調製は、上で図示している。この手順では、ジエノン１０３．１は、Ｏ−（２−メルカプトエチル）ヒドロキシルアミン１０８．１（Ｂｉｏｏｒｇａｎｉｃｈｅｓｋａｙａ Ｋｈｉｍ．，１９８６，１２，１６６２）と反応されて、オキシム１０８．２が生じる。ステロイド性１，４−ジエン−３−オンと置換ヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている；この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物間で実行される。次いで、この生成物は、光延反応において、ホスホン酸ジアルキル３−ヒドロキシフェニル１０８．３（Ａｕｒｏｒａ）と反応されて、チオエーテルオキシム１０８．４が生じる。光延反応による芳香族エーテルの調製は、例えば、「Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ」、Ｒ．Ｃ．Ｌａｒｏｃｋ，ＶＣＨ，１９８９，４４８頁および「Ａｄｖａｎｃｅｄ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ」、Ｐａｒｔ Ｂ，Ｆ．Ａ．ＣａｒｅｙおよびＲ．Ｊ．Ｓｕｎｄｂｅｒｇ，Ｐｌｅｎｕｍ，２００１，１５３−４頁およびＯｒｇ．Ｒｅａｃｔ．，１９９２，４２，３３５で記述されている。このフェノールおよびアルコールまたはチオール成分は、非プロトン性溶媒（例えば、テトラヒドロフラン）中で、アゾジカルボン酸ジアルキルおよびトリアリールホスフィンの存在下にて、共に反応されて、それらのエーテルまたはチオエーテル生成物が得られる。この手順もまた、Ｏｒｇ．Ｒｅａｃｔ．，１９９２，４２，３３５−６５６で記述されている。次いで、チオエーテル生成物１０８．４は、実施例１０３で記述されているように、加水分解され、２１−クロロ生成物１０８．６に変換される。

The preparation of phosphonates, where the phosphonate is linked by an oxyimino group and a thioether linkage, is illustrated above. In this procedure, dienone 103.1 is reacted with O- (2-mercaptoethyl) hydroxylamine 108.1 (Bioorganicheskaya Khim., 1986, 12, 1662) to give oxime 108.2. The reaction of steroidal 1,4-dien-3-one with substituted hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795; this reaction is carried out in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate, and equimolar amounts of the reactants. Executed between. This product is then reacted with a dialkyl 3-hydroxyphenyl phosphonate 108.3 (Aurora) in a Mitsunobu reaction to give the thioether oxime 108.4. Preparation of aromatic ethers by Mitsunobu reaction is described in, for example, “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, p. 448 and “Advanced Organic Chemistry”, Part B, F .; A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, pages 153-4 and Org. React. 1992, 42, 335. The phenol and alcohol or thiol components are reacted together in the presence of a dialkyl azodicarboxylate and a triarylphosphine in an aprotic solvent (eg, tetrahydrofuran) to give their ether or thioether product. . This procedure is also described in Org. React. 1992, 42, 335-656. The thioether product 108.4 is then hydrolyzed and converted to the 21-chloro product 108.6 as described in Example 103.

  Using the above procedure, but using a different hydroxy or mercapto substituted hydroxylamine and / or a different hydroxyaryl substituted phosphonate instead of hydroxylamine 108.3, a product similar to 108.6 is obtained.

  (Example 109)

ホスホン酸エステル（ここで、そのホスホネート基は、芳香族またはヘテロ芳香族基、ヘテロ原子または多様な炭素鎖によって、そのピラゾール環の１’位または２’ 位に結合されている）の調製は、上で図示している。この手順では、ＢＭＤ保護ジエノン１０３．５は、還元されて、１，２−ジヒドロ生成物１０９．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０に記載されるように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物１０９．２が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジン１０９．３（ここで、Ｒ^２は、アルキル、アラルキル、アリールまたはヘテロアリールであり、ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応により、異性体２’−アリールピラゾール１０９．４および１’−アリールピラゾール１０９．５が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物の間で実行される。次いで、ピラゾール１０９．４および１０９．５は、例えば、実施例１１０および１１１で記述された手順により、ＢＭＤ保護中間体１０９．６および１０９．７を経由して、２１−クロロホスホネート１０９．９および１０９．１１に変換される。

The preparation of a phosphonate ester, wherein the phosphonate group is attached to the 1 ′ or 2 ′ position of the pyrazole ring by an aromatic or heteroaromatic group, a heteroatom or various carbon chains, Illustrated above. In this procedure, BMD protected dienone 103.5 is reduced to give 1,2-dihydro product 109.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. The product is then Am. Chem. Soc. , 1964, 86, 1520, reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product 109 .2 is obtained. The compound is then alkyl, aralkyl, aryl or heteroaryl hydrazine 109.3 (wherein R ² is alkyl, aralkyl, aryl or heteroaryl, wherein substituent X is a phosphonate group or subsequently Any of the groups that are converted to phosphonate-containing substituents). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2′-arylpyrazole 109.4 and 1′-arylpyrazole 109.5. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). Pyrazole 109.4 and 109.5 can then be converted to 21-chlorophosphonate 109.9 and via BMD protected intermediates 109.6 and 109.7, for example, by the procedure described in Examples 110 and 111. Is converted to 109.11.

  (Example 110)

ホスホン酸エステル（ここで、そのホスホネート基は、カーバメートまたはアミノ連鎖によって、そのピラゾール環の１’位または２’位に結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド１０９．２は、上記のように、３−アミノフェニルヒドラジン１１０．１（ＥＰ ４３７１０５）と反応されて、ピラゾール１１０．２および１１０．３が得られる。次いで、２’−置換異性体１１０．２は、ジメチルホルムアミド溶液中にて、周囲温度で、１モル当量のホスホン酸ジアルキル２−ヒドロキシエチル１１０．４（Ｅｐｓｉｌｏｎ）およびカルボニルジイミダゾールと反応されて、カーバメート１１０．５が生じる。カーバメートの調製は、「Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ」、Ａ．Ｒ．Ｋａｔｒｉｔｚｋｙ，編，Ｐｅｒｇａｍｏｎ，１９９５，第６巻，４１６ｆｆ頁および「Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ」、Ｓ．Ｒ．ＳａｎｄｌｅｒおよびＷ．Ｋａｒｏ，Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９８６，２６０ｆｆ頁で記述されている。この手順では、このアミンは、不活性非プロトン性溶媒（例えば、ジクロロメタンまたはテトラヒドロフラン）中にて、ホスゲンまたはそれらの官能性等価物（例えば、カルボニルジイミダゾール、トリホスゲン、ペンタフルオロフェニルカーバメートなど）と反応されて、対応する活性化アシルアミンが得られる。次いで、後者の化合物は、アルコールと反応されて、このカーバメートが生じる。次いで、このＢＭＤ保護基は、除去され、その生成物は、２１−クロロ生成物１１０．７に変換される。

The preparation of a phosphonate ester, where the phosphonate group is attached to the 1 ′ or 2 ′ position of the pyrazole ring by a carbamate or amino linkage, is illustrated above. In this procedure, ketoaldehyde 109.2 is reacted with 3-aminophenylhydrazine 110.1 (EP 437105) as described above to give pyrazoles 110.2 and 110.3. The 2′-substituted isomer 110.2 is then reacted with 1 molar equivalent of a dialkyl 2-hydroxyethyl phosphonate 110.4 (Epsilon) and carbonyldiimidazole in dimethylformamide solution at ambient temperature, Carbamate 110.5 is produced. The preparation of carbamates is described in “Comprehensive Organic Functional Group Transformations”, A.M. R. Katritzky, ed., Pergamon, 1995, Vol. 6, page 416ff and “Organic Functional Group Preparations”, S.A. R. Sandler and W.W. Karo, Academic Press, 1986, pp. 260ff. In this procedure, the amine is reacted with phosgene or a functional equivalent thereof (eg, carbonyldiimidazole, triphosgene, pentafluorophenyl carbamate, etc.) in an inert aprotic solvent (eg, dichloromethane or tetrahydrofuran). To obtain the corresponding activated acylamine. The latter compound is then reacted with an alcohol to yield this carbamate. The BMD protecting group is then removed and the product is converted to the 21-chloro product 110.7.

  Alternatively, 1′-substituted pyrazole 110.3 is reacted with dialkylformylmethyl phosphonate 110.8 (Zh. Obschei. Khim., 1987, 57, 2793) and sodium triacetoxyborohydride in a reductive amination reaction. Thus, amine 110.9 is obtained. Preparation of amines by a reductive amination procedure is described, for example, in “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, p. 421, and “Advanced Organic Chemistry”, Part B, F .; A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, 269. In this procedure, the amine component and the aldehyde or ketone component are Org. Chem. , 1990, 55, 2552, optionally in the presence of a reducing agent (eg borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride) They are reacted together in the presence of an acid (eg, tetraisopropoxide titanate). The product 110.9 is then deprotected to give the triol 110.10. Which is converted to the 21-chloro analog 110.11.

  Using the above procedure, but using different formyl or hydroxyl substituted phosphonates and / or different amino substituted hydrazines, products similar to 110.7 and 110.11 are obtained. These functionalization procedures are interchangeable between pyrazole substrates 110.2 and 110.3.

  (Example 111)

これらのホスホネート（ここで、そのホスホネート基は、フェニル環およびアミド連鎖によって、結合している）の調製は、上で図示している。この手順では、ケトアルデヒド１０９．２は、上記のように、３−カルボキシフェニルヒドラジン１１１．１（Ａｐｉｎ）と反応されて、ピラゾール１１１．２および１１１．３が生成される。１’−置換異性体１１１．１は、ジシクロヘキシルカルボジイミドの存在下にて、ホスホン酸ジアルキル３−アミノフェニル１１１．４（Ａｕｒｏｒａ）と反応されて、アミド１１１．５が得られる。カルボン酸および誘導体からのアミドの調製は、例えば、「Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ」、Ｓ．Ｒ．ＳａｎｄｌｅｒおよびＷ．Ｋａｒｏ，Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９６８，２７４頁および「Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ」、Ｒ．Ｃ．Ｌａｒｏｃｋ，ＶＣＨ，１９８９，９７２ｆｆ頁で記述されている。このカルボン酸は、活性化剤（例えば、ジシクロヘキシルカルボジイミドまたはジイソプロピルカルボジイミド）の存在下にて、必要に応じて、例えば、ヒドロキシベンゾトリアゾール，Ｎ−ヒドロキシスクシンイミドまたはＮ−ヒドロキシピリドンの存在下にて、非プロトン性溶媒（例えば、ピリジン、ＤＭＦまたはジクロロメタン）中で、このアミンと反応されて、このアミドが得られる。

The preparation of these phosphonates, where the phosphonate group is attached by a phenyl ring and an amide linkage, is illustrated above. In this procedure, ketoaldehyde 109.2 is reacted with 3-carboxyphenylhydrazine 111.1 (Apin) as described above to produce pyrazoles 111.2 and 111.3. The 1′-substituted isomer 111.1 is reacted with dialkyl 3-aminophenyl 111.4 phosphonate 111.4 (Aurora) in the presence of dicyclohexylcarbodiimide to give amide 111.5. Preparation of amides from carboxylic acids and derivatives is described, for example, in “Organic Functional Group Preparations”, S.M. R. Sandler and W.W. Karo, Academic Press, 1968, p. 274 and “Comprehensive Organic Transformations”, R.A. C. Larock, VCH, 1989, pages 972ff. The carboxylic acid can be used in the presence of an activator (e.g., dicyclohexylcarbodiimide or diisopropylcarbodiimide) and optionally, e.g., in the presence of hydroxybenzotriazole, N-hydroxysuccinimide or N-hydroxypyridone. Reaction with the amine in a protic solvent such as pyridine, DMF or dichloromethane provides the amide.

  Alternatively, the carboxylic acid can be first converted to an activated derivative (eg, its acid chloride, anhydride, mixed anhydride, imidazolide, etc.) and then in the presence of an organic base (eg, pyridine), Reaction with the amine provides the amide.

  Conversion of the carboxylic acid to the corresponding acid chloride can be accomplished by reacting the carboxylic acid in an inert organic solvent (eg, dichloromethane), optionally in the presence of a catalytic amount of dimethylformamide, (eg, Can be caused by treatment with thionyl chloride or oxalyl chloride).

  The product is then deprotected to give triol 111.6, which is converted to 21-chloro compound 111.7.

  Alternatively, 2′-substituted pyrazole 111.3 is coupled with dialkylmethylaminomethyl 111.8 phosphonate as described above to give amidophosphonate 111.9, which is deprotected and formed The product is converted to the 21-chloro analog 111.11.

  Using the above procedure, but using different carboxy-substituted aralkyl, aryl or heteroarylalkoxyhydrazines and / or different dialkylamino-substituted phosphonates instead of carboxyphenylhydrazine 111.1, compounds 111.7 and 111.11 A product similar to is obtained.

  (Example 112)

これらのホスホン酸エステル（ここで、そのホスホネート基は、多様な炭素連鎖によって、結合されている）の調製は、上で図示している。この手順では、ケトアルデヒド１０９．２は、ヒドラジンと反応されて、ピラゾール誘導体１１２．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、周囲温度で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物１１２．２（ここで、Ｒ^２およびＸは、上で定義したとおりである）と反応されて、アルキル化生成物１１２．３および１１２．４が生成される。置換ピラゾールのアルキル化は、例えば、「Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ」、Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｌｏｎｇｍａｎ，１９９２，３０９頁で記述されている。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、ジメチルアミノピリジン、リチウムヘキサメチルジシラジドなど）の存在下にて、等モル量のこれらの基質の間で、実行される。生成物１１２．３および１１２．４は、Ｘがジアルキルホスホノである場合以外は、本明細書中で記述された手順を使用して、ホスホネート１１２．５および１１２．６に変換され、次いで、脱保護／アシル化すると、２１−クロロ化合物１１２．８および１１２．１０が得られる。

The preparation of these phosphonate esters, where the phosphonate groups are linked by various carbon linkages, is illustrated above. In this procedure, ketoaldehyde 109.2 is reacted with hydrazine to give pyrazole derivative 112.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc, 1964, 86, 1520. This reaction is carried out in acetic acid at ambient temperature. This pyrazole product is then reacted with bromomethyl compound 112.2, where R ² and X are as defined above to produce alkylated products 112.3 and 112.4. The Alkylation of substituted pyrazoles is described, for example, in “Heterocyclic Chemistry”, T.W. L. Gilchrist, Longman, 1992, page 309. This reaction is carried out between equimolar amounts of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.) Executed. Products 112.3 and 112.4 are converted to phosphonates 112.5 and 112.6 using the procedures described herein, except when X is a dialkylphosphono, then Deprotection / acylation yields 21-chloro compounds 112.8 and 112.10.

  (Example 113)

ピラゾール１１２．１は、テトラヒドロフラン溶液にて、上記のように、１モル当量のホスホン酸ジアルキルブロモブテニル１１３．１（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１）およびリチウムヘキサメチルジシラジドと反応されて、アルキル化ピラゾール１１３．２および１１３．３が得られる。脱保護の後に塩素化すると、２１−クロロ生成物１１３．５および１１３．７が生じる。

Pyrazole 112.1 was prepared in tetrahydrofuran solution as described above with 1 molar equivalent of dialkyl bromobutenyl phosphonate 113.1 (J. Med. Chem., 1992, 35, 1371) and lithium hexamethyldisilazide. To give alkylated pyrazoles 113.2 and 113.3. Chlorination after deprotection yields 21-chloro products 113.5 and 113.7.

  (Example 114)

ピラゾール１１２．１は、テトラヒドロフラン溶液中にて、上記のように、１，４−ジブロモブタ−２−イン１１４．１（Ａｌｄｒｉｃｈ）と反応されて、ピラゾール１１４．２および１１４．３が得られる。これらの生成物は、Ａｒｂｕｚｏｖ反応にかけられ、ここで、そのブロモメチル置換基は、１２０℃での亜リン酸トリアルキルとの反応により、ジアルキルホスホノメチル置換基に変換されて、その側鎖の脱保護および塩素化後、２１−クロロホスホネート１１４．５および１１４．７が調製される。このＡｒｂｕｚｏｖ反応は、Ｈａｎｄｂ．Ｏｒｇａｎｏｐｈｏｓｐｈｏｒｕｓ Ｃｈｅｍ．，１９９２，１１５−７２で記述されている。この手順では、その基質は、６０℃〜約１６０℃で、５〜５０倍モル過剰の亜リン酸トリアルキルと共に加熱される。上記手順を使用するが、二臭化物１１４．１に代えて、異なる二臭化物を使用して、１１４．５および１１４．７と類似した生成物が得られる。

Pyrazole 112.1 is reacted with 1,4-dibromobut-2-yne 114.1 (Aldrich) in tetrahydrofuran solution as described above to give pyrazoles 114.2 and 114.3. These products are subjected to an Arbuzov reaction, where the bromomethyl substituent is converted to a dialkylphosphonomethyl substituent by reaction with a trialkyl phosphite at 120 ° C. to remove the side chain. After protection and chlorination, 21-chlorophosphonate 114.5 and 114.7 are prepared. This Arbuzov reaction is described in Handb. Organophosphorus Chem. 1992, 115-72. In this procedure, the substrate is heated at 60 ° C. to about 160 ° C. with a 5-50 fold molar excess of trialkyl phosphite. Using the above procedure, but using different dibromides instead of dibromide 114.1, products similar to 114.5 and 114.7 are obtained.

  (Example 115)

ホスホネート基を有する本発明の化合物およびそれらの合成に有用な中間体化合物の調製は、本明細書中で図示している。β−ケトニトリル１１５．２は、クライゼン条件下にてマロノニトリルエステルと縮合することにより、フェニル酢酸１１５．１から産生される。ヒドロキシルアミンと反応させると、５−アミノ−１，２−オキサゾールが得られ、これは、シアノモルホリンと縮合すると、所望のＳＭＰ−１１４アナログが得られる。

The preparation of the compounds of the present invention having phosphonate groups and intermediate compounds useful for their synthesis are illustrated herein. β-Ketonitrile 115.2 is produced from phenylacetic acid 115.1 by condensation with malononitrile ester under Claisen conditions. Reaction with hydroxylamine gives 5-amino-1,2-oxazole, which when condensed with cyanomorpholine gives the desired SMP-114 analog.

  (Example 116)

アニソール誘導体１１６．１は、ルイス酸（例えば、三臭化ホウ素）で処理することにより、脱メチル化される。得られたフェノールは、Ｅ−１，４−ジブロモブテンでアルキル化され、得られた一臭化物は、溶媒（例えば、トルエン）中にて、（または他のＡｒｂｕｚｏｖ反応条件で：Ｅｎｇｅｌ，Ｒ．，「Ｓｙｎｔｈｅｓｉｓ ｏｆ Ｃａｒｂｏｎ−ｐｈｏｓｐｈｏｒｕｓ Ｂｏｎｄｓ」、ＣＲＣ ｐｒｅｓｓ，１９８８を参照）、亜リン酸トリエチルと共に加熱されて、所望のホスホン酸のジエチルエステル１１６．２が産生される。このカルボン酸エステルのケン化すると、ＳＭＰ−１１４アナログの合成に取り込む準備が出来ているフェニル酢酸が得られる。

Anisole derivative 116.1 is demethylated by treatment with a Lewis acid (eg, boron tribromide). The resulting phenol is alkylated with E-1,4-dibromobutene and the resulting monobromide is obtained in a solvent (eg, toluene) (or under other Arbuzov reaction conditions: Engel, R., "Synthesis of Carbon-phosphorus Bonds", CRC press, 1988), heated with triethyl phosphite to produce the diethyl ester 116.2 of the desired phosphonic acid. Saponification of this carboxylic acid ester yields phenylacetic acid ready to be incorporated into the synthesis of SMP-114 analogs.

  (Example 117)

本発明の化合物の調製は、１，４−ジブロモブテンを１，３−ジブロモプロパンで置き換えて、実施例１１６の手順で調製できる。

The compound of the invention can be prepared by the procedure of Example 116, replacing 1,4-dibromobutene with 1,3-dibromopropane.

  (Example 118)

ホモバニリン酸エチル１１８．１中の遊離フェノールは、トリフリト酸アリールに変換され、そのビフェニルモチーフは、フェニルボロン酸とのスズキカップリングにより、産生される（Ｃｈｅｍ．Ｒｅｖ．，１９９５，９５，２４５７を参照）。残りの工程は、実施例１１６で記述したものと類似している。

The free phenol in ethyl homovanillate 118.1 is converted to an aryl trifritate, and the biphenyl motif is produced by Suzuki coupling with phenylboronic acid (see Chem. Rev., 1995, 95, 2457). ). The remaining steps are similar to those described in Example 116.

  (Example 119)

４−ブロモフェニル酢酸エチルは、スズキ方法（上記参照のこと）を使用して、４−メトキシフェニルボロン酸とカップリングされる。残りの工程は、実施例１１６で記述したものと類似している。

Ethyl 4-bromophenylacetate is coupled with 4-methoxyphenylboronic acid using the Suzuki method (see above). The remaining steps are similar to those described in Example 116.

  (Example 120)

６α，９α−ジフルオロ−１６β−メチル−１１β，１７α，２１−トリヒドロキシプレグナ−１，４−ジエン−３，２１−ジオン１２０Ａ（米国特許第４，６１９，９２１号）は、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｔ．Ｗ．ＧｒｅｅｎｅおよびＰ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，第二版１９９０，２２３頁で記述されているように、パラホルムアルデヒドおよび酸触媒（例えば、塩酸）と反応されて、ＢＭＤ誘導体１２０．１が生じる。次いで、このホスホネート部分は、下記の手順を使用して導入され、ホスホン酸エステル１２０．２が生成される。次いで、このＢＭＤ部分は、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｔ．Ｗ．ＧｒｅｅｎｅおよびＰ．Ｇ．Ｍ．Ｗｕｔｓ，Ｗｉｌｅｙ，第二版１９９０，２２３頁で記述されているように、例えば、５０％酢酸水溶液で処理することにより加水分解されて、トリオール１２０．３が得られる。次いで、後者の化合物は、Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，１９８６，３４，１６１３で記述されている手順を使用して、１７，２１−環状オルトエステル１２０．４に変換される。この基質は、ジメチルホルムアミド中にて、７０℃で、２モル当量のオルトプロピオン酸トリエチルおよび触媒量のｐ−トルエンスルホン酸と反応される。次いで、その生成物は、ジメチルホルムアミド中にて、周囲温度で、過剰の塩化トリメチルシリルと反応されて、２１−クロロ１７−プロピオネート生成物１２０．５が生成される。

6α, 9α-difluoro-16β-methyl-11β, 17α, 21-trihydroxypregna-1,4-diene-3,21-dione 120A (US Pat. No. 4,619,921) is described in “Protective Groups in Organic Synthesis ", T.W. W. Greene and P.M. G. M.M. As described in Wuts, Wiley, 2nd edition, 1990, page 223, it is reacted with paraformaldehyde and an acid catalyst (eg hydrochloric acid) to give the BMD derivative 120.1. This phosphonate moiety is then introduced using the following procedure to produce the phosphonate ester 120.2. This BMD portion is then described in “Protective Groups in Organic Synthesis”, T.M. W. Greene and P.M. G. M.M. As described in Wuts, Wiley, 2nd edition, 1990, page 223, the triol 120.3 is obtained by hydrolysis, for example by treatment with a 50% aqueous acetic acid solution. The latter compound is then described in Chem. Pharm. Bull. , 1986, 34, 1613, is converted to the 17,21-cyclic orthoester 120.4. This 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 produce the 21-chloro 17-propionate product 120.5.

  Alternatively, the substrate 120.3 is Med. Chem. (1987), 30: 1581, is converted to the product 120.5. In this procedure, the 21-hydroxyl group is activated by conversion to 21-mesylate by reaction with mesyl chloride in pyridine; the mesylate group is then reacted with lithium chloride in dimethylformamide. To give a 21-chloro intermediate, whose 17-hydroxyl group is esterified to give the 21-chloro-17-propionate derivative 120.5. 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.

  (Example 121)

ＢＭＤ保護誘導体１２０．１は、アミンまたはヒドロキシルアミン１２１．１（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルまたはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールまたはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）またはアルコール溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、このイミンまたはオキシムが得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、このＢＭＤ保護側鎖化合物１２１．２は、上記のように、トリオール１２１．３に変換され、次いで、２１−クロロ１７−プロピオネート生成物１２１．４に変換される。

The BMD protected derivative 120.1 is an amine or hydroxylamine 121.1 (where R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally contains a heteroatom O, S or N). Or a functional group (such as amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O, S or And X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcohol solvent (eg, ethanol), optionally in the presence of an acid catalyst. This imine or oxime is obtained. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. This BMD protected side chain compound 121.2 is then converted to the triol 121.3 as described above and then to the 21-chloro 17-propionate product 121.4.

ホスホネート基を含むヒドロキシルアミンエーテルの調製は、上で図示している。ホスホネート１２１．５（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン１２１．６（Ａｌｄｒｉｃｈ）と反応されて、エーテル１２１．７が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル１２１．８が得られる。

The preparation of hydroxylamine ethers containing phosphonate groups is illustrated above. Phosphonate 121.5 (where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 121.6 (Aldrich) to give ether 121.7. Generated. This reaction is performed between equimolar amounts of the reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine). Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 121.8.

  (Example 122)

基質１２０．１は、ジアルキルホスホノメチルヒドロキシルアミン１２２．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロエチルスルホニルオキシメチル（Ｔｅｔ．Ｌｅｔｔ．，１９８６，２７，：１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシム１２２．２が得られる。次いで、脱保護すると、トリオール１２２．３が得られ、そこから、２１−クロロ１７−プロピオネート化合物１２２．４が調製される。このオキシム形成反応は、周囲温度で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。

Substrate 120.1 is dialkylphosphonomethylhydroxylamine 122.1, which is a dialkyltrifluoroethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27 ,: 1477) and BOC-hydroxyl as described above. Prepared from the amine) to give the oxime 122.2. Deprotection then affords the triol 122.3, from which the 21-chloro 17-propionate compound 122.4 is prepared. This oxime formation reaction is carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at ambient temperature.

  Using the above procedure, but using a different oxime ether 121.1 instead of hydroxylamine ether 122.1, the corresponding product 121.4 is obtained.

  (Example 123)

ジエノン１２１．１は、上記のように、Ｏ−（４−ブロモ−２−チエニルメトキシ）ヒドロキシルアミン１２３．１（これは、上記のように、４−ブロモ−２−ブロモメチルチオフェンから調製した（ＷＯ ９４／２０４５６））およびＢＯＣ−保護ヒドロキシルアミンと反応されて、その側鎖の脱保護後、オキシム１２３．２が得られる。次いで、この生成物は、パラジウム触媒の存在下にて、リン酸ジアルキル１２３．３と反応されて、ホスホネート１２３．４が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。次いで、この２１−水酸基１２３．４は、本明細書中で記述されているように、２１−クロロ１７−プロピオネート誘導体１２３．５に変換される。

Dienone 121.1 was prepared as described above from O- (4-bromo-2-thienylmethoxy) hydroxylamine 123.1 (which was prepared from 4-bromo-2-bromomethylthiophene as described above ( WO 94/20456)) and BOC-protected hydroxylamine to give oxime 123.2 after deprotection of its side chain. This product is then reacted with a dialkyl phosphate 123.3 in the presence of a palladium catalyst to give the phosphonate 123.4. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0). This 21-hydroxyl group 123.4 is then converted to the 21-chloro 17-propionate derivative 123.5 as described herein.

  Alternatively, bromo product 123.2 is coupled with dialkylbutenyl phosphonate 123.6 (Org. Lett. 2001, 3, 217) to give phosphonate 123.7. The coupling of aryl halides and olefins by this Heck reaction is described in, for example, A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry 503ff (Plenum, 2001) and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)), optionally in the presence of a base (eg triethylamine or potassium carbonate). If necessary, the styrenoid double bond present in the product 123.7 is reduced, for example by reaction with diimide, to produce the saturated analog 123.9. Reduction of olefinic bonds is described in R.A. C. Larock, Comprehensive Organic Transformations 6ff (VCH 1989). This conversion is performed, for example, by catalytic hydrogenation using a palladium on carbon catalyst and hydrogen or hydrogen donor, or by using diimide or diborane. Products 123.7 and 123.9 are then converted to 21-chloro 17-propionate analogs 123.8 and 123.10.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromothienylmethoxy reagent 123.1, compounds 123.5, 123.8 And a product similar to 123.10 is obtained.

  (Example 124)

基質１２１．１は、ホスホン酸ジアルキル４−アミノ−２−チエニル１２４．１（これは、上記のように、４−アミノ−２−ブロモチオフェン（Ｔｅｔ．１９８７，４３，３２９５）と亜リン酸ジアルキルとの間のパラジウム触媒カップリングにより、調製される）と反応されて、脱保護後、イミン生成物１２４．２が得られる。このイミン形成反応は、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われる。次いで、この生成物は、２１−クロロ１７−プロピオネート化合物１２４．３に変換される。

Substrate 121.1 is a dialkyl 4-amino-2-thienyl phosphonate 124.1 (which, as described above, is 4-amino-2-bromothiophene (Tet. 1987, 43, 3295) and dialkyl phosphite. Prepared by palladium-catalyzed coupling between and after deprotection to give imine product 124.2. This imine formation reaction is carried out in a hydrocarbon solvent (eg toluene or xylene) at reflux temperature in the presence of a basic catalyst (eg sodium methoxide) or an acidic catalyst (eg p-toluenesulfonic acid). And conducted under azeotropic conditions. This product is then converted to the 21-chloro 17-propionate compound 124.3.

  Using the above procedure, but using a different amino substituted aryl phosphonate or heteroaryl phosphonate instead of 4-aminothienyl phosphonate 124.1, a product similar to 124.3 is obtained.

  (Example 125)

ジエノン１２１．１は、Ｏ−（４−アミノブチル）ヒドロキシルアミン１２５．１（Ｐｏｌ．Ｊ．Ｃｈｅｍ．１９８１，５５，１１６３）と反応されて、オキシム１２５．２が生じる。ステロイド性１，４−ジエン−３−オンと置換ヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている；この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物間で実行される。次いで、この生成物は、ホスホン酸ジアルキル２−ヒドロキシエチル１２５．３（Ｅｐｓｉｌｏｎ）およびカルボニルジイミダゾールと反応されて、カーバメートキシム１２５．４が生じる。カーバメートの調製は、Ａ．Ｒ．Ｋａｔｒｉｔｚｋｙ，Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ，６，４１６ｆｆ（Ｐｅｒｇａｍｏｎ，１９９５）およびＳ．Ｒ．ＳａｎｄｌｅｒおよびＷ．Ｋａｒｏ，Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ，２６０ｆｆ（Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９８６）で記述されている。この手順では、このアミンは、不活性非プロトン性溶媒（例えば、ジクロロメタンまたはテトラヒドロフラン）中にて、ホスゲンおよびそれらの官能性等価物（例えば、カルボニルジイミダゾール、トリホスゲン、ペンタフルオロフェニルカーボネートなど）と反応されて、対応する活性化アシルアミンが得られる。次いで、後者の化合物は、アルコールと反応されて、そのカーバメートが生じる。次いで、カーバメート生成物１２５．４は、ここで記述されているように、２１−クロロ１７−プロピオネート生成物１２５．６に変換される。

Dienone 121.1 is reacted with O- (4-aminobutyl) hydroxylamine 125.1 (Pol. J. Chem. 1981, 55, 1163) to give oxime 125.2. The reaction of steroidal 1,4-dien-3-one with substituted hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795; this reaction is carried out in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate, and equimolar amounts of the reactants. Executed between. This product is then reacted with dialkyl 2-hydroxyethyl phosphonate 125.3 (Epsilon) and carbonyldiimidazole to give carbamate oxime 125.4. The preparation of carbamate is described in A. R. Katritzky, Comprehensive Organic Functional Group Transformations, 6,416ff (Pergamon, 1995) and S.R. R. Sandler and W.W. Karo, Organic Functional Group Preparations, 260ff (Academic Press, 1986). In this procedure, the amine is reacted with phosgene and their functional equivalents (eg, carbonyldiimidazole, triphosgene, pentafluorophenyl carbonate, etc.) in an inert aprotic solvent (eg, dichloromethane or tetrahydrofuran). To obtain the corresponding activated acylamine. The latter compound is then reacted with an alcohol to produce its carbamate. The carbamate product 125.4 is then converted to the 21-chloro 17-propionate product 125.6 as described herein.

  Using the above procedure, but using a different amino substituted hydroxylamine and / or a different hydroxy substituted phosphonate instead of hydroxylamine 125.3, a product similar to 125.6 is obtained.

  (Example 126)

ＢＭＤ保護ジエノン１２１．１は、還元されて、１，２−ジヒドロ生成物１２６．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物１２６．２が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジン１２６．３（ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応により、異性体２’−アリールピラゾール１２６．４および１’−アリールピラゾール１２６．５が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物の間で実行される。次いで、ピラゾール１２６．４および１２６．５は、例えば、実施例１２２および１２３で記述された手順により、ＢＭＤ保護中間体１２６．６および１２６．７を経由して、２１−クロロ１７−プロピオネートホスホネート１２６．９および１２６．１１に変換される。

BMD protected dienone 121.1 is reduced to give 1,2-dihydro product 126.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. The product is then Am. Chem. Soc. , 1964, 86, 1520, reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product. 126.2 is obtained. This compound is then reacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 126.3, where substituent X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent. The For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2′-arylpyrazole 126.4 and 1′-arylpyrazole 126.5. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). Pyrazole 126.4 and 126.5 can then be converted to 21-chloro 17-propionate via BMD protected intermediates 126.6 and 126.7, for example, by the procedure described in Examples 122 and 123. Converted to phosphonates 126.9 and 126.11.

  (Example 127)

ケトアルデヒド１２６．２は、上記のように、３−カルボキシプロピルヒドラジン１２７．１（Ｉｎｄ．Ｊ．Ｅｘｐ．Ｂｉｏｌ．１９９４，３２，２１８）と反応されて、ピラゾール１２７．２および１２７．３が得られる。次いで、２’−置換異性体１２７．２は、ジメチルホルムアミド溶液中にて、周囲温度で、１モル当量のホスホン酸ジアルキル４−アミノフェニル１２７．４（Ｅｐｓｉｌｏｎ）およびジシクロヘキシルカルボジイミドと反応されて、アミド１２７．５が生じる。カルボン酸および誘導体からのアミドの調製は、例えば、Ｓ．Ｒ．ＳａｎｄｌｅｒおよびＷ．Ｋａｒｏ，Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ，２７４（Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９６８）およびＲ．Ｃ．Ｌａｒｏｃｋ，Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ，９７２ｆｆ（ＶＣＨ，１９８９）で記述されている。このカルボン酸は、活性化剤（例えば、ジシクロヘキシルカルボジイミドまたはジイソプロピルカルボジイミド）の存在下にて、必要に応じて、例えば、ヒドロキシベンズトリアゾール、Ｎ−ヒドロキシスクシンイミドまたはＮ−ヒドロキシピリドンの存在下にて、非プロトン性溶媒（例えば、ピリジン、ＤＭＦまたはジクロロメタン）中で、このアミンと反応されて、このアミドが得られる。

Ketoaldehyde 126.2 is reacted with 3-carboxypropylhydrazine 127.1 (Ind. J. Exp. Biol. 1994, 32, 218) to give pyrazoles 127.2 and 127.3 as described above. It is done. The 2'-substituted isomer 127.2 is then reacted with 1 molar equivalent of dialkyl 4-aminophenyl phosphonate 127.4 (Epsilon) and dicyclohexylcarbodiimide in dimethylformamide solution at ambient temperature to give the amide 127.5 results. Preparation of amides from carboxylic acids and derivatives is described, for example, in S.H. R. Sandler and W.W. Karo, Organic Functional Group Preparations, 274 (Academic Press, 1968) and R.A. C. Larock, Comprehensive Organic Transformations, 972ff (VCH, 1989). The carboxylic acid can be used in the presence of an activator (e.g., dicyclohexylcarbodiimide or diisopropylcarbodiimide), optionally in the presence of, for example, hydroxybenztriazole, N-hydroxysuccinimide, or N-hydroxypyridone. Reaction with the amine in a protic solvent such as pyridine, DMF or dichloromethane provides the amide.

  Alternatively, the carboxylic acid is first converted to an activated derivative (eg, its acid chloride, anhydride, mixed anhydride, imidazolide, etc.) and then in the presence of an organic base (eg, pyridine) Reaction with an amine gives this amide.

  Conversion of the carboxylic acid to the corresponding acid chloride can be accomplished by reacting the carboxylic acid in an inert organic solvent (eg, dichloromethane), optionally in the presence of a catalytic amount of dimethylformamide, (eg, Caused by treatment with thionyl chloride or oxalyl chloride). The BMD protecting group is then removed and the product is converted to the 21-chloro 17-propionate product 127.7.

  1'-substituted pyrazole 127.3 is coupled with dialkylaminomethyl 127.8 (Interchim) phosphonate as described above to give amide 127.9. The product 127.9 is then deprotected to give the triol 127.10, the latter compound being converted to 21-chloro 17-propionate 127.11.

  Using the above procedure, but using different amino substituted phosphonates, and / or different carboxy substituted hydrazines, products similar to 127.7 and 127.11 are obtained. These functionalization procedures are interchangeable between the pyrazole substrates 127.2 and 127.3.

  (Example 128)

ケトアルデヒド１２６．２は、上記のように、アリルヒドラジン１２８．１（Ｚｈ．Ｏｒｇ．Ｋｈｉｍ．，１９６７，３，９８３）と反応されて、ピラゾール１２８．２および１２８．３が生成される。本明細書中で記載のように、１’−置換異性体１２８．２は、ホスホン酸ジアルキル３−ブロモフェニル１２８．４（Ｅｐｓｉｌｏｎ）とカップリングされて、ホスホネート１２８．５が得られる。次いで、この生成物は、脱保護されて、トリオール１２８．６が得られ、これは、２１−クロロ１７−プロピオネート化合物１２８．７に変換される。

Ketoaldehyde 126.2 is reacted with allylhydrazine 128.1 (Zh. Org. Khim., 1967, 3,983) as described above to produce pyrazoles 128.2 and 128.3. As described herein, 1'-substituted isomer 128.2 is coupled with dialkyl 3-bromophenyl 128.4 (Epsilon) phosphonate to give phosphonate 128.5. The product is then deprotected to give the triol 128.6, which is converted to the 21-chloro 17-propionate compound 128.7.

  2′-substituted pyrazole 128.3 is coupled with dialkyl 5-bromo-2-thienyl phosphonate 128.8 (Syn., 2003, 455) as described above to prepare phosphonate 128.9, This is deprotected and the product is converted to the 21-chloro 17-propionate analog 128.11.

  Using the above procedure, but using different alkenyl hydrazines and / or different dialkyl bromo-substituted phosphonates instead of propenyl hydrazine 128.1, products similar to compounds 128.7 and 128.11 are obtained.

  (Example 129)

ケトアルデヒド１２６．２は、ヒドラジンと反応されて、ピラゾール誘導体１２９．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、室温で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物１２９．２（ここで、Ｒ^２およびＸは、上で定義したとおりである）と反応されて、アルキル化生成物１２９．３および１２９．４が生成される。置換ピラゾールのアルキル化は、例えば、Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ，３０９（Ｌｏｎｇｍａｎ，１９９２）で記述されている。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、ジメチルアミノピリジン、リチウムヘキサメチルジシラジドなど）の存在下にて、等モル量のこれらの基質の間で、実行される。生成物１２９．３および１２９．４は、Ｘがジアルキルホスホノである場合以外は、本明細書中で記述された手順を使用して、ホスホネート１２９．５および１２９．６に変換され、次いで、脱保護／塩素化／アシル化すると、２１−クロロ１７−プロピオネート化合物１２９．８および１２９．１０が得られる。

Ketoaldehyde 126.2 is reacted with hydrazine to give pyrazole derivative 129.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc, 1964, 86, 1520. This reaction is carried out in acetic acid at room temperature. This pyrazole product is then reacted with bromomethyl compound 129.2 where R ² and X are as defined above to produce alkylated products 129.3 and 129.4. The Alkylation of substituted pyrazoles is described, for example, in T.W. L. Gilchrist, Heterocyclic Chemistry, 309 (Longman, 1992). This reaction is carried out between equimolar amounts of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.) Executed. Products 129.3 and 129.4 are converted to phosphonates 129.5 and 129.6 using the procedures described herein except when X is a dialkylphosphono, then Deprotection / chlorination / acylation yields 21-chloro 17-propionate compounds 129.8 and 129.10.

  (Example 130)

実施例１２９で記述した手順に従って、ピラゾール１２９．１は、臭化２−ブロモベンジル１３０．１と反応されて、ピラゾール１３０．２および１３０．３が得られる。次いで、これらの生成物は、上記のように、亜リン酸ジアルキルとカップリングされて、本明細書中で記載のように、側鎖脱保護および変性後、２１−クロロ１７−プロピオネート１３０．５および１３０．７が得られる。

Following the procedure described in Example 129, pyrazole 129.1 is reacted with 2-bromobenzyl bromide 130.1 to give pyrazoles 130.2 and 130.3. These products are then coupled with dialkyl phosphites, as described above, and after side chain deprotection and modification as described herein, 21-chloro 17-propionate 130.5. And 130.7 are obtained.

  (Example 131)

実施例１２９で記述した手順に従って、ピラゾール１２９．１は、テトラヒドロフラン溶液中にて、４−ブロモメチルシクロヘキサノン１３１．１（ＷＯ ９７／３７９５９）と反応されて、アルキル化生成物１３１．２および１３１．３が得られる。次いで、１’−置換異性体１３１．２は、還元アミノ化反応において、ホスホン酸ジアルキルアミノメチル１３１．８（Ｉｎｔｅｒｃｈｉｍ）およびシアノホウ水素化ナトリウムと反応されて、脱保護および側鎖変性後、２１−クロロ１７−プロピオネート１３１．５が生じる。

Following the procedure described in Example 129, pyrazole 129.1 was reacted with 4-bromomethylcyclohexanone 131.1 (WO 97/37959) in tetrahydrofuran solution to give alkylated products 131.2 and 131. 3 is obtained. The 1'-substituted isomer 131.2 is then reacted in a reductive amination reaction with dialkylaminomethyl phosphonate 131.8 (Interchim) and sodium cyanoborohydride, after deprotection and side chain modification, 21- Chloro 17-propionate 131.5 is formed.

  Preparation of amines by reductive amination procedures is described, for example, in R.A. C. Larock, Comprehensive Organic Transformations, 421 (VCH, 1989) and F.R. A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry, Part B, 269 (Plenum, 2001). In this procedure, the amine component and the aldehyde or ketone component are Org. Chem. , 1990, 55, 2552, optionally in the presence of a reducing agent (eg borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride) They are reacted together in the presence of an acid (eg, tetraisopropyl titanate).

  The 2'-substituted pyrazole 131.3 is subjected to the same series of reactions to give the amine phosphonate 131.7.

  Using the above procedure, but using different bromomethyl substituted aldehydes or ketones and / or different amino substituted phosphonates, products similar to 131.5 and 131.7 are obtained.

  (Example 132)

シクレソニド１３２Ａ（米国特許第５，４８２，９３４号）の２０−ケトン基が保護されて、誘導体１３２．１が得られる保護−脱保護配列。このケトンは、例えば、その環状エチレンケタールに変換することにより、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９５５，７７，１９０４で記述されているように、トルエン溶液中にて、還流温度で、エチレングリコールおよび酸触媒と反応させることにより、保護される。脱保護は、Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｃｈｅｍ．Ｃｏｍｍ．，１９８７，１３５１で記述されているように、アセトン水溶液中にて、ピリジニウムトシレートと反応させることにより、引き起こされる。

A protection-deprotection sequence in which the 20-ketone group of ciclesonide 132A (US Pat. No. 5,482,934) is protected to give derivative 132.1. This ketone can be obtained, for example, by converting it to its cyclic ethylene ketal. Am. Chem. Soc. , 1955, 77, 1904, by reaction with ethylene glycol and an acid catalyst in a toluene solution at reflux temperature. Deprotection is described in J. Org. Chem. Soc. Chem. Comm. , 1987, 1351, by reacting with pyridinium tosylate in an aqueous acetone solution.

  Alternatively, the 20-ketone is protected by conversion to N, N-dimethylhydrazone. This dimethylhydrazone can be obtained from Org. Syn. , 1970, 50, 102, by reaction of ketone 132A with N, N-dimethylhydrazine in ethanol-acetic acid. This group is described in J. Org. Am. Chem. Soc. , 1979, 101, 5841, by treatment with sodium acetate and acetic acid in aqueous tetrahydrofuran.

  Alternatively, the 20-ketone is protected as the diethylamine adduct. In this procedure, substrate 132A is Chem. Soc. Chem. Comm. , 1983, 406, and reacted with titanium tetrakis (diethylamide) to give this adduct. This ketone is deprotected by reacting with water in an aqueous organic solvent.

  The protected compound 132.1 is then converted to the phosphonate-containing analog 132.2 using the following procedure, and the protecting group is then removed as described above to give the phosphonate 132.3. .

  (Example 133)

保護誘導体１３３．１は、アミンまたはヒドロキシルアミン１３３．２（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルまたはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールもしくはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシなどである。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）または含アルコール溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、イミンまたはオキシム１３３．３が得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、この保護基は、本明細書中に記載のように除去されて、２０−ケトホスホネート生成物１３３．４が得られる。

The protected derivative 133.1 is an amine or hydroxylamine 133.2, where R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally includes a heteroatom O, S or N ), Or a functional group (such as an amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O, S or N And X is either 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. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcohol-containing solvent (eg, ethanol), optionally in the presence of an acid catalyst. Thus, imine or oxime 133.3 is obtained. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. The protecting group is then removed as described herein to give the 20-ketophosphonate product 133.4.

  (Example 133A)

ホスホネート基を含むヒドロキシルアミンエーテルの調製は、本明細書中で図示している。この手順では、ホスホネート１３３．５（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン１３３．６（Ａｌｄｒｉｃｈ）と反応されて、エーテル１３３．７が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル１３３．８が得られる。上記手順はまた、置換ヒドロキシルアミン（これらは、ホスホネートの前駆体である）を調製するのに使用される。

The preparation of hydroxylamine ethers containing phosphonate groups is illustrated herein. In this procedure, the phosphonate 133.5 (where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 133.6 (Aldrich) to give an ether 133.7 is generated. This reaction is performed between equimolar amounts of the reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine). Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 133.8. The above procedure is also used to prepare substituted hydroxylamines, which are precursors of phosphonates.

  (Example 134)

基質１３３．１（ここで、その２０−ケトンは、ジメチルヒドラゾン誘導体として、保護されている）は、ジアルキルホスホノメチルヒドロキシルアミン１３３．８（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシム１３４．２が得られる。次いで実施例１３２で記述されているように、脱保護すると、２０−ケトホスホネート１３４．３が得られる。このオキシム形成反応は、室温で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。

Substrate 133.1 (where the 20-ketone is protected as a dimethylhydrazone derivative) is a dialkylphosphonomethylhydroxylamine 133.8 (which is a dialkyltrifluoromethyl phosphonate as described above). Reaction with sulfonyloxymethyl (prepared from Tetrahedron Lett., 1986, 27, 1477) and BOC-hydroxylamine) provides oxime 134.2. Deprotection then yields 20-ketophosphonate 134.3 as described in Example 132. This oxime formation reaction is carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at room temperature.

  Using the above procedure, but using a different oxime ether 133.2 instead of hydroxylamine ether 133.8, the corresponding product 133.4 is obtained.

  (Example 135)

ジエノン１３３．１（ここで、この２０−ケトンは、ジメチルヒドラゾンとして保護される）は、上記のように、Ｏ−（４−ブロモベンジルオキシ）ヒドロキシルアミン１３５．１（これは、上記のように、臭化４−ブロモベンジルおよびＢＯＣ−保護ヒドロキシルアミン１３３．６から調製した）と反応されて、オキシム１３５．２が得られる。次いで、この保護基は、除去されて、２０−ケト生成物１３５．３が生じる。次いで、後者の生成物は、パラジウム触媒の存在下にて、リン酸ジアルキル１３５．４と反応されて、ホスホネート１３５．５が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、約１００℃で、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。

Dienone 133.1 (where the 20-ketone is protected as a dimethylhydrazone) is, as above, O- (4-bromobenzyloxy) hydroxylamine 135.1 (as above). , Prepared from 4-bromobenzyl bromide and BOC-protected hydroxylamine 133.6) to give oxime 135.2. The protecting group is then removed to yield the 20-keto product 135.3. The latter product is then reacted with a dialkyl phosphate 135.4 in the presence of a palladium catalyst to give the phosphonate 135.5. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed at about 100 ° C. in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0).

  Alternatively, bromo compound 135.3 is coupled with dialkyl vinyl phosphonate 135.6 (Aldrich) to give phosphonate 135.7. The coupling of aryl halides and olefins by this Heck reaction is described in, for example, A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry 503ff (Plenum, 2001) and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)) and optionally in the presence of a base such as triethylamine or potassium carbonate. Optionally, the styrenoid double bond present in the product 135.7 is reduced, for example by reaction with diimide, to produce the saturated analog 135.8. Reduction of olefinic bonds is described in R.A. C. Larock, Comprehensive Organic Transformations 6ff (VCH 1989). This conversion is performed, for example, by catalytic hydrogenation using a palladium-on-carbon catalyst and hydrogen or hydrogen donor, or by using diimide or diborane.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromobenzyloxy reagent 135.1, compounds 135.5, 135.7 And products similar to 135.8 are obtained.

  (Example 136)

基質１３３．１（ここで、その２０−ケトンは、ジメチルヒドラゾンとして、保護されている）は、ホスホン酸ジアルキル４−アミノ−２−フリル１３６．１（これは、上記のように、４−アミノ−２−ブロモフラン（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８７，４３，３２９５）および亜リン酸ジアルキルの間のパラジウム触媒カップリング反応により、調製した）と反応されて、脱保護後、イミン生成物１３６．２が得られる。このイミン形成反応は、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われる。

Substrate 133.1 (where the 20-ketone is protected as dimethylhydrazone) is a dialkyl 4-amino-2-furyl phosphonate 136.1 (as described above, 4-amino 2-bromofuran (prepared by palladium-catalyzed coupling reaction between Tetrahedron Lett., 1987, 43, 3295) and dialkyl phosphite to give imine product 136.2 after deprotection. It is done. This imine formation reaction is carried out in a hydrocarbon solvent (eg toluene or xylene) at reflux temperature in the presence of a basic catalyst (eg sodium methoxide) or an acidic catalyst (eg p-toluenesulfonic acid). And conducted under azeotropic conditions.

  Using the above procedure, but using a different amino-substituted aryl phosphonate or heteroaryl phosphonate instead of 4-amino-2-furyl phosphonate 136.1, a product similar to 136.2 is obtained.

  (Example 137)

ジエノン１３３．１（ここで、この２０−ケトンは、ジメチルヒドラゾンとして保護される）は、Ｏ−（２−カルボキシエチル）ヒドロキシルアミン１３７．１（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９０，３３，１４２３）と反応されて、オキシム１３７．２が生じる。ステロイド性１，４−ジエン−３−オンと置換ヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている；この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物の間で実行される。次いで、生成物１３７．２は、ホスホン酸ジアルキル４−アミノフェニル１３７．３（Ｅｐｓｉｌｏｎ）およびジシクロヘキシルカルボジイミドとカップリングされて、脱保護後、アミドオキシム１３７．４が生じる。カルボン酸および誘導体からのアミドの調製は、例えば、Ｓ．Ｒ．ＳａｎｄｌｅｒおよびＷ．Ｋａｒｏ，Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ ２７４（Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９６８）ならびにＲ．Ｃ．Ｌａｒｏｃｋ，Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ ９７２ｆｆ（ＶＣＨ，１９８９）で記述されている。このカルボン酸は、活性化剤（例えば、ジシクロヘキシルカルボジイミドまたはジイソプロピルカルボジイミド）の存在下にて、必要に応じて、例えば、ヒドロキシベンゾトリアゾール、Ｎ−ヒドロキシスクシンイミドまたはＮ−ヒドロキシピリドンの存在下にて、非プロトン性溶媒（例えば、ピリジン、ＤＭＦまたはジクロロメタン）中で、このアミンと反応されて、このアミドが得られる。

Dienone 133.1 (where the 20-ketone is protected as dimethylhydrazone) is O- (2-carboxyethyl) hydroxylamine 137.1 (J. Med. Chem., 1990, 33, 1423). To give oxime 137.2. The reaction of steroidal 1,4-dien-3-one with substituted hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795; this reaction is carried out in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate, and equimolar amounts of the reactants. Executed between. The product 137.2 is then coupled with dialkyl 4-aminophenyl 137.3 (Epsilon) phosphonate and dicyclohexylcarbodiimide to yield the amide oxime 137.4 after deprotection. Preparation of amides from carboxylic acids and derivatives is described, for example, in S.H. R. Sandler and W.W. Karo, Organic Functional Group Preparations 274 (Academic Press, 1968) and R.A. C. Larock, Comprehensive Organic Transformations 972ff (VCH, 1989). The carboxylic acid can be used in the presence of an activator (e.g., dicyclohexylcarbodiimide or diisopropylcarbodiimide), optionally in the presence of, for example, hydroxybenzotriazole, N-hydroxysuccinimide, or N-hydroxypyridone. Reaction with the amine in a protic solvent such as pyridine, DMF or dichloromethane provides the amide.

  Alternatively, the carboxylic acid can be first converted to an activated derivative (eg, its acid chloride, anhydride, mixed anhydride, imidazolide, etc.) and then in the presence of an organic base (eg, pyridine), Reaction with the amine provides the amide.

  Conversion of the carboxylic acid to the corresponding acid chloride can be accomplished by reacting the carboxylic acid in an inert organic solvent (eg, dichloromethane), optionally in the presence of a catalytic amount of dimethylformamide, (eg, Can be caused by treatment with thionyl chloride or oxalyl chloride).

  Using the above procedure, but using a different carboxy-substituted hydroxylamine and / or a different amino-substituted phosphonate instead of carboxy-substituted hydroxylamine 137.1, a product similar to 137.4 is obtained.

  (Example 138)

ジエノン１３２Ａは、還元されて、１，２−ジヒドロ生成物１３８．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物１３８．２が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジン１３８．３（ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応により、異性体２’−および１’−アリールピラゾール１３８．４および１３８．５が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物の間で実行される。次いで、ピラゾール１３８．４および１３．５は、例えば、実施例１３９に記載される手順によって、ホスホネート１３８．６および１３８．７に変換される。

Dienone 132A is reduced to give the 1,2-dihydro product 138.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. The product is then Am. Chem. Soc. , 1964, 86, 1520, reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product. 138.2 is obtained. This compound is then reacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 138.3, where substituent X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent. The For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2'- and 1'-arylpyrazoles 138.4 and 138.5. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). Pyrazole 138.4 and 13.5 are then converted to phosphonates 138.6 and 138.7, for example, by the procedure described in Example 139.

  (Example 139)

ケトアルデヒド１３８．２は、上記のように、４−ヒドロキシフェニルヒドラジン１３９．１（ＥＰ ４３７１０５）と反応されて、ピラゾール１３９．２および１３９．３が得られる。次いで、２’−置換異性体１３９．２は、ジメチルホルムアミド溶液中にて、約７０℃で、ホスホン酸ジアルキルブロモブテニル１３９．４（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１）および炭酸カリウムと反応されて、エーテルホスホネート１３９．５が生じる。

Ketoaldehyde 138.2 is reacted with 4-hydroxyphenylhydrazine 139.1 (EP 437105) as described above to give pyrazoles 139.2 and 139.3. The 2′-substituted isomer 139.2 is then converted to dialkyl bromobutenyl phosphonate 139.4 (J. Med. Chem., 1992, 35, 1371) and carbonic acid in dimethylformamide solution at about 70 ° C. Reacted with potassium to give ether phosphonate 139.5.

  The isomer pyrazole 139.3 is reacted with dialkyl mercaptomethyl phosphonate 139.6 (J. Med. Chem., 1985, 26, 1688) in the Mitsunobu reaction to give the thioether phosphonate 139.7. Preparation of aromatic ethers and thioethers by Mitsunobu reaction is described in, for example, R.A. C. Larock, Comprehensive Organic Transformations 448 (VCH, 1989), F.M. A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry, Part B 153-4 (Plenum, 2001) and Org. React. 1992, 42, 335. The phenol and alcohol or thiol component are reacted together in the presence of a dialkyl azodicarboxylate and a triarylphosphine in an aprotic solvent (eg, tetrahydrofuran) to give their ether or thioether product. . This procedure is also described in Org. React. 1992, 42, 335-656.

  Using the above procedure, but using different hydroxy-substituted hydrazines and / or different bromo- or mercapto-substituted phosphonates, products similar to 139.5 and 139.7 are obtained.

  (Example 140)

ケトアルデヒド１３８．２は、上記のように、４−アミノフェニルヒドラジン１４０．１（Ｅｐｓｉｌｏｎ）と反応されて、ピラゾール１４０．２および１４０．３が生成される。２’−置換異性体１４０．２は、上記のように、ジアルキルホスホノ酢酸１４０．４（Ａｌｄｒｉｃｈ）およびジシクロヘキシルカルボジイミドとカップリングされて、アミドホスホネート１４０．５が得られる。

Ketoaldehyde 138.2 is reacted with 4-aminophenylhydrazine 140.1 (Epsilon) to produce pyrazoles 140.2 and 140.3 as described above. The 2'-substituted isomer 140.2 is coupled with dialkylphosphonoacetic acid 140.4 (Aldrich) and dicyclohexylcarbodiimide as described above to give the amide phosphonate 140.5.

  Alternatively, 1′-substituted pyrazole 140.3 is reacted with dialkyl 3-hydroxypropyl phosphonate 140.6 (Zh. Obschei. Khim., 1973, 43, 2364) and carbonyldiimidazole to form carbamate phosphonate 140.7. Is prepared. The preparation of carbamate is described in Comprehensive Organic Functional Group Transformations Vol. 6 416ff (AR Katritzky, (ed.), Pergamon, 1995) and S. R. Sandler and W.W. Karo, Organic Functional Group Preparations 260ff (Academic Press, 1986). In this procedure, the amine is reacted with phosgene or a functional equivalent thereof (eg, carbonyldiimidazole, triphosgene, pentafluorophenyl carbonate, etc.) in an inert aprotic solvent (eg, dichloromethane or tetrahydrofuran). To obtain the corresponding activated acylamine. The latter compound is then reacted with an alcohol to produce its carbamate.

  Similar to compounds 140.5 and 140.7 using the above procedure but using different amino substituted hydrazines and / or different dialkylcarboxy or hydroxy substituted phosphonates instead of 4-aminophenylhydrazine 140.1 A product is obtained.

  (Example 141)

ケトアルデヒド１３８．２は、ヒドラジンと反応されて、ピラゾール誘導体１４１．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、室温で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物１４１．２（ここで、Ｒ^２およびＸは、上で定義したとおりである）または反応性ブロモヘテロ芳香族試薬と反応されて、アルキル化生成物１４１．３および１４１．４が生成される。置換ピラゾールのアルキル化は、例えば、Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ ３０９（Ｌｏｎｇｍａｎ，１９９２）で記述されている。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、ジメチルアミノピリジン、リチウムヘキサメチルジシラジドなど）の存在下にて、等モル量のこれらの基質の間で、実行される。生成物１４１．３および１４１．４は、Ｘがジアルキルホスホノである場合以外は、本明細書中で記述された手順を使用して、ホスホネート１４１．５および１４１．６に変換される。

Ketoaldehyde 138.2 is reacted with hydrazine to give pyrazole derivative 141.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc. 1964, 86, 1520. This reaction is carried out in acetic acid at room temperature. The pyrazole product is then reacted with a bromomethyl compound 141.2 (where R ² and X are as defined above) or a reactive bromoheteroaromatic reagent to yield the alkylated product 141.3. And 141.4 are generated. Alkylation of substituted pyrazoles is described, for example, in T.W. L. Gilchrist, Heterocyclic Chemistry 309 (Longman, 1992). This reaction is carried out between equimolar amounts of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.) Executed. Products 141.3 and 141.4 are converted to phosphonates 141.5 and 141.6 using the procedures described herein except when X is a dialkylphosphono.

  (Example 142)

ピラゾール１４１．１は、上記のように、ホスホン酸ジアルキルアセトニル１４２．１（Ｔｅｔｒｅｈｅｄｒｏｎ Ｌｅｔｔ．，１９７８，３４，６４９）と反応されて、ピラゾール１４１．２および１４１．３が得られる。

Pyrazole 141.1 is reacted with dialkylacetonyl phosphonate 142.1 (Tetrehedon Lett., 1978, 34,649) as described above to give pyrazoles 141.2 and 141.3.

  (Example 143)

ピラゾール１４１．１は、テトラヒドロフラン溶液中にて、２，５−ビス（ブロモメチル）チオフェン１４３．１（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９９９，５５，４７０９）およびカリウムヘキサメチルジシラジドと反応されて、アルキル化生成物１４３．２および１４３．３が得られる。次いで、２’−置換異性体１４３．２は、Ａｒｂｕｚｏｖ反応において、亜リン酸トリアルキルと反応されて、ホスホネート１４３．４が生じる。このＡｒｂｕｚｏｖ反応は、Ｈａｎｄｂ．Ｏｒｇａｎｏｐｈｏｓｐｈｏｒｕｓ Ｃｈｅｍ．，１９９２，１１５で記述されている。この手順（ここで、ブロモ置換基は、対応するホスホネートに変換される）では、その基質は、約６０℃〜約１６０℃で、５〜５０倍モル過剰の亜リン酸トリアルキルと共に加熱されて、この変換が引き起こされる。

Pyrazole 141.1 is reacted with 2,5-bis (bromomethyl) thiophene 143.1 (Tetrahedron Lett., 1999, 55, 4709) and potassium hexamethyldisilazide in tetrahydrofuran solution to form an alkylation product. The products 143.2 and 143.3 are obtained. The 2′-substituted isomer 143.2 is then reacted with a trialkyl phosphite in an Arbuzov reaction to give the phosphonate 143.4. This Arbuzov reaction is described in Handb. Organophosphorus Chem. 1992, 115. In this procedure, where the bromo substituent is converted to the corresponding phosphonate, the substrate is heated at about 60 ° C. to about 160 ° C. with a 5-50 fold molar excess of trialkyl phosphite. This conversion is caused.

  The 2′-substituted pyrazole 143.3 is reacted with 1 molar equivalent of a dialkyl 3-aminophenyl phosphonate 143.5 and cesium carbonate in dimethylformamide solution at 70 ° C. to give the amine phosphonate 143.6. It is done.

  Using the above procedure, but using different dibromides, and / or different amino substituted phosphonates, products similar to 143.4 and 143.6 are obtained.

  (Example 144)

デフラザコルト１４４Ａ（米国特許第３，４３６，３８９号）の２０−ケトン基における保護−脱保護手順は、示されるように保護されて、誘導体１４４．１が得られる。このケトンは、例えば、その環状エチレンケタールに変換することにより、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９５５，７７，１９０４で記述されているように、トルエン溶液中にて、還流温度で、エチレングリコールおよび酸触媒と反応させることにより、保護される。脱保護は、Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｃｈｅｍ．Ｃｏｍｍ．，１９８７，１３５１で記述されているように、アセトン水溶液中にて、ピリジニウムトシレートと反応させることにより、引き起こされる。

The protection-deprotection procedure at the 20-ketone group of deflazacort 144A (US Pat. No. 3,436,389) is protected as indicated to give derivative 144.1. This ketone can be obtained, for example, by converting it to its cyclic ethylene ketal. Am. Chem. Soc. , 1955, 77, 1904, by reaction with ethylene glycol and an acid catalyst in a toluene solution at reflux temperature. Deprotection is described in J. Org. Chem. Soc. Chem. Comm. , 1987, 1351, by reacting with pyridinium tosylate in an aqueous acetone solution.

  Alternatively, the 20-ketone is protected by conversion to N, N-dimethylhydrazone. This dimethylhydrazone can be obtained from Org. Syn. , 1970, 50, 102, by the reaction of ketone 144A with N, N-dimethylhydrazine in ethanol-acetic acid. This group is described in J. Org. Am. Chem. Soc. , 1979, 101, 5841, by treatment with sodium acetate and acetic acid in aqueous tetrahydrofuran.

  Alternatively, the 20-ketone is protected as the diethylamine adduct. In this procedure, substrate 144A is Chem. Soc. Chem. Comm. , 1983, 406, and reacted with titanium tetrakis (diethylamide) to give this adduct. This ketone is deprotected by reacting with water in an aqueous organic solvent.

  The protected compound 144.1 is then converted to the phosphonate-containing analog 144.2 using the following procedure, and the protecting group is then removed as described above to give the phosphonate 144.3. .

  (Example 145)

保護誘導体１４５．１は、アミンまたはヒドロキシルアミン１４５．２（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルまたはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールもしくはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）または含アルコール溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、イミンまたはオキシム１４５．３が得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、この保護基は、本明細書中で記述されているように、除去されて、２０−ケトホスホネート生成物１４５．４が得られる。

The protected derivative 145.1 is an amine or hydroxylamine 145.2 where R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally includes a heteroatom O, S or N ), Or a functional group (such as an amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O, S or N And X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcohol-containing solvent (eg, ethanol), optionally in the presence of an acid catalyst. To give imine or oxime 145.3. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. The protecting group is then removed as described herein to give the 20-ketophosphonate product 145.4.

  (Example 145A)

ホスホネート基を含むヒドロキシルアミンエーテルの調製は、本明細書中で図示している。この手順では、ホスホネート１４５．５（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン１４５．６（Ａｌｄｒｉｃｈ）と反応されて、エーテル１４５．７が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル１４５．８が得られる。上記手順はまた、置換ヒドロキシルアミン（これらは、ホスホネートの前駆体である）を調製するために使用される。

The preparation of hydroxylamine ethers containing phosphonate groups is illustrated herein. In this procedure, a phosphonate 145.5 (where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 145.6 (Aldrich) to give an ether 145.7 is generated. This reaction is performed between equimolar amounts of the reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine). Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 145.8. The above procedure is also used to prepare substituted hydroxylamines, which are precursors of phosphonates.

  (Example 146)

基質１４５．１（ここで、その２０−ケトンは、ジメチルヒドラゾン誘導体として、保護されている）は、ジアルキルホスホノメチルヒドロキシルアミン１４６．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシム１４６．２が得られる。次いで、実施例１４４で記述されているように、脱保護すると、２０−ケトホスホネート１４６．３が得られる。このオキシム形成反応は、室温で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。

Substrate 145.1 (where the 20-ketone is protected as a dimethylhydrazone derivative) is a dialkylphosphonomethylhydroxylamine 146.1 (as described above, which is a dialkyltrifluoromethyl phosphonate, as described above). Reaction with sulfonyloxymethyl (prepared from Tetrahedron Lett., 1986, 27, 1477) and BOC-hydroxylamine) gives oxime 146.2. Deprotection then provides 20-ketophosphonate 146.3 as described in Example 144. This oxime formation reaction is carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at room temperature.

  Using the above procedure, but using a different oxime ether 145.2 instead of hydroxylamine ether 146.1, the corresponding product 145.4 is obtained.

  (Example 147)

ジエノン１４５．１（ここで、その２０−ケトンは、ジメチルヒドラゾンとして、保護されている）は、上記のように、Ｏ−（３−ブロモフェニルエトキシ）−ヒドロキシルアミン１４７．１（これは、上記のように、臭化３−ブロモフェニルエチルから調製した（フランス特許ＦＲ １４８１０５２））およびＢＯＣ−保護ヒドロキシルアミン１４５．６と反応されて、オキシム１４７．２が得られる。次いで、この保護基は、除去されて、２０−ケト生成物１４７．３が生じる。次いで、後者の生成物は、パラジウム触媒の存在下にて、リン酸ジアルキル１４７．４と反応されて、ホスホネート１４７．５が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、約１００℃で、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。

Dienone 145.1 (where the 20-ketone is protected as dimethylhydrazone) is, as above, O- (3-bromophenylethoxy) -hydroxylamine 147.1 (which is Prepared from 3-bromophenylethyl bromide (French patent FR 1481052)) and reacted with BOC-protected hydroxylamine 145.6 to give oxime 147.2. The protecting group is then removed to yield the 20-keto product 147.3. The latter product is then reacted with a dialkyl phosphate 147.4 in the presence of a palladium catalyst to give the phosphonate 147.5. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed at about 100 ° C. in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0).

  Alternatively, bromo compound 147.3 is coupled with dialkylpropenyl phosphonate 147.6 (Aldrich) to give phosphonate 147.7. The coupling of aryl halides and olefins by this Heck reaction is described in, for example, A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry 503ff (Plenum, 2001) and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)) and optionally in the presence of a base such as triethylamine or potassium carbonate. If necessary, the styrenoid double bond present in product 147.7 is reduced, for example by reaction with diimide, to produce saturated analog 147.8. Reduction of olefinic bonds is described in R.A. C. Larock, Comprehensive Organic Transformations 6ff (VCH 1989). This conversion is performed, for example, by catalytic hydrogenation using a palladium-on-carbon catalyst and hydrogen or hydrogen donor, or by using diimide or diborane.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromophenylethyl reagent 147.1, compounds 147.5, 147.7 And a product similar to 147.8 is obtained.

  (Example 148)

基質１４５．１（ここで、その２０−ケトンは、ジメチルヒドラゾンとして、保護されている）は、ホスホン酸ジアルキル３−アミノフェニル１４８．１（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９８４，２７，６５４）と反応されて、脱保護後、イミン生成物１４８．２が得られる。このイミン形成反応は、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われる。

Substrate 145.1, where the 20-ketone is protected as dimethylhydrazone, is dialkyl 3-aminophenyl 148.1 (J. Med. Chem., 1984, 27, 654) phosphonate. After reaction and deprotection, the imine product 148.2 is obtained. This imine formation reaction is carried out in a hydrocarbon solvent (eg toluene or xylene) at reflux temperature in the presence of a basic catalyst (eg sodium methoxide) or an acidic catalyst (eg p-toluenesulfonic acid). And conducted under azeotropic conditions.

  Using the above procedure, but using a different amino-substituted aryl phosphonate or heteroaryl phosphonate instead of 3-aminophenyl phosphonate 148.1, a product similar to 148.2 is obtained.

  (Example 149)

ジエノン１４５．１（ここで、その２０−ケトンは、ジメチルヒドラゾンとして保護されている）は、Ｏ−（２−ヒドロキシエチル）ヒドロキシルアミン１４９．１（Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｃｈｅｍ．Ｃｏｍｍ．，１９８６，９０３）と反応されて、オキシム１４９．２が生じる。ステロイド性１，４−ジエン−３−オンと置換ヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている；この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物の間で実行される。次いで、生成物１４９．２は、ホスホン酸ジアルキル４−アミノフェニル１４９．３（Ｅｐｓｉｌｏｎ）およびカルボニルジイミダゾールとカップリングされ、脱保護後、カーバメートオキシム１４９．４が生じる。カーバメートの調製は、Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ 第６巻４１６ｆｆ（Ａ．Ｒ．Ｋａｔｒｉｔｚｋｙ（編），Ｐｅｒｇａｍｏｎ，１９９５）ならびにＳ．Ｒ．ＳａｎｄｌｅｒおよびＷ．Ｋａｒｏ，Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ ２６０ｆｆ（Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９８６）で記述されている。この手順では、このアミンは、不活性非プロトン性溶媒（例えば、ジクロロメタンまたはテトラヒドロフラン）中にて、ホスゲンまたはそれらの官能性等価物（例えば、カルボニルジイミダゾール、トリホスゲン、ペンタフルオロフェニルカーボネートなど）と反応されて、対応する活性化アシルアミンが得られる。次いで、後者の化合物は、アルコールと反応されて、このカーバメートが生じる。

Dienone 145.1 (where the 20-ketone is protected as dimethylhydrazone) is O- (2-hydroxyethyl) hydroxylamine 149.1 (J. Chem. Soc. Chem. Comm., 1986). , 903) to give the oxime 149.2. The reaction of steroidal 1,4-dien-3-one with substituted hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795; this reaction is carried out in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate, and equimolar amounts of the reactants. Executed between. The product 149.2 is then coupled with dialkyl 4-aminophenyl phosphonate 149.3 (Epsilon) and carbonyldiimidazole to yield carbamate oxime 149.4 after deprotection. The preparation of carbamate is described in Comprehensive Organic Functional Group Transformations Vol. 6 416ff (AR Katritzky (ed.), Pergamon, 1995) and S. R. Sandler and W.W. Karo, Organic Functional Group Preparations 260ff (Academic Press, 1986). In this procedure, the amine is reacted with phosgene or a functional equivalent thereof (eg, carbonyldiimidazole, triphosgene, pentafluorophenyl carbonate, etc.) in an inert aprotic solvent (eg, dichloromethane or tetrahydrofuran). To obtain the corresponding activated acylamine. The latter compound is then reacted with an alcohol to yield this carbamate.

  Using the above procedure, but using a different hydroxy substituted hydroxylamine and / or a different amino substituted phosphonate instead of the hydroxy substituted hydroxylamine 149.1, a product similar to 149.4 is obtained.

  (Example 150)

ジエノン１４４Ａは、還元されて、１，２−ジヒドロ生成物１５０．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物１５０．２が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジン１５０．３（ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応により、異性体２’−および１’−アリールピラゾール１５０．４および１５０．５が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物の間で実行される。次いで、ピラゾール１５０．４および１５０．５は、例えば、ここで記述された手順により、ホスホネート１５０．６および１５０．７に変換される。

Dienone 144A is reduced to give 1,2-dihydro product 150.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. The product is then Am. Chem. Soc. , 1964, 86, 1520, reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product. 150.2 is obtained. This compound is then reacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 150.3, wherein substituent X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent. The For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2'- and 1'-arylpyrazoles 150.4 and 150.5. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). Pyrazoles 150.4 and 150.5 are then converted to phosphonates 150.6 and 150.7, for example, by the procedure described herein.

  (Example 151)

ケトアルデヒド１５０．２は、上記のように、３−カルボキシフェニルヒドラジン１５１．１（Ａｐｉｎ）と反応されて、ピラゾール１５１．２および１５１．３が生成される。次いで、２’−置換異性体１５１．２は、ジメチルホルムアミド溶液中にて、室温で、ホスホン酸ジアルキル３−アミノプロピル１５１．４（Ａｃｒｏｓ）およびジシクロヘキシルカルボジイミドとカップリングされて、アミドホスホネート１５１．５が得られる。カルボン酸および誘導体からのアミドの調製は、例えば、Ｓ．Ｒ．ＳａｎｄｌｅｒおよびＷ．Ｋａｒｏ，Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ ２７４（Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９８６）ならびにＲ．Ｃ．Ｌａｒｏｃｋ，Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ ９７２ｆｆ（ＶＣＨ，１９８９）で記述されている。このカルボン酸は、活性化剤（例えば、ジシクロヘキシルカルボジイミドまたはジイソプロピルカルボジイミド）の存在下にて、必要に応じて、例えば、ヒドロキシベンゾトリアゾール，Ｎ−ヒドロキシスクシンイミドまたはＮ−ヒドロキシピリドンの存在下にて、非プロトン性溶媒（例えば、ピリジン、ＤＭＦまたはジクロロメタン）中で、このアミンと反応されて、このアミドが得られる。

Ketoaldehyde 150.2 is reacted with 3-carboxyphenylhydrazine 151.1 (Apin) as described above to produce pyrazoles 151.2 and 151.3. The 2′-substituted isomer 151.2 was then coupled with dialkyl 3-aminopropyl 151.4 phosphonate (Acros) and dicyclohexylcarbodiimide in dimethylformamide solution at room temperature to give the amide phosphonate 151.5. Is obtained. Preparation of amides from carboxylic acids and derivatives is described, for example, in S.H. R. Sandler and W.W. Karo, Organic Functional Group Preparations 274 (Academic Press, 1986) and R.A. C. Larock, Comprehensive Organic Transformations 972ff (VCH, 1989). The carboxylic acid can be used in the presence of an activator (e.g., dicyclohexylcarbodiimide or diisopropylcarbodiimide) and optionally, e.g., in the presence of hydroxybenzotriazole, N-hydroxysuccinimide or N-hydroxypyridone. Reaction with the amine in a protic solvent such as pyridine, DMF or dichloromethane provides the amide.

  Alternatively, the carboxylic acid can be first converted to an activated derivative (eg, its acid chloride, anhydride, mixed anhydride, imidazolide, etc.) and then in the presence of an organic base (eg, pyridine), Reaction with the amine provides the amide.

  Conversion of the carboxylic acid to the corresponding acid chloride can be accomplished by reacting the carboxylic acid in an inert organic solvent (eg, dichloromethane), optionally in the presence of a catalytic amount of dimethylformamide, (eg, Can be caused by treatment with thionyl chloride or oxalyl chloride).

  Isomeric pyrazole 151.3 is reacted with dialkyl 2-aminophenyl 151.6 phosphonate 151.6 (Acros) as described above to give amidophosphonate 151.7.

  Using the above procedure, but using different carboxy-substituted hydrazines and / or different amino-substituted phosphonates, products similar to 151.5 and 151.7 are obtained.

  (Example 152)

ケトアルデヒド１５０．２は、上記のように、１，３−ビス（ヒドラジノ）ベンゼン１５２．１（Ｂｕｌｌ．Ｓｏｃ．Ｃｈｉｍ．Ｆｒ．，１９７５，１３７１）と反応されて、ピラゾール１５２．２および１５２．３が生成される。２’−置換異性体１５２．２は、テトラヒドロフラン溶液中にて、室温で、１モル当量のジアルキルホスホノアセトアルデヒド（Ａｕｒｏｒａ）と反応されて、ヒドラゾンホスホネート１５２．５が得られる。

Ketoaldehyde 150.2 is reacted with 1,3-bis (hydrazino) benzene 152.1 (Bull. Soc. Chim. Fr., 1975, 1371) as described above to give pyrazoles 152.2 and 152. 3 is generated. The 2'-substituted isomer 152.2 is reacted with 1 molar equivalent of dialkylphosphonoacetaldehyde (Aurora) in tetrahydrofuran solution at room temperature to give hydrazone phosphonate 152.5.

  Alternatively, 1'-substituted pyrazole 152.3 is coupled with dialkylphosphonobutyric acid 152.6 (Epsilon) and dicyclohexylcarbodiimide as described above to prepare phosphonate 152.7.

  Using the above procedure, but using 1,3-bis (hydrazino) phenylhydrazine 152.1 instead of a different bishydrazine and / or a different dialkylformyl or carboxy-substituted phosphonate, compounds 152.5 and 152. A product similar to 7 is obtained.

  (Example 153)

ケトアルデヒド１５０．２は、ヒドラジンと反応されて、ピラゾール誘導体１５３．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、室温で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物１５３．２（ここで、Ｒ^２およびＸは、上で定義したとおりである）または反応性ブロモヘテロ芳香族試薬と反応されて、アルキル化生成物１５３．３および１５３．４が生成される。置換ピラゾールのアルキル化は、例えば、Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ ３０９（Ｌｏｎｇｍａｎ，１９９２）で記述されている。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、ジメチルアミノピリジン、リチウムヘキサメチルジシラジドなど）の存在下にて、等モル量のこれらの基質の間で、実行される。生成物１５３．３および１５３．４は、Ｘがジアルキルホスホノである場合以外は、本明細書中で記述された手順を使用して、ホスホネート１５３．５および１５３．６に変換される。

Ketoaldehyde 150.2 is reacted with hydrazine to give pyrazole derivative 153.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc. 1964, 86, 1520. This reaction is carried out in acetic acid at room temperature. The pyrazole product is then reacted with a bromomethyl compound 153.2 (where R ² and X are as defined above) or a reactive bromoheteroaromatic reagent to yield the alkylated product 153.3. And 153.4 are generated. Alkylation of substituted pyrazoles is described, for example, in T.W. L. Gilchrist, Heterocyclic Chemistry 309 (Longman, 1992). This reaction is carried out between equimolar amounts of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.) Executed. Products 153.3 and 153.4 are converted to phosphonates 153.5 and 153.6 using the procedures described herein except when X is a dialkylphosphono.

  (Example 154)

ピラゾール１５３．１は、ジメチルホルムアミド溶液中にて、７０℃で、１モル当量のホスホン酸ジアルキルブロモプロピル１５４．１（Ｓｙｎｔｈｅｌｅｃ）および炭酸セシウムと反応されて、ピラゾール１５４．２および１５４．３が得られる。

Pyrazole 153.1 is reacted with 1 molar equivalent of dialkylbromopropyl phosphonate 154.1 (Synthelec) and cesium carbonate in dimethylformamide solution at 70 ° C. to give pyrazoles 154.2 and 154.3. It is done.

  (Example 155)

ピラゾール１５３．１は、テトラヒドロフラン溶液中にて、１，４−ビス（ブロモメチル）ベンゼン１５５．１およびカリウムヘキサメチルジシラジドと反応されて、アルキル化生成物１５５．２および１５５．３が得られる。次いで、２’−置換異性体１５５．２は、Ａｒｂｕｚｏｖ反応において、亜リン酸トリアルキルと反応されて、ホスホネート１５５．４が生じる。このＡｒｂｕｚｏｖ反応は、Ｈａｎｄｂ．Ｏｒｇａｎｏｐｈｏｓｐｈｏｒｕｓ Ｃｈｅｍ．，１９９２，１１５で記述されている。この手順（ここで、ブロモ置換基は、対応するホスホネートに変換される）では、その基質は、約６０℃〜約１６０℃で、５〜５０倍モル過剰の亜リン酸トリアルキルと共に加熱されて、この変換が引き起こされる。

Pyrazole 153.1 is reacted with 1,4-bis (bromomethyl) benzene 155.1 and potassium hexamethyldisilazide in tetrahydrofuran solution to give alkylated products 155.2 and 155.3. . The 2′-substituted isomer 155.2 is then reacted with a trialkyl phosphite in an Arbuzov reaction to give the phosphonate 155.4. This Arbuzov reaction is described in Handb. Organophosphorus Chem. 1992, 115. In this procedure, where the bromo substituent is converted to the corresponding phosphonate, the substrate is heated at about 60 ° C. to about 160 ° C. with a 5-50 fold molar excess of trialkyl phosphite. This conversion is caused.

  2′-Substituted pyrazole 155.3 is obtained at 70 ° C. in dimethylformamide solution with 1 molar equivalent of dialkylmercaptoethyl phosphonate 155.5 (Zh. Obschei. Khim., 1973, 43, 2364) To give thioether phosphonate 155.6.

  Using the above procedure, but using different dibromides and / or different mercapto substituted phosphonates, products similar to 155.4 and 155.6 are obtained.

  (Example 156)

メドロキシプロゲステロン１５６Ａ（米国特許第３，０４３，８３２号、同第３，０６１，６１６号および同第３，３７７，３６４号）は、保護されて、誘導体１５６．１が得られる。このケトンは、例えば、その環状エチレンケタールに変換することにより、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９５５，７７，１９０４で記述されているように、トルエン溶液中にて、還流温度で、エチレングリコールおよび酸触媒と反応させることにより、保護される。脱保護は、Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｃｈｅｍ．Ｃｏｍｍ．，１９８７，１３５１で記述されているように、アセトン水溶液中にて、ピリジニウムトシレートと反応させることにより、引き起こされる。

Medroxyprogesterone 156A (US Pat. Nos. 3,043,832, 3,061,616 and 3,377,364) is protected to give derivative 156.1. This ketone can be obtained, for example, by converting it to its cyclic ethylene ketal. Am. Chem. Soc. , 1955, 77, 1904, by reaction with ethylene glycol and an acid catalyst in a toluene solution at reflux temperature. Deprotection is described in J. Org. Chem. Soc. Chem. Comm. , 1987, 1351, by reacting with pyridinium tosylate in an aqueous acetone solution.

  Alternatively, the 20-ketone is protected by conversion to N, N-dimethylhydrazone. This dimethylhydrazone can be obtained from Org. Syn. , 1970, 50, 102, by the reaction of ketone 156A with N, N-dimethylhydrazine in ethanol-acetic acid. This group is described in J. Org. Am. Chem. Soc. , 1979, 101, 5841, by treatment with sodium acetate and acetic acid in aqueous tetrahydrofuran.

  Alternatively, the 20-ketone is protected as the diethylamine adduct. In this procedure, substrate 156A is Chem. Soc. Chem. Comm. , 1983, 406, and reacted with titanium tetrakis (diethylamide) to give this adduct. This ketone is deprotected by reacting with water in an aqueous organic solvent.

  The protected compound 156.1 is then converted to the phosphonate-containing analog 156.2 using the following procedure, and the protecting group is then removed as described above to give the phosphonate 156.3. .

  (Example 157)

ケトン保護誘導体１５６．１は、ヒドロキシルアミンまたはアミン１５７．１（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルもしくはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールもしくはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）または含アルコール溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物の間で行われて、オキシム１５７．２が得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、この保護基は、実施例１５６で記述されているように、除去されて、２０−ケトホスホネート生成物１５７．３が得られる。

The ketone protected derivative 156.1 is a hydroxylamine or amine 157.1 (where R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally includes a heteroatom O, S or N). Or a functional group (such as amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O, S or And X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcohol-containing solvent (eg, ethanol), optionally in the presence of an acid catalyst. The oxime 157.2 is obtained. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. The protecting group is then removed as described in Example 156 to give the 20-ketophosphonate product 157.3.

  (Example 157A)

ホスホネート基を含むヒドロキシルアミンエーテルの調製は、ここで図示している。ホスホネート１５７．４（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン１５７．５（Ａｌｄｒｉｃｈ）と反応されて、エーテル１５７．６が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル１５７．７が得られる。上記手順はまた、置換ヒドロキシルアミン（これらは、ホスホネートの前駆体である）を調製するのに使用される。

The preparation of hydroxylamine ethers containing phosphonate groups is illustrated here. Phosphonate 157.4 (where Lv is a leaving group (eg bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 157.5 (Aldrich) to give ether 157.6. Generated. This reaction is performed between equimolar amounts of the reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine). Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 157.7. The above procedure is also used to prepare substituted hydroxylamines, which are precursors of phosphonates.

  (Example 158)

ホスホネート（ここで、このホスホネートは、イミノキシ基によって、結合されている）の調製は、ここで図示している。この手順では、基質１５６．１（ここで、その２０−ケトンは、ジメチルヒドラゾン誘導体として、保護されている）は、ジアルキルホスホノメチルヒドロキシルアミン１５８．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシム１５８．２が得られる。次いで、実施例１５６で記載のように、脱保護すると、２０−ケトホスホネート１５８．３が得られる。このオキシム形成反応は、室温で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。

The preparation of phosphonates, where the phosphonate is linked by an iminoxy group, is illustrated here. In this procedure, the substrate 156.1 (where the 20-ketone is protected as a dimethylhydrazone derivative) is converted to a dialkylphosphonomethylhydroxylamine 158.1 (which is a phosphonic acid as described above). Reaction with dialkyltrifluoromethylsulfonyloxymethyl (prepared from Tetrahedron Lett., 1986, 27, 1477) and BOC-hydroxylamine) provides oxime 158.2. Deprotection then provides 20-ketophosphonate 158.3 as described in Example 156. This oxime formation reaction is carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at room temperature.

  Using the above procedure, but using a different oxime ether 157.1 instead of hydroxylamine ether 158.1, the corresponding product 157.3 is obtained.

  (Example 159)

ジエノン１５６．１（ここで、その２０−ケトンは、ジメチルヒドラゾンとして、保護されている）は、上記のように、Ｏ−（５−ブロモ−３−ピリジルメトキシ）ヒドロキシルアミン１５９．１（これは、上記のように、５−ブロモ−３−ブロモメチルピリジン（ＷＯ ９５／２８４００）およびＢＯＣ−保護ヒドロキシルアミン１５７．５から調製した）と反応されて、オキシム１５９．２が得られる。次いで、この保護基は、除去されて、２０−ケト生成物１５９．３が生じる。次いで、後者の生成物は、パラジウム触媒の存在下にて、亜リン酸ジアルキル１５９．４と反応されて、ホスホネート１５９．５が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、約１００℃で、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。

Dienone 156.1, where the 20-ketone is protected as dimethylhydrazone, is, as described above, O- (5-bromo-3-pyridylmethoxy) hydroxylamine 159.1 (which is And prepared as described above with 5-bromo-3-bromomethylpyridine (WO 95/28400) and BOC-protected hydroxylamine 157.5) to give oxime 159.2. The protecting group is then removed to yield the 20-keto product 159.3. The latter product is then reacted with a dialkyl phosphite 159.4 in the presence of a palladium catalyst to give the phosphonate 159.5. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed at about 100 ° C. in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0).

  Alternatively, bromo compound 159.3 is coupled with dialkyl vinyl phosphonate 159.6 (Aldrich) to give phosphonate 159.7. The coupling of aryl halides and olefins by this Heck reaction is described in, for example, A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry 503ff (Plenum, 2001) and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)) and optionally in the presence of a base such as triethylamine or potassium carbonate. Optionally, the styrenoid double bond present in the product 159.7 is reduced, for example by reaction with diimide, to produce the saturated analog 159.8. Reduction of olefinic bonds is described in R.A. C. Larock, Comprehensive Organic Transformations 6ff (VCH 1989). This conversion is performed, for example, by catalytic hydrogenation using a palladium on carbon catalyst and hydrogen or hydrogen donor, or by using diimide or diborane.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromopyridyl reagent 159.1, compounds 159.5, 159.7 and A product similar to 159.8 is obtained.

  (Example 160)

ジエノン１５６．１（ここで、その２０−ケトンは、ジメチルヒドラゾンとして、保護されている）は、２−ヒドロキシエチルヒドロキシルアミン１６０．１（Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｃｈｅｍ．Ｃｏｍｍ．，１９８６，９０３）と反応されて、オキシム１６０．２が生じる。不飽和ステロイド性ケトンとヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている；この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物の間で実行される。次いで、生成物１６０．２は、ホスホン酸ジアルキル４−アミノフェニル１６０．３（Ｅｐｓｉｌｏｎ）およびカルボニルジイミダゾールとカップリングされて、脱保護後、カーバメートオキシム１６０．４が生じる。カーバメートの調製は、Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ 第６巻 ４１６ｆｆ（Ａ．Ｒ．Ｋａｔｒｉｔｚｋｙ，（編），Ｐｅｒｇａｍｏｎ，１９９５）ならびにＳ．Ｒ．ＳａｎｄｌｅｒおよびＷ．Ｋａｒｏ，Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ ２６０ｆｆ（Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９８６）で記述されている。この手順では、このアミンは、不活性非プロトン性溶媒（例えば、ジクロロメタンまたはテトラヒドロフラン）中にて、ホスゲンまたはそれらの官能性等価物（例えば、カルボニルジイミダゾール、トリホスゲン、ペンタフルオロフェニルカーボネートなど）と反応されて、対応する活性化アシルアミンが得られる。次いで、後者の化合物は、アルコールと反応されて、このカーバメートが生じる。

Dienone 156.1 (where the 20-ketone is protected as dimethylhydrazone) is 2-hydroxyethylhydroxylamine 160.1 (J. Chem. Soc. Chem. Comm., 1986, 903). To give oxime 160.2. The reaction of unsaturated steroidal ketones with hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795; this reaction is carried out in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate, and equimolar amounts of the reactants. Executed between. The product 160.2 is then coupled with dialkyl 4-aminophenyl 160.3 phosphonate (Epsilon) and carbonyldiimidazole to yield carbamate oxime 160.4 after deprotection. The preparation of carbamate is described in Comprehensive Organic Functional Group Transformations Vol. 6 416ff (AR Katritzky, (ed.), Pergamon, 1995) and R. Sandler and W.W. Karo, Organic Functional Group Preparations 260ff (Academic Press, 1986). In this procedure, the amine is reacted with phosgene or a functional equivalent thereof (eg, carbonyldiimidazole, triphosgene, pentafluorophenyl carbonate, etc.) in an inert aprotic solvent (eg, dichloromethane or tetrahydrofuran). To obtain the corresponding activated acylamine. The latter compound is then reacted with an alcohol to yield this carbamate.

  Using the above procedure, but using a different hydroxy-substituted hydroxylamine and / or a different amino-substituted phosphonate instead of hydroxy-substituted hydroxylamine 160.1, a product similar to 160.4 is obtained.

  (Example 161)

エノン１６１．１（ここで、その２０−ケトンは、環状エチレンケタールとして、保護されている）は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．８６：１５２０（１９６４）で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物１６１．２が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジン１６１．３（ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応により、この２０−ケトンの脱保護後、異性体２’−および１’−アリールピラゾール１６１．４および１６１．５が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物の間で実行される。次いで、ピラゾール１６１．４および１６１．５は、例えば、本明細書中に記載の手順によって、ホスホネート１６１．６および１６１．７に変換される。

Enone 161.1, where the 20-ketone is protected as a cyclic ethylene ketal, Am. Chem. Soc. 86: 1520 (1964), reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product. 161.2 is obtained. This compound is then reacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 161.3, wherein substituent X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent. The For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2'- and 1'-arylpyrazoles 161.4 and 161.5 after deprotection of the 20-ketone. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). Pyrazoles 161.4 and 161.5 are then converted to phosphonates 161.6 and 161.7, for example, by the procedure described herein.

  (Example 162)

ケトアルデヒド１６１．２は、上記のように、３−カルボキシフェニルヒドラジン１６２．１（Ａｐｉｎ）と反応されて、ピラゾール１６２．２および１６２．３が生成される。次いで、２’−置換異性体１６２．２は、ジメチルホルムアミド溶液中にて、室温で、１モル当量のホスホン酸ジアルキル２−アミノエチル１６２．４（Ａｌｄｒｉｃｈ）およびジシクロヘキシルカルボジイミドと反応されて、アミドホスホネート１６２．５が得られる。カルボン酸および誘導体からのアミドの調製は、例えば、Ｓ．Ｒ．ＳａｎｄｌｅｒおよびＷ．Ｋａｒｏ，Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ ２７４（Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９６８）ならびにＲ．Ｃ．Ｌａｒｏｃｋ，Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ ９７２ｆｆ（ＶＣＨ，１９８９）で記述されている。このカルボン酸は、活性化剤（例えば、ジシクロヘキシルカルボジイミドまたはジイソプロピルカルボジイミド）の存在下にて、必要に応じて、例えば、ヒドロキシベンゾトリアゾール，Ｎ−ヒドロキシスクシンイミドまたはＮ−ヒドロキシピリドンの存在下にて、非プロトン性溶媒（例えば、ピリジン、ＤＭＦまたはジクロロメタン）中で、このアミンと反応されて、このアミドが得られる。

Ketoaldehyde 161.2 is reacted with 3-carboxyphenylhydrazine 162.1 (Apin) as described above to produce pyrazoles 162.2 and 162.3. The 2'-substituted isomer 162.2 is then reacted with 1 molar equivalent of a dialkyl 2-aminoethyl phosphonate 162.4 (Aldrich) and dicyclohexylcarbodiimide in a dimethylformamide solution at room temperature to give an amide phosphonate. 162.5 is obtained. Preparation of amides from carboxylic acids and derivatives is described, for example, in S.H. R. Sandler and W.W. Karo, Organic Functional Group Preparations 274 (Academic Press, 1968) and R.A. C. Larock, Comprehensive Organic Transformations 972ff (VCH, 1989). The carboxylic acid can be used in the presence of an activator (e.g., dicyclohexylcarbodiimide or diisopropylcarbodiimide) and optionally, e.g., in the presence of hydroxybenzotriazole, N-hydroxysuccinimide or N-hydroxypyridone. Reaction with the amine in a protic solvent such as pyridine, DMF or dichloromethane provides the amide.

  Alternatively, the carboxylic acid can be first converted to an activated derivative (eg, its acid chloride, anhydride, mixed anhydride, imidazolide, etc.) and then in the presence of an organic base (eg, pyridine), Reaction with the amine provides the amide.

  Conversion of the carboxylic acid to the corresponding acid chloride can be accomplished by reacting the carboxylic acid in an inert organic solvent (eg, dichloromethane), optionally in the presence of a catalytic amount of dimethylformamide, (eg, Can be caused by treatment with thionyl chloride or oxalyl chloride).

  The isomer pyrazole 162.3 was prepared as described above with 1 molar equivalent of a dialkyl 4-amino-2-thienyl phosphonate 162.6 (as described above with 4-amino-2-bromothiophene (Tetrahedron Lett. , 1987, 43, 3295) and a dialkyl phosphite reaction, which is prepared by a palladium-catalyzed coupling reaction to give amidophosphonate 162.7.

  Using the above procedure, but using different carboxy-substituted hydrazines and / or different amino-substituted phosphonates, products similar to 162.5 and 162.7 are obtained.

  (Example 163)

ケトアルデヒド１６１．２は、上記のように、３−ブロモフェニルヒドラジン１６３．１（Ｆｌｕｋａ）と反応されて、ピラゾール１６３．２および１６３．３が生成される。次いで、２’−置換異性体１６３．２は、上記のように、ホスホン酸ジアルキル１６３．４とカップリングされて、ホスホネート１６３．５が得られる。

Ketoaldehyde 161.2 is reacted with 3-bromophenylhydrazine 163.1 (Fluka) as described above to produce pyrazoles 163.2 and 163.3. The 2'-substituted isomer 163.2 is then coupled with a dialkyl phosphonate 163.4 as described above to give the phosphonate 163.5.

  Alternatively, 1'-substituted pyrazole 163.3 is coupled with a dialkyl vinyl phosphonate 163.6 (Aldrich) and a palladium catalyst as described above to prepare vinyl phosphonate 163.7. If necessary, the product is reduced as described above to give analog 163.8.

  Similar to compounds 163.5 and 163.7, 163.8 using the above procedure but using different bromo-substituted hydrazines and / or different dialkylalkenyl phosphonates instead of bromophenylhydrazine 163.1 A product is obtained.

  (Example 164)

ケトアルデヒド１６１．２は、ヒドラジンと反応されて、その２０−ケトンの脱保護後、ピラゾール誘導体１６４．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、室温で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物１６４．２（ここで、Ｒ^２およびＸは、上で定義したとおりである）または反応性ブロモヘテロ芳香族試薬と反応されて、アルキル化生成物１６４．３および１６４．４が生成される。置換ピラゾールのアルキル化は、例えば、Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ ３０９（Ｌｏｎｇｍａｎ，１９９２）で記述されている。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、ジメチルアミノピリジン、リチウムヘキサメチルジシラジドなど）の存在下にて、等モル量のこれらの基質の間で、実行される。生成物１６４．３および１６４．４は、Ｘがジアルキルホスホノである場合以外は、本明細書中で記述された手順を使用して、ホスホネート１６４．５および１６４．６に変換される。

Ketoaldehyde 161.2 is reacted with hydrazine to give the pyrazole derivative 164.1 after deprotection of the 20-ketone. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc. 1964, 86, 1520. This reaction is carried out in acetic acid at room temperature. The pyrazole product is then reacted with a bromomethyl compound 164.2 (where R ² and X are as defined above) or a reactive bromoheteroaromatic reagent to yield the alkylated product 164.3. And 164.4 are generated. Alkylation of substituted pyrazoles is described, for example, in T.W. L. Gilchrist, Heterocyclic Chemistry 309 (Longman, 1992). This reaction is carried out between equimolar amounts of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.) Executed. Products 164.3 and 164.4 are converted to phosphonates 164.5 and 164.6 using the procedures described herein except when X is a dialkylphosphono.

  (Example 165)

ピラゾール１６４．１は、ジメチルホルムアミド溶液中にて、７０℃で、１モル当量のホスホン酸ジアルキル４−ブロモメチル１６５．１（Ｌａｎｃａｓｔｅｒ）およびリチウムヘキサメチルジシラジドと反応されて、ピラゾール１６５．２および１６５．３が得られる。

Pyrazole 164.1 was reacted with 1 molar equivalent of dialkyl 4-bromomethyl 165.1 (Lancaster) phosphonate and lithium hexamethyldisilazide in dimethylformamide solution at 70 ° C. to give pyrazole 165.2 and 165.3 is obtained.

  Using the above procedure, but using different bromo-substituted phosphonates, products similar to 165.2 and 165.3 are obtained.

  (Example 166)

ピラゾール１６４．１は、テトラヒドロフラン溶液中にて、４−ブロモメチルシクロヘキサノン１６６．１（ＷＯ ９７／３７９５９）およびカリウムヘキサメチルジシラジドと反応されて、アルキル化生成物１６６．２および１６６．３が得られる。次いで、２’−置換異性体１６６．２は、還元アミノ化反応において、ホスホン酸ジアルキルアミノメチル１６６．５（Ｉｎｔｅｒｃｈｉｍ）およびトリアセトキシホウ水素化ナトリウムと反応されて、アミンホスホネート１６６．４が生じる。還元アミノ化手順によるアミンの調製は、例えば、Ｒ．Ｃ．Ｌａｒｏｃｋ，Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ，４２１（ＶＣＨ）ならびにＦ．Ａ．ＣａｒｅｙおよびＲ．Ｊ．Ｓｕｎｄｂｅｒｇ，Ａｄｖａｎｃｅｄ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ，Ｐａｒｔ Ｂ，２６９（Ｐｌｅｎｕｍ，２００１）で記述されている。この手順では、そのアミン成分およびアルデヒドまたはケトン成分は、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９０，５５，２５５２で記述されているように、還元剤（例えば、ボラン、シアノホウ水素化ナトリウム、トリアセトキシホウ水素化ナトリウムまたは水素化ジイソブチルアルミニウム）の存在下にて、必要に応じて、ルイス酸（例えば、チタン酸テトライソプロピル）の存在下にて、共に反応される。

Pyrazole 164.1 is reacted with 4-bromomethylcyclohexanone 166.1 (WO 97/37959) and potassium hexamethyldisilazide in tetrahydrofuran solution to give alkylated products 166.2 and 166.3. can get. The 2'-substituted isomer 166.2 is then reacted with a dialkylaminomethyl phosphonate 166.5 (Interchim) and sodium triacetoxyborohydride in a reductive amination reaction to give the amine phosphonate 166.4. Preparation of amines by reductive amination procedures is described, for example, in R.A. C. Larock, Comprehensive Organic Transformations, 421 (VCH) and F.R. A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry, Part B, 269 (Plenum, 2001). In this procedure, the amine component and the aldehyde or ketone component are Org. Chem. , 1990, 55, 2552, optionally in the presence of a reducing agent (eg borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride) They are reacted together in the presence of an acid (eg, tetraisopropyl titanate).

  The 1'-substituted pyrazole 166.3 is converted to the isomeric amine phosphonate 166.6 by the same reaction.

  Using the above procedure, but using different bromo-substituted aldehydes or ketones and / or different amino-substituted phosphonates, products similar to 166.4 and 166.6 are obtained.

  (Example 167)

９α−クロロ−１６α−メチル−１１β，１７α，２１−トリヒドロキシプレグナ−１，４−ジエン−３，２１−ジオン１６７Ａ（米国特許第４，４７２，３９３号）は、Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ，（Ｔ．Ｗ．ＧｒｅｅｎｅおよびＰ．Ｇ．Ｍ．Ｗｕｔｓによる），Ｗｉｌｅｙ，第２版１９９０，ｐ．２２３で記述されているように、パラホルムアルデヒドおよび酸触媒（例えば、塩酸）と反応されて、ＢＭＤ誘導体１６７．１が生じる。次いで、このホスホネート部分は、下記の手順を使用して導入され、ホスホン酸エステル１６７．２が生成される。次いで、このＢＭＤ部分は、Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ，（Ｔ．Ｗ．ＧｒｅｅｎｅおよびＰ．Ｇ．Ｍ．Ｗｕｔｓによる），Ｗｉｌｅｙ，第２版１９９０，ｐ．２２３で記述されているように、例えば、５０％酢酸水溶液で処理することにより加水分解されて、トリオール１６７．３が得られる。次いで、後者の化合物は、Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，１９８６，３４，１６１３で記述されている手順を使用して、１７，２１−環状オルトエステル１６７．５に変換される。この基質は、ジメチルホルムアミド中にて、７０℃で、２モル当量のオルト−２−フロ酸トリエチル１６５．４（Ｚｈ．Ｏｒｇ．Ｋｈｉｍ．，１９８０，５０，１３４８）および触媒量のｐ−トルエンスルホン酸と反応される。次いで、その生成物は、ジメチルホルムアミド中にて、室温で、過剰の塩化トリメチルシリルと反応されて、２１−クロロ１７−（２−フロエート）生成物１６７．６が生成される。

9α-Chloro-16α-methyl-11β, 17α, 21-trihydroxypregna-1,4-diene-3,21-dione 167A (US Pat. No. 4,472,393) is described in Protective Groups in Organic Synthesis, (By TW Greene and PGM WMuts), Wiley, 2nd edition 1990, p. As described in H.223, it is reacted with paraformaldehyde and an acid catalyst (eg, hydrochloric acid) to yield the BMD derivative 167.1. This phosphonate moiety is then introduced using the following procedure to produce the phosphonate ester 167.2. This BMD portion is then described in Protective Groups in Organic Synthesis, (by TW Greene and PMGM Wuts), Wiley, 2nd edition 1990, p. As described in H.223, for example, it is hydrolyzed by treatment with 50% aqueous acetic acid to give triol 167.3. The latter compound is then described in Chem. Pharm. Bull. , 1986, 34, 1613, to the 17,21-cyclic orthoester 167.5. This substrate was prepared in dimethylformamide at 70 ° C. with 2 molar equivalents of triethyl ortho-2-furoate 165.4 (Zh. Org. Khim., 1980, 50, 1348) and a catalytic amount of p-toluenesulfone. Reacted with acid. The product is then reacted with excess trimethylsilyl chloride in dimethylformamide at room temperature to produce the 21-chloro 17- (2-furoate) product 167.6.

  Alternatively, substrate 167.3 can be prepared according to J. Org. Med. Chem. , 1987, 30, 1581 to the product 167.6. In this procedure, the 21-hydroxyl group is activated by conversion to 21-mesylate by reaction with mesyl chloride in pyridine; the mesylate group is then reacted with lithium chloride in dimethylformamide. To give the 21-chloro intermediate, and its 17-hydroxyl group is esterified to give the 21-chloro-17- (2-furoate) derivative 167.6. 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.

  (Example 168)

ＢＭＤ保護誘導体１６７．１は、アミンまたはヒドロキシルアミン１６８．１（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルもしくはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールもしくはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）または含アルコール溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、このイミンまたはオキシムが得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、このＢＭＤ保護側鎖化合物１６８．２は、次いでここで記述されているように、トリオール１６８．３に変換され、次いで、２１−クロロ１７−（２−フロエート）生成物１６８．４に変換される。

The BMD protected derivative 167.1 is an amine or hydroxylamine 168.1 (where R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally contains a heteroatom O, S or N). Or a functional group (such as amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O, S or And X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcohol-containing solvent (eg, ethanol), optionally in the presence of an acid catalyst. This imine or oxime is obtained. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. This BMD protected side chain compound 168.2 is then converted to the triol 168.3, as described herein, and then to the 21-chloro 17- (2-furoate) product 168.4. Is done.

ホスホネート基を含むヒドロキシルアミンエーテルの調製は、ここで図示されている。この手順では、ホスホネート１６８．５（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン１６８．６（Ａｌｄｒｉｃｈ）と反応されて、エーテル１６８．７が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル１６８．８が得られる。

The preparation of hydroxylamine ethers containing phosphonate groups is illustrated here. In this procedure, phosphonate 168.5 (where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 168.6 (Aldrich) to give an ether 168.7 is generated. This reaction is performed between equimolar amounts of the reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine). Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 168.8.

  (Example 169)

基質１６７．１は、ジアルキルホスホノメチルヒドロキシルアミン１６９．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔ．Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシム１６９．２が得られる。次いで、脱保護すると、トリオール１６９．３が得られ、そこから、実施例１６７で記述された手順を使用して、２１−クロロ１７−（２−フロエート）化合物１６９．４が調製される。このオキシム形成反応は、室温で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。

Substrate 167.1 is a dialkylphosphonomethylhydroxylamine 169.1 (as described above, dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27, 1477) and BOC-hydroxylamine. To give oxime 169.2. Deprotection then affords triol 169.3, from which the 21-chloro 17- (2-furoate) compound 169.4 is prepared using the procedure described in Example 167. This oxime formation reaction is carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at room temperature.

  Using the above procedure, but using a different oxime ether 167.1 instead of hydroxylamine ether 169.1, the corresponding product 169.4 is obtained.

  (Example 170)

ジエノン１６７．１は、上記のように、Ｏ−（５−ブロモ−３−ピリジルメトキシ）ヒドロキシルアミン１７０．１（これは、上記のように、５−ブロモ−３−ブロモメチルピリジンから調製した（ＥＰ ５１１８６５））およびＢＯＣ−保護ヒドロキシルアミン１６８．６と反応されて、その側鎖の脱保護後、オキシム１７０．２が得られる。次いで、この生成物は、パラジウム触媒の存在下にて、亜リン酸ジアルキル１７０．３と反応されて、ホスホネート１７０．４が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、約１００℃で、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。次いで、この２１−ヒドロキシ化合物１７０．４は、実施例１６７で記述されているように、２１−クロロ１７−（２−フロエート）誘導体１７０．５に変換される。

Dienone 167.1 was prepared as described above from O- (5-bromo-3-pyridylmethoxy) hydroxylamine 170.1 (which was prepared from 5-bromo-3-bromomethylpyridine as described above ( EP 51865)) and BOC-protected hydroxylamine 168.6 to give oxime 170.2 after deprotection of its side chain. This product is then reacted with a dialkyl phosphite 170.3 in the presence of a palladium catalyst to give the phosphonate 170.4. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed at about 100 ° C. in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0). This 21-hydroxy compound 170.4 is then converted to the 21-chloro 17- (2-furoate) derivative 170.5 as described in Example 167.

  Alternatively, bromo compound 170.2 is coupled with dialkyl vinyl phosphonate 170.6 (Aldrich) to give phosphonate 170.7. The coupling of aryl halides and olefins by this Heck reaction is described in, for example, A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry 503ff (Plenum, 2001) and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)) and optionally in the presence of a base such as triethylamine or potassium carbonate. If necessary, the double bond present in the product 170.7 is reduced, for example by reaction with diimide, to produce the saturated analog 170.9. Reduction of olefinic bonds is described in R.A. C. Larock, Comprehensive Organic Transformations 6ff (VCH, 1989). This conversion is performed, for example, by catalytic hydrogenation using a palladium-on-carbon catalyst and hydrogen or hydrogen donor, or by using diimide or diborane. The products 170.7 and 170.9 are then converted to 21-chloro 17- (2-furoate) analogs 170.8 and 170.10.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromopyridylmethoxy reagent 170.1, compounds 170.5, 170.8 And a product similar to 170.10.

  (Example 171)

ホスホネート（ここで、このホスホネートは、イミノ基によって、結合されている）の調製は、ここで図示している。この手順では、基質１６７．１は、ホスホン酸ジアルキル４−アミノフェニル１７１．１（Ｅｐｓｉｌｏｎ）と反応されて、脱保護後、イミン生成物１７１．２が得られる。このイミン形成反応は、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われる。次いで、この生成物は、２１−クロロ１７−（２−フロエート）化合物１７１．３に変換される。

The preparation of phosphonates, where the phosphonate is linked by an imino group, is illustrated here. In this procedure, substrate 167.1 is reacted with dialkyl 4-aminophenyl 171.1 (Epsilon) phosphonate to give, after deprotection, imine product 171.2. This imine formation reaction is carried out in a hydrocarbon solvent (eg toluene or xylene) at reflux temperature in the presence of a basic catalyst (eg sodium methoxide) or an acidic catalyst (eg p-toluenesulfonic acid). And conducted under azeotropic conditions. This product is then converted to the 21-chloro 17- (2-furoate) compound 171.3.

  Using the above procedure, but using a different amino-substituted aryl or heteroaryl phosphonate instead of 4-aminophenyl phosphonate 171.1, a product similar to 171.3 is obtained.

  (Example 172)

ジエノン１６７．１は、Ｏ−（２−アミノエチル）ヒドロキシルアミン１７２．１（Ｐｏｌ．Ｊ．Ｃｈｅｍ．，１９８１，５５，１１６３）と反応されて、オキシム１７２．２が生じる。ステロイド性１，４−ジエン−３−オンと置換ヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている；この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物の間で実行される。次いで、この生成物は、還元アミノ化手順において、ホスホン酸ジアルキル４−ホルミルフェニル１７２．３（Ｅｐｓｉｌｏｎ）およびトリアセトキシホウ水素化ナトリウムと反応されて、アミンオキシム１７２．４が生じる。還元アミノ化手順によるアミンの調製は、例えば、Ｒ．Ｃ．Ｌａｒｏｃｋ，Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ、４２１（ＶＣＨ）ならびにＦ．Ａ．ＣａｒｅｙおよびＲ．Ｊ．Ｓｕｎｄｂｅｒｇ，Ａｄｖａｎｃｅｄ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ、Ｐａｒｔ Ｂ ２６９（Ｐｌｅｎｕｍ，２００１）で記述されている。この手順では、そのアミン成分およびアルデヒドまたはケトン成分は、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９０，５５，２５５２で記述されているように、還元剤（例えば、ボラン、シアノホウ水素化ナトリウム、トリアセトキシホウ水素化ナトリウムまたは水素化ジイソブチルアルミニウム）の存在下にて、必要に応じて、ルイス酸（例えば、チタン酸テトライソプロピル）の存在下にて、共に反応される。

Dienone 167.1 is reacted with O- (2-aminoethyl) hydroxylamine 172.1 (Pol. J. Chem., 1981, 55, 1163) to give oxime 172.2. The reaction of steroidal 1,4-dien-3-one with substituted hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795; this reaction is carried out in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate, and equimolar amounts of the reactants. Executed between. This product is then reacted in a reductive amination procedure with dialkyl 4-formylphenyl phosphonate 172.3 (Epsilon) and sodium triacetoxyborohydride to give the amine oxime 172.4. Preparation of amines by reductive amination procedures is described, for example, in R.A. C. Larock, Comprehensive Organic Transformations, 421 (VCH) and F.R. A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry, Part B 269 (Plenum, 2001). In this procedure, the amine component and the aldehyde or ketone component are Org. Chem. , 1990, 55, 2552, optionally in the presence of a reducing agent (eg borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride) They are reacted together in the presence of an acid (eg, tetraisopropyl titanate).

  The amine product 172.4 is then converted to the 21-chloro 17- (2-furoate) product 171.6 as described herein.

  Using the above procedure, but using a different amino substituted hydroxylamine and / or a different formyl substituted phosphonate instead of hydroxylamine 172.3, a product similar to 177.6 is obtained.

  (Example 173)

ＢＭＤ保護ジエノン１６７．１は、還元されて、１，２−ジヒドロ生成物１７３．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物１７３．２が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジン１７３．３（ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどであり得る。この反応により、異性体２’−および１’−アリールピラゾール１７３．４および１７３．５が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物の間で実行される。次いで、ピラゾール１７３．４および１７３．５は、例えば、本明細書中で記述した手順により、ＢＭＤ保護中間体１７３．６および１７３．７を経由して、２１−クロロ１７−（２−フロエート）ホスホネート１７３．９および１７３．１１に変換される。

BMD protected dienone 167.1 is reduced to give 1,2-dihydro product 173.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. The product is then Am. Chem. Soc. , 1964, 86, 1520, reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product. 173.2 is obtained. This compound is then reacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 173.3, where substituent X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent. The For example, X can be a dialkylphosphono, bromo, hydroxy, amino, carboxyl, and the like. This reaction yields the isomers 2'- and 1'-arylpyrazoles 173.4 and 173.5. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). Pyrazole 173.4 and 173.5 can then be converted to 21-chloro 17- (2-furoate) via BMD protected intermediates 173.6 and 173.7, for example, according to the procedure described herein. Converted to phosphonates 173.9 and 173.11.

  (Example 174)

ケトアルデヒド１７３．２は、上記のように、４−ブロモベンジルヒドラジン１７４．１（Ａｎｎ．，１９６８，７１７，１０４）と反応されて、ピラゾール１７４．２および１７４．３が得られる。次いで、２’−置換異性体１７４．２は、実施例１７０で記述されているように、亜リン酸ジアルキルとカップリングされて、ホスホネート１７３．４が生じる。次いでそのＢＭＤ保護基が除去され、この生成物は、２１−クロロ１７−（２−フロエート）生成物１７３．６に変換される。

Ketoaldehyde 173.2 is reacted with 4-bromobenzylhydrazine 174.1 (Ann., 1968, 717, 104) as described above to give pyrazoles 174.2 and 174.3. The 2′-substituted isomer 174.2 is then coupled with a dialkyl phosphite as described in Example 170 to give the phosphonate 173.4. The BMD protecting group is then removed and the product is converted to the 21-chloro 17- (2-furoate) product 173.6.

  The isomer pyrazole 174.3 is subjected to the same series of reactions to give the isomer product 173.9.

  Using the above procedure, but using different bromo-substituted hydrazines, products similar to 173.6 and 173.9 are obtained.

  (Example 174)

ケトアルデヒド１７３．２は、上記のように、４−ヒドロキシフェニルヒドラジン１７４．１（ＥＰ ４３７１０５）と反応されて、ピラゾール１７４．２および１７４．３が生成される。１’−置換異性体１７４．２は、ジメチルホルムアミド中にて、７０℃で、ホスホン酸ジアルキル２−ブロモエチル１７４．４（Ａｌｄｒｉｃｈ）および炭酸カリウムと反応されて、エーテルホスホネート１７４．５が得られる。次いで、この生成物は、脱保護されて、トリオール１７４．６が得られ、これは、２１−クロロ１７−（２−フロエート）化合物１７４．７に変換される。

Ketoaldehyde 173.2 is reacted with 4-hydroxyphenylhydrazine 174.1 (EP 437105) as described above to produce pyrazoles 174.2 and 174.3. The 1′-substituted isomer 174.2 is reacted with dialkyl 2-bromoethyl phosphonate 174.4 (Aldrich) and potassium carbonate in dimethylformamide at 70 ° C. to give the ether phosphonate 174.5. The product is then deprotected to give triol 174.6, which is converted to the 21-chloro 17- (2-furoate) compound 174.7.

  Alternatively, 2′-substituted pyrazole 174.3 is coupled with dialkyl 2-mercaptoethyl phosphonate 174.8 (Zh. Obsche. Khim., 1973, 43, 2364) in Mitsunobu reaction to produce thioether phosphonate 174. 9 is prepared, which is deprotected and the product is converted to the 21-chloro 17- (2-furoate) analog 174.11. Preparation of aromatic ethers and thioethers by Mitsunobu reaction is described in, for example, R.A. C. Larock, Comprehensive Organic Transformations, 448 (VCH, 1989); A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry, Part B 153-4 (Plenum, 2001) and Org. React. 1992, 42, 335. The phenol and alcohol or thiol component are reacted together in the presence of a dialkyl azodicarboxylate and a triarylphosphine in an aprotic solvent (eg, tetrahydrofuran) to give their ether or thioether product. . This procedure is also described in Org. React. 1992, 42, 335-656.

  Similar to compounds 174.7 and 174.11, using the above procedure but using a different hydroxy-substituted hydrazine and / or a different dialkylbromo- or mercapto-substituted phosphonate instead of 4-hydroxyphenylhydrazine 174.1 The product obtained is obtained.

  (Example 175)

ケトアルデヒド１７３．２は、ヒドラジンと反応されて、ピラゾール誘導体１７５．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、室温で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物１７５．６（ここで、Ｒ^２およびＸは、上で定義したとおりである）または反応性ブロモヘテロ芳香族試薬と反応されて、アルキル化生成物１７５．３および１７５．４が生成される。置換ピラゾールのアルキル化は、例えば、Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ ３０９（Ｌｏｎｇｍａｎ，１９９２）で記述されている。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、ジメチルアミノピリジン、リチウムヘキサメチルジシラジドなど）の存在下にて、等モル量のこれらの基質の間で、実行される。生成物１７５．３および１７５．４は、Ｘがジアルキルホスホノである場合以外は、本明細書中で記述された手順を使用して、ホスホネート１７５．５および１７５．６に変換され、次いで、脱保護／塩素化／アシル化すると、２１−クロロ１７−（２−フロエート）化合物１７５．８および１７５．１０が得られる。

Ketoaldehyde 173.2 is reacted with hydrazine to give pyrazole derivative 175.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc. 1964, 86, 1520. This reaction is carried out in acetic acid at room temperature. The pyrazole product is then reacted with a bromomethyl compound 175.6 (where R ² and X are as defined above) or a reactive bromoheteroaromatic reagent to yield the alkylated product 175.3. And 175.4 are generated. Alkylation of substituted pyrazoles is described, for example, in T.W. L. Gilchrist, Heterocyclic Chemistry 309 (Longman, 1992). This reaction is carried out between equimolar amounts of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.) Executed. Products 175.3 and 175.4 are converted to phosphonates 175.5 and 175.6 using the procedures described herein, except when X is a dialkylphosphono, then Deprotection / chlorination / acylation yields 21-chloro 17- (2-furoate) compounds 175.8 and 175.10.

  (Example 176)

ピラゾール１７５．１は、２，５−ジブロモピリミジン１７６．１（Ｃｈｅｍ．Ｌｅｔｔ．，１９９２，５８３）と反応されて、ピラゾール１７６．２および１７６．３が得られる。次いで、これらの生成物は、上記のように、亜リン酸ジアルキルとカップリングされて、側鎖脱保護および変性後、上記のように、２１−クロロ１７−（２−フロエート）１７６．５および１７６．７が得られる。

Pyrazole 175.1 is reacted with 2,5-dibromopyrimidine 176.1 (Chem. Lett., 1992, 583) to give pyrazoles 176.2 and 176.3. These products are then coupled with dialkyl phosphites, as described above, and after side chain deprotection and denaturation, as described above, 21-chloro 17- (2-furoate) 176.5 and 176.7 is obtained.

  (Example 177)

ピラゾール１７５．１は、テトラヒドロフラン溶液中にて、１，２−ビス（ブロモメチル）シクロブタン１７７．１（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９８１，４６，３５３０）およびカリウムヘキサメチルジシラジドと反応されて、アルキル化生成物１７７．１および１７７．２が得られる。次いで、１’−置換異性体１７７．２は、Ａｒｂｕｚｏｖ反応において、亜リン酸トリアルキルと反応されて、脱保護および側鎖変性後、２１−クロロ１７−（２−フロエート）１７７．５が得られる。このＡｒｂｕｚｏｖ反応は、Ｈａｎｄｂ．Ｏｒｇａｎｏｐｈｏｓｐｈｏｒｕｓ Ｃｈｅｍ．，１９９２，１１５で記述されている。この手順（ここで、ブロモ置換基は、対応するホスホネートに変換される）では、その基質は、約６０℃〜約１６０℃で、５〜５０倍モル過剰の亜リン酸トリアルキルと共に加熱されて、この変換が引き起こされる。

Pyrazole 175.1 was reacted with 1,2-bis (bromomethyl) cyclobutane 177.1 (J. Org. Chem., 1981, 46, 3530) and potassium hexamethyldisilazide in tetrahydrofuran solution, The alkylated products 177.1 and 177.2 are obtained. The 1′-substituted isomer 177.2 is then reacted with a trialkyl phosphite in an Arbuzov reaction to give 21-chloro 17- (2-furoate) 177.5 after deprotection and side chain modification. It is done. This Arbuzov reaction is described in Handb. Organophosphorus Chem. 1992, 115. In this procedure, where the bromo substituent is converted to the corresponding phosphonate, the substrate is heated at about 60 ° C. to about 160 ° C. with a 5-50 fold molar excess of trialkyl phosphite. This conversion is caused.

  The 2'-substituted pyrazole 177.3 is subjected to the same series of reactions to give the amine phosphonate 177.7.

  Using the above procedure, but using different dibromides, products similar to 177.5 and 177.7 are obtained.

  (Example 178)

ブデソニド１７８Ａの２０−ケトン基および／または２１−水酸基が保護されて誘導体１７８．１が得られる保護−脱保護手順。このケトンは、例えば、その環状エチレンケタールに変換することにより、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．１９５５，７７，１９０４で記述されているように、トルエン溶液中にて、還流温度で、エチレングリコールおよび酸触媒と反応させることにより、保護される。脱保護は、Ｊ．Ｃｈｅｍ．Ｓｏｃ．，Ｃｈｅｍ．Ｃｏｍｍ．，１９８７，１３５１で記述されているように、アセトン水溶液中にて、ピリジニウムトシレートと反応させることにより、引き起こされる。

A protection-deprotection procedure in which the 20-ketone group and / or 21-hydroxyl group of budesonide 178A is protected to give derivative 178.1. This ketone can be obtained, for example, by converting it to its cyclic ethylene ketal. Am. Chem. Soc. 1955, 77, 1904, protected by reaction with ethylene glycol and an acid catalyst in a toluene solution at reflux temperature. Deprotection is described in J. Org. Chem. Soc. , Chem. Comm. , 1987, 1351, by reacting with pyridinium tosylate in an aqueous acetone solution.

  Alternatively, the 20-ketone is protected by conversion to N, N-dimethylhydrazone. This dimethylhydrazone can be obtained from Org. Syn. , 1970, 50, 102, by the reaction of ketone 178A with N, N-dimethylhydrazine in ethanol-acetic acid. This group is described in J. Org. Am. Chem. Soc. , 1979, 101, 5841, by treatment with sodium acetate and acetic acid in aqueous tetrahydrofuran.

  Alternatively, the 20-ketone is protected as the diethylamine adduct. In this procedure, substrate 178A is Chem. Soc. , Chem. Comm. , 1983, 406, and reacted with titanium tetrakis (diethylamide) to give this adduct. This ketone is deprotected by reacting with water in an aqueous organic solvent.

  This 21-hydroxyl group is protected, for example, by reacting with 1 molar equivalent of acetyl chloride in dichloromethane / pyridine by conversion to its acetate. This 21-acetoxy group is removed by reacting with 1 molar equivalent of lithium hydroxide in an aqueous dimethoxyethane solution.

  Alternatively, the 21-hydroxyl group is Am. Chem. Soc. , 1972, 94, 6190, by reaction with 1 molar equivalent of tertiary butylchlorodimethylsilane and imidazole in a dimethylformamide solution by conversion to tertiary butyldimethylsilyl ether. Is protected. This silyl ether is disclosed in J. Am. Chem. Soc. , 1972, 94, 6190, by reaction with tetrabutylammonium fluoride in tetrahydrofuran solution.

  The protected compound 178.1 is then converted to the phosphonate-containing analog 178.2 using the following procedure, and the protecting group is then removed as described above to give the phosphonate 178.3. .

  (Example 179)

ケトン保護誘導体１７９．１は、アミンまたはヒドロキシルアミン１７９．２（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルもしくはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールもしくはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどであり得る。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）または含アルコール溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、イミンまたはオキシム１７９．３が得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、この保護基は、本明細書中で記述されているように、除去されて、２０−ケトホスホネート生成物１７９．４が得られる。

The ketone protected derivative 179.1 is an amine or hydroxylamine 179.2 (wherein R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally contains a heteroatom O, S or N). Or a functional group (such as amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O, S or And X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X can be a dialkylphosphono, bromo, hydroxy, amino, carboxyl, and the like. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcohol-containing solvent (eg, ethanol), optionally in the presence of an acid catalyst. To give imine or oxime 179.3. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. The protecting group is then removed as described herein to give the 20-ketophosphonate product 179.4.

  (Example 179A)

ホスホネート基を含むヒドロキシルアミンエーテルの調製もまた、図示している。この手順では、ホスホネート１７９．５（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン１７９．６（Ａｌｄｒｉｃｈ）と反応されて、エーテル１７９．７が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムまたはジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル１７９．８が得られる。上記手順はまた、置換ヒドロキシルアミン（これらは、ホスホネートの前駆体である）を調製するために使用される。

The preparation of hydroxylamine ethers containing phosphonate groups is also illustrated. In this procedure, a phosphonate 179.5 (where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 179.6 (Aldrich) to give an ether 179.7 is generated. This reaction is performed between equimolar amounts of the reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium hydroxide or dimethylaminopyridine). Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 179.8. The above procedure is also used to prepare substituted hydroxylamines, which are precursors of phosphonates.

  (Example 180)

基質１７９．１（ここで、その２０−ケトンは、ジメチルヒドラゾン誘導体として、保護されている）は、ジアルキルホスホノメチルヒドロキシルアミン１８０．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔ．Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシム１８０．２が得られる。実施例１７９で記述されているように、脱保護すると、２０−ケトホスホネート１８０．３が得られる。このオキシム形成反応は、室温で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。

Substrate 179.1 (where the 20-ketone is protected as a dimethylhydrazone derivative) is a dialkylphosphonomethylhydroxylamine 180.1 (as described above, which is a dialkyltrifluoromethyl phosphonate as described above). Reaction with sulfonyloxymethyl (prepared from Tet. Lett., 1986, 27, 1477) and BOC-hydroxylamine) provides oxime 180.2. Deprotection yields 20-ketophosphonate 180.3 as described in Example 179. This oxime formation reaction is carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at room temperature.

  Using the above procedure, but using a different oxime ether 179.2 instead of hydroxylamine ether 180.1, the corresponding product 179.4 is obtained.

  (Example 181)

化合物１７９．１（ここで、そのホスホネート基は、ベンジルオキシオキシム基によって、結合されている）の調製は、上で図示している。この手順では、ジエノン１７９．１（ここで、その２０−ケトンは、ジメチルヒドラゾンとして、保護されている）は、上記のように、Ｏ−（２−ブロモベンジル）ヒドロキシルアミン１８１．１（これは、上記のように、臭化２−ブロモベンジルおよびＢＯＣ−保護ヒドロキシルアミン１７９．６から調製した）と反応されて、オキシム１８１．２が得られる。次いで、この保護基は、除去されて、２０−ケト生成物１８１．３が生じる。次いで、後者の生成物は、パラジウム触媒の存在下にて、亜リン酸ジアルキル１８１．４と反応されて、ホスホネート１８１．５が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、約１００℃で、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。

The preparation of compound 179.1, where the phosphonate group is attached by a benzyloxyoxime group, is illustrated above. In this procedure, dienone 179.1 (where the 20-ketone is protected as a dimethylhydrazone) is, as described above, O- (2-bromobenzyl) hydroxylamine 181.1 (which is , Prepared from 2-bromobenzyl bromide and BOC-protected hydroxylamine 179.6 as described above) to give oxime 181.2. The protecting group is then removed to yield the 20-keto product 181.3. The latter product is then reacted with a dialkyl phosphite 181.4 in the presence of a palladium catalyst to give the phosphonate 181.5. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed at about 100 ° C. in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0).

  Alternatively, bromo compound 181.3 is coupled with dialkyl vinyl phosphonate 181.6 (Aldrich) to give phosphonate 181.7. The coupling of aryl halides with olefins by this Heck reaction is described, for example, in Advanced Organic Chemistry, (by FA Carey and RJ Sundberg), Plenum, 2001, p. 503ff and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)) and optionally in the presence of a base such as triethylamine or potassium carbonate. Optionally, the styrenoid double bond present in product 181.7 is reduced, for example by reaction with diimide, to produce saturated analog 181.8. Reduction of olefinic bonds is described in Comprehensive Organic Transformations (by RC Larock), VCH, 1989, p. It is described in 6ff. This conversion is performed, for example, by catalytic hydrogenation using a palladium-on-carbon catalyst and hydrogen or hydrogen donor, or by using diimide or diborane.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromobenzyl reagent 181.1, compounds 181.5, 181.7 and A product similar to 181.8 is obtained.

  (Example 182)

基質１７１．１（ここで、その２０−ケトンは、ジメチルヒドラゾンとして、保護されている）は、ホスホン酸ジアルキル４−アミノフェニル１８２．１（Ｅｐｓｉｌｏｎ）と反応されて、脱保護後、イミン生成物１８２．２が得られる。このイミン形成反応は、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われる。

Substrate 171.1, where the 20-ketone is protected as dimethylhydrazone, is reacted with dialkyl 4-aminophenyl 182.1 (Epsilon) phosphonate to yield the imine product after deprotection. 182.2 is obtained. This imine formation reaction is carried out in a hydrocarbon solvent (eg toluene or xylene) at reflux temperature in the presence of a basic catalyst (eg sodium methoxide) or an acidic catalyst (eg p-toluenesulfonic acid). And conducted under azeotropic conditions.

  Using the above procedure, but using a different amino-substituted aryl phosphonate or heteroaryl phosphonate instead of 4-aminophenyl phosphonate 182.1, a product similar to 182.2 is obtained.

  (Example 183)

ホスホネート（ここで、そのホスホネートは、オキシイミノ基およびカーバメート連鎖によって、結合されている）の調製は、ここで図示している。この手順では、ジエノン１７１．１（ここで、その２０−ケトンは、ジメチルヒドラゾンとして保護される）は、４−アミノブチルヒドロキシルアミン１８３．１（Ｐｏｌ．Ｊ．Ｃｈｅｍ．，１９８１，５５，１１６３）と反応されて、オキシム１８３．２が生じる（ステロイド性１，４−ジエン−３−オンと置換ヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている）。この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物の間で実行される。次いで、生成物１８３．２は、ホスホン酸ジアルキル２−ヒドロキシエチル１８３．３（Ｅｐｓｉｌｏｎ）およびカルボニルジイミダゾール（ＣＤＩ）とカップリングされて、脱保護後、カーバメートオキシム１８３．４が生じる。カーバメートの調製は、Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ，Ａ．Ｒ．Ｋａｔｒｉｔｚｋｙ，（編），Ｐｅｒｇａｍｏｎ，１９９５，第６巻，ｐ４１６ｆｆおよびＯｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ，（Ｓ．Ｒ．ＳａｎｄｌｅｒおよびＷ．Ｋａｒｏによる），Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９８６，ｐ．２６０ｆｆで記述されている。この手順では、このアミンは、不活性非プロトン性溶媒（例えば、ジクロロメタンまたはテトラヒドロフラン）中にて、ホスゲンまたはそれらの官能性等価物（例えば、カルボニルジイミダゾール、トリホスゲン、ペンタフルオロフェニルカーボネートなど）と反応されて、対応する活性化アシルアミンが得られる。次いで、後者の化合物は、アルコールと反応されて、このカーバメートが生じる。

The preparation of phosphonates, where the phosphonate is linked by an oximino group and a carbamate linkage, is illustrated here. In this procedure, dienone 171.1 (where the 20-ketone is protected as dimethylhydrazone) is 4-aminobutylhydroxylamine 183.1 (Pol. J. Chem., 1981, 55, 1163). To give oxime 183.2 (reaction of steroidal 1,4-dien-3-one with substituted hydroxylamine is described in J. Steroid Bioch., 1976, 7, 795). This reaction is carried out between equimolar amounts of the reactants in a polar organic solvent such as pyridine or methanol, optionally in the presence of acetic acid or sodium acetate. Product 183.2 is then coupled with dialkyl 2-hydroxyethyl phosphonate 183.3 (Epsilon) and carbonyldiimidazole (CDI) to yield carbamate oxime 183.4 after deprotection. The preparation of carbamate is described in Comprehensive Organic Functional Group Transformations, A.M. R. Katritzky, (eds.), Pergamon, 1995, Vol. 6, p416ff and Organic Functional Group Preparations (by SR Sandler and W. Karo), Academic Press, 1986, p. It is described at 260ff. In this procedure, the amine is reacted with phosgene or a functional equivalent thereof (eg, carbonyldiimidazole, triphosgene, pentafluorophenyl carbonate, etc.) in an inert aprotic solvent (eg, dichloromethane or tetrahydrofuran). To obtain the corresponding activated acylamine. The latter compound is then reacted with an alcohol to yield this carbamate.

  Using the above procedure, but using a different amino substituted hydrazine and / or a different hydroxy substituted phosphonate instead of amino substituted hydrazine 183.1, a product similar to 183.4 is obtained.

  (Example 184)

ジエノン１７８．３（ここで、その２１−水酸基は、実施例１７８で記述されているように、保護されている）は、還元されて、１，２−ジヒドロ生成物１８４．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物１８４．２が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジン１８４．３（ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどであり得る。この反応により、その２１−水酸基を脱保護した後、異性体２’−アリールピラゾール１８４．４および１’−アリールピラゾール１８４．５が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物の間で実行される。次いで、ピラゾール１８４．４および１８４．５は、例えば、実施例１８０および１８１で記述した手順により、ホスホネート１８４．６および１８４．７に変換される。

Dienone 178.3 (wherein the 21-hydroxyl group is protected as described in Example 178) is reduced to give the 1,2-dihydro product 184.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. The product is then Am. Chem. Soc. , 1964, 86, 1520, reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product. 184.2 is obtained. This compound is then reacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 184.3, where substituent X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent. The For example, X can be a dialkylphosphono, bromo, hydroxy, amino, carboxyl, and the like. This reaction yields the isomers 2'-arylpyrazole 184.4 and 1'-arylpyrazole 184.5 after deprotecting its 21-hydroxyl group. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). The pyrazoles 184.4 and 184.5 are then converted to the phosphonates 184.6 and 184.7, for example by the procedure described in Examples 180 and 181.

  (Example 185)

ケトアルデヒド１８４．２は、上記のように、４−ブロモフェニルヒドラジン１８５．１（Ｊ．Ｏｒｇａｎｏｍｅｔ．Ｃｈｅｍ．，１９９９，６２，５８１）と反応されて、ピラゾール１８５．２および１８５．３が得られる。次いで、２’−置換異性体１８５．２は、上記のように、リン酸ジアルキル１８４．４と反応されて、ホスホネート１８５．５が生じる。

Ketoaldehyde 184.2 is reacted with 4-bromophenylhydrazine 185.1 (J. Organomet. Chem., 1999, 62, 581) to give pyrazoles 185.2 and 185.3 as described above. . The 2'-substituted isomer 185.2 is then reacted with a dialkyl phosphate 184.4 as described above to give the phosphonate 185.5.

  Isomeric pyrazole 185.3 is reacted with 1 molar equivalent of dialkyl 4-vinylphenyl phosphonate 185.6 (Macromolecules, 1998, 31, 2918) in the Heck reaction as described above to give phosphonate 185.7. Arise.

  Using the above procedure, but using different bromo-substituted hydrazines and / or different alkyl-substituted phosphonates, products similar to 185.5 and 185.7 are obtained.

  (Example 186)

ケトアルデヒド１８４．２は、上記のように、４−ヒドロキシフェニルヒドラジン１８６．１（ＥＰ ４３７１０５）と反応されて、ピラゾール１８６．２および１８６．３が生成される。次いで、２’−置換異性体１８６．２は、ジメチルホルムアミド溶液中にて、７０°で、１モル当量のホスホン酸ジアルキルブロモプロピル１８６．４（Ｊ．Ａｍｅｒ．Ｃｈｅｍ．Ｓｏｃ．，２０００，１２２，１５５４）および炭酸セシウムと反応されて、エーテルホスホネート１８６．５が得られる。

Ketoaldehyde 184.2 is reacted with 4-hydroxyphenylhydrazine 186.1 (EP 437105) as described above to produce pyrazoles 186.2 and 186.3. The 2′-substituted isomer 186.2 was then obtained in a dimethylformamide solution at 70 ° with 1 molar equivalent of dialkylbromopropyl phosphonate 186.4 (J. Amer. Chem. Soc., 2000, 122, 1554) and cesium carbonate to give ether phosphonate 186.5.

  Alternatively, 1′-substituted pyrazole 186.3 is coupled with dialkyl 2-mercaptoethyl phosphonate 186.6 (Zh. Obsche. Khim., 1973, 43, 2364) in Mitsunobu reaction to produce thioether phosphonate 186. 7 is prepared. Preparation of aromatic ethers and thioethers by Mitsunobu reaction is described, for example, in Comprehensive Organic Transformations, R.A. C. Larock, VCH, 1989, p. 448 and Advanced Organic Chemistry, Part B, F .; A. Carey and R.C. J. et al. Sundberg, Plenum, 2001, pages 153-4 and Org. React. 1992, 42, 335. The phenol and alcohol or thiol component are reacted together in the presence of a dialkyl azodicarboxylate and a triarylphosphine in an aprotic solvent (eg, tetrahydrofuran) to give their ether or thioether product. . This procedure is also described in Org. React. 1992, 42, 335-656.

  Similar to compounds 186.5 and 186.7 using the above procedure but using different hydroxyaryl hydrazines and / or different dialkyl bromo- or mercapto-substituted phosphonates instead of hydroxyphenyl hydrazine 186.1 A product is obtained.

  (Example 187)

ケトアルデヒド１８４．２は、ヒドラジンと反応されて、ピラゾール誘導体１８７．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、周囲温度で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物１８７．２（ここで、Ｒ^２およびＸは、上で定義したとおりである）または反応性ブロモヘテロ芳香族試薬と反応されて、アルキル化生成物１８７．３および１８７．４が生成される。置換ピラゾールのアルキル化は、例えば、Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ，Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｌｏｎｇｍａｎ，１９９２，３０９頁で記述されている。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、ジメチルアミノピリジン、リチウムヘキサメチルジシラジドなど）の存在下にて、等モル量のこれらの基質の間で、実行される。生成物１８７．３および１８７．４は、Ｘがジアルキルホスホノである場合以外は、本明細書中で記述された手順を使用して、ホスホネート１８７．５および１８７．６に変換される。

Ketoaldehyde 184.2 is reacted with hydrazine to give pyrazole derivative 187.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc. 1964, 86, 1520. This reaction is carried out in acetic acid at ambient temperature. This pyrazole product is then reacted with a bromomethyl compound 187.2 (where R ² and X are as defined above) or a reactive bromoheteroaromatic reagent to yield the alkylated product 187.3. And 187.4 are generated. Alkylation of substituted pyrazoles is described, for example, in Heterocyclic Chemistry, T .; L. Gilchrist, Longman, 1992, page 309. This reaction is carried out between equimolar amounts of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.) Executed. Products 187.3 and 187.4 are converted to phosphonates 187.5 and 187.6 using the procedures described herein except when X is a dialkylphosphono.

  (Example 188)

ピラゾール１８７．１は、ジメチルホルムアミド溶液中にて、７０°で、１モル当量のホスホン酸ジアルキル４−ブロモメチルフェニル１８８．１（Ｔｅｔ．，１９９８，５４，９３４１）およびリチウムヘキサメチルジシラジドと反応されて、ピラゾール１８８．２および１８８．３が得られる。上記手順を使用するが、異なるブロモメチル置換ホスホネートを使用して、１８８．２および１８８．３と類似した生成物が得られる。

Pyrazole 187.1 was synthesized in a dimethylformamide solution at 70 ° with 1 molar equivalent of dialkyl 4-bromomethylphenyl phosphonate 188.1 (Tet., 1998, 54, 9341) and lithium hexamethyldisilazide. Reacted to give pyrazoles 188.2 and 188.3. Using the above procedure, but using different bromomethyl substituted phosphonates, products similar to 188.2 and 188.3 are obtained.

  (Example 189)

ピラゾール１８７．１は、テトラヒドロフラン溶液中にて、１，３−ビス（ブロモメチル）シクロペンタン１８９．１（Ｂｕｌｌ．Ｓｏｃ．Ｃｈｉｍ．Ｆｒ．，１９７５，１２９５）および水素化ナトリウムと反応されて、アルキル化生成物１８９．２および１８９．３が得られる。次いで、２’−置換異性体１８９．２は、Ａｒｂｕｚｏｖ反応において、亜リン酸トリアルキルと反応されて、ホスホネート１８９．４が生じる。このＡｒｂｕｚｏｖ反応は、Ｈａｎｄｂ．Ｏｒｇａｎｏｐｈｏｓｐｈｏｒｕｓ Ｃｈｅｍ．，１９９２，１１５で記述されている。この手順（ここで、ブロモ置換基は、対応するホスホネートに変換される）では、その基質は、約６０°〜約１６０°で、５〜５０倍モル過剰の亜リン酸トリアルキルと共に加熱されて、この変換が引き起こされる。

Pyrazole 187.1 was reacted with 1,3-bis (bromomethyl) cyclopentane 189.1 (Bull. Soc. Chim. Fr., 1975, 1295) and sodium hydride in tetrahydrofuran solution to give alkylated Products 189.2 and 189.3 are obtained. The 2'-substituted isomer 189.2 is then reacted with a trialkyl phosphite in an Arbuzov reaction to give the phosphonate 189.4. This Arbuzov reaction is described in Handb. Organophosphorus Chem. 1992, 115. In this procedure, where the bromo substituent is converted to the corresponding phosphonate, the substrate is heated at about 60 ° to about 160 ° with a 5-50 fold molar excess of trialkyl phosphite. This conversion is caused.

  The 2′-substituted pyrazole 189.3 is reacted with 1 molar equivalent of dialkylmethylaminomethyl phosphonate 189.5 and cesium carbonate in dimethylformamide solution at 70 ° to give amine phosphonate 189.6. .

  Using the above procedure, but using different dihalides and / or different amino-substituted phosphonates, products similar to 189.4 and 189.6 are obtained.

  (Example 190)

保護−脱保護手順（ここで、リメキソロン１９０Ａの２０−ケトン基は、保護されて、誘導体１９０．１が得られる。このケトンは、例えば、その環状エチレンケタールに変換することにより、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９５５，７７，１９０４で記述されているように、トルエン溶液中にて、還流温度で、エチレングリコールおよび酸触媒と反応させることにより、保護される。脱保護は、Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｃｈｅｍ．Ｃｏｍｍ．，１９８７，１３５１で記述されているように、アセトン水溶液中にて、ピリジニウムトシレートと反応させることにより、引き起こされる。

Protection-deprotection procedure (where the 20-ketone group of rimexolone 190A is protected to give derivative 190.1. This ketone can be converted, for example, to its cyclic ethylene ketal by J. Am. Chem. Soc., 1955, 77, 1904, is protected by reacting with ethylene glycol and an acid catalyst in a toluene solution at reflux temperature, deprotection is described in J. Chem. Soc.Chem.Com., 1987, 1351, caused by reaction with pyridinium tosylate in an aqueous acetone solution.

  Alternatively, the 20-ketone is protected by conversion to N, N-dimethylhydrazone. This dimethylhydrazone can be obtained from Org. Syn. , 1970, 50, 102, by the reaction of ketone 190A with N, N-dimethylhydrazine in ethanol-acetic acid. This group is described in J. Org. Am. Chem. Soc. , 1979, 101, 5841, by treatment with sodium acetate and acetic acid in aqueous tetrahydrofuran.

  Alternatively, the 20-ketone is protected as the diethylamine adduct. In this procedure, substrate 190.1 is Chem. Soc. , Chem. Comm. , 1983, 406, and reacted with titanium tetrakis (diethylamide) to give this adduct. This ketone is deprotected by reacting with water in an aqueous organic solvent.

  The protected compound 190.2 is then converted to the phosphonate-containing analog 190.3 using the following procedure, and the protecting group is then removed as described above to give the phosphonate 190.3. .

  (Example 191)

ケトン保護誘導体１９０．１は、アミンまたはヒドロキシルアミン１９１．１（ここで、Ｒ^２は、アルキル、アルケニル、シクロアルキルまたはシクロアルケニル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）、または官能基（例えば、アミド、エステル、オキシム、スルホキシドまたはスルホンなど）、または必要に応じて置換したアリール、ヘテロアリールまたはアラルキル基（これは、必要に応じて、ヘテロ原子Ｏ、ＳまたはＮを含む）であり、そしてＸは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応は、非プロトン性溶媒（例えば、ピリジンまたはキシレン）またはアルコール溶媒（例えば、エタノール）中で、必要に応じて、酸触媒の存在下にて、等モル量の反応物間で行われて、イミンまたはオキシム１９１．２が得られる。ステロイド性３−ケトンのオキシムの調製は、Ａｎａｌ．Ｂｉｏｃｈ．，１９７８，８６，１３３およびＪ．Ｍａｓｓ．Ｓｐｅｃｔｒｏｍ．，１９９５，３０，４９７で記述されている。次いで、この保護基は、実施例１９０で記述されるように除去されて、２０−ケトホスホネート生成物１９１．３が得られる。

The ketone protected derivative 190.1 is an amine or hydroxylamine 191.1 where R ² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group (which optionally includes a heteroatom O, S or N Or a functional group (such as amide, ester, oxime, sulfoxide or sulfone), or an optionally substituted aryl, heteroaryl or aralkyl group (which optionally includes a heteroatom O, S or And X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent). For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction is performed between equimolar amounts of reactants in an aprotic solvent (eg, pyridine or xylene) or an alcohol solvent (eg, ethanol), optionally in the presence of an acid catalyst. The imine or oxime 191.2 is obtained. Preparation of steroidal 3-ketone oximes is described in Anal. Bioch. , 1978, 86, 133 and J.A. Mass. Spectrom. 1995, 30, 497. The protecting group is then removed as described in Example 190 to give the 20-ketophosphonate product 191.3.

  (Example 191A)

ホスホネート基を含むヒドロキシルアミンエーテルの調製もまた、図示している。この手順では、ホスホネート１９１．４（ここで、Ｌｖは、脱離基（例えば、ブロモまたはトリフルオロメチルスルホニルオキシ）である）は、ＢＯＣ−ヒドロキシルアミン１９１．５（Ａｌｄｒｉｃｈ）と反応されて、エーテル１９１．６が生成される。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、水酸化カリウムジメチルアミノピリジン）の存在下にて、等モル量の反応物間で行われる。次いで、例えば、トリフルオロ酢酸で処理することにより脱保護すると、ヒドロキシルアミンエーテル１９１．７が得られる。上記手順はまた、置換ヒドロキシルアミン（これらは、ホスホネートの前駆体である）を調製するのに使用される。

The preparation of hydroxylamine ethers containing phosphonate groups is also illustrated. In this procedure, a phosphonate 191.4 (where Lv is a leaving group (eg, bromo or trifluoromethylsulfonyloxy)) is reacted with BOC-hydroxylamine 191.5 (Aldrich) to give an ether 191.6 is generated. This reaction is carried out between equimolar amounts of the reactants in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, potassium dimethylaminopyridine). Subsequent deprotection, for example by treatment with trifluoroacetic acid, gives hydroxylamine ether 191.7. The above procedure is also used to prepare substituted hydroxylamines, which are precursors of phosphonates.

  (Example 192)

基質１９０．１（ここで、その２０−ケトンは、ジメチルヒドラゾン誘導体として、保護されている）は、ジアルキルホスホノメチルヒドロキシルアミン１９２．１（これは、上記のように、ホスホン酸ジアルキルトリフルオロメチルスルホニルオキシメチル（Ｔｅｔ．Ｌｅｔｔ．，１９８６，２７，１４７７）およびＢＯＣ−ヒドロキシルアミンから調製した）と反応されて、オキシム１９２．２が得られる。実施例１９１で記述されているように、脱保護すると、２０−ケトホスホネート１９２．３が得られる。このオキシム形成反応は、典型的には、周囲温度で、エタノール−酢酸溶液中にて、等モル量の反応物間で実行される。

Substrate 190.1, where the 20-ketone is protected as a dimethylhydrazone derivative, is a dialkylphosphonomethylhydroxylamine 192.1 (which is a dialkyltrifluoromethyl phosphonate as described above). Reaction with sulfonyloxymethyl (prepared from Tet. Lett., 1986, 27, 1477) and BOC-hydroxylamine) gives oxime 192.2. Deprotection provides 20-ketophosphonate 192.3 as described in Example 191. This oxime formation reaction is typically carried out between equimolar amounts of reactants in an ethanol-acetic acid solution at ambient temperature.

  Using the above procedure, but using a different oxime ether 192.1 instead of hydroxylamine ether 192.1, the corresponding product 191.3 is obtained.

  (Example 193)

ジエノン１９０．１（ここで、その２０−ケトンは、ジメチルヒドラゾンとして、保護されている）は、上記のように、Ｏ−（３−ブロモベンジル）ヒドロキシルアミン１９３．１（これは、上記のように、臭化３−ブロモベンジルから調製した）およびＢＯＣ−保護ヒドロキシルアミン１９１．５と反応されて、オキシム１９３．２が得られる。次いで、この保護基は、除去されて、２０−ケト生成物１９３．３が生じる。次いで、後者の生成物は、パラジウム触媒の存在下にて、リン酸ジアルキル１９３．４と反応されて、ホスホネート１９３．５が得られる。臭化アリールと亜リン酸ジアルキルとの間のカップリング反応によるホスホン酸アリールの調製は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１で記述されている。この反応は、約１００℃で、不活性溶媒（例えば、トルエン）中で、塩基（例えば、トリエチルアミン）および触媒量のテトラキス（トリフェニルホスフィン）パラジウム（０）の存在下にて、実行される。

Dienone 190.1 (where the 20-ketone is protected as dimethylhydrazone) is, as above, O- (3-bromobenzyl) hydroxylamine 193.1 (as described above). Prepared from 3-bromobenzyl bromide) and BOC-protected hydroxylamine 191.5 to give oxime 193.2. The protecting group is then removed to yield the 20-keto product 193.3. The latter product is then reacted with a dialkyl phosphate 193.4 in the presence of a palladium catalyst to give the phosphonate 193.5. The preparation of aryl phosphonates by a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Am. Med. Chem. 1992, 35, 1371. This reaction is performed at about 100 ° C. in an inert solvent (eg, toluene) in the presence of a base (eg, triethylamine) and a catalytic amount of tetrakis (triphenylphosphine) palladium (0).

  Alternatively, bromo compound 193.3 is coupled with dialkylpropenyl phosphonate 193.6 (Aldrich) to give phosphonate 193.7. The coupling of aryl halides and olefins by this Heck reaction is described in, for example, A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry 503ff (Plenum, 2001) and Acc. Chem. Res. 1979, 12, 146. The aryl bromide and olefin can be synthesized in a polar solvent (eg, dimethylformamide or dioxane) with a palladium (0) catalyst (eg, tetrakis (triphenylphosphine) palladium (0)) or a palladium (II) catalyst (eg, acetic acid). Coupling in the presence of palladium (II)), optionally in the presence of a base (eg triethylamine or potassium carbonate). If desired, the styrenoid double bond present in product 193.7 is reduced, for example by reaction with diimide, to produce saturated analog 193.8. Reduction of olefinic bonds is described in R.A. C. Larock, Comprehensive Organic Transformations 6ff (VCH 1989). This conversion is performed, for example, by catalytic hydrogenation using a palladium on carbon catalyst and hydrogen or hydrogen donor, or by using diimide or diborane.

  Using the above procedure, but using different bromo-substituted aryl or heteroarylalkoxyhydroxylamines and / or different dialkylalkenyl phosphonates instead of bromobenzyl reagent 193.1, compounds 193.5, 193.7 and A product similar to 193.8 is obtained.

  (Example 194)

基質１９０．１（ここで、その２０−ケトンは、ジメチルヒドラゾン誘導体として、保護されている）は、ホスホン酸ジアルキル４−アミノ−２−フリル１９４．１（これは、上記のように、４−アミノ−２−ブロモフラン（Ｔｅｔ．，１９８７，４３，３２９５）および亜リン酸ジアルキルの間のパラジウム触媒カップリング反応により、調製した）と反応されて、脱保護後、イミン生成物１９４．２が得られる。このイミン形成反応は、炭化水素溶媒（例えば、トルエンまたはキシレン）中にて、還流温度で、塩基性触媒（例えば、ナトリウムメトキシド）または酸性触媒（例えば、ｐ−トルエンスルホン酸）の存在下にて、共沸条件下にて行われる。

Substrate 190.1 (where the 20-ketone is protected as a dimethylhydrazone derivative) is a dialkyl 4-amino-2-furyl phosphonate 194.1 (as described above, 4- (Prepared by a palladium-catalyzed coupling reaction between amino-2-bromofuran (Tet., 1987, 43, 3295) and dialkyl phosphite) to give the imine product 194.2 after deprotection. It is done. This imine formation reaction is carried out in a hydrocarbon solvent (eg toluene or xylene) at reflux temperature in the presence of a basic catalyst (eg sodium methoxide) or an acidic catalyst (eg p-toluenesulfonic acid). And conducted under azeotropic conditions.

  Using the above procedure, but using a different amino substituted aryl phosphonate or heteroaryl phosphonate instead of 4-aminofuryl phosphonate 194.1, a product similar to 194.2 is obtained.

  (Example 195)

ジエノン１９０．１（ここで、その２０−ケトンは、ジメチルヒドラゾンとして、保護されている）は、２−カルボキシエチルヒドロキシルアミン１９５．１（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９０，３３，１４２３）と反応されて、オキシム１９５．２が生じる。ステロイド性１，４−ジエン−３−オンとヒドロキシルアミンとの反応は、Ｊ．Ｓｔｅｒｏｉｄ Ｂｉｏｃｈ．，１９７６，７，７９５で記述されている；この反応は、極性有機溶媒（例えば、ピリジンまたはメタノール）中で、必要に応じて、酢酸または酢酸ナトリウムの存在下にて、等モル量の反応物の間で実行される。次いで、生成物１９５．２は、ホスホン酸ジアルキル４−アミノフェニル１９５．３（Ｅｐｓｉｌｏｎ）およびジシクロヘキシルカルボジイミドと反応されて、脱保護後、アミドオキシム１９５．４が生じる。カルボン酸および誘導体からのアミドの調製は、例えば、Ｓ．Ｒ．ＳａｎｄｌｅｒおよびＷ．Ｋａｒｏ，Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ ２７４（Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９６８）およびＲ．Ｃ．Ｌａｒｏｃｋ，Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ，９７２ｆｆ（ＶＣＨ，１９８９）で記述されている。このカルボン酸は、活性化剤（例えば、ジシクロヘキシルカルボジイミドまたはジイソプロピルカルボジイミド）の存在下にて、必要に応じて、例えば、ヒドロキシベンゾトリアゾール、Ｎ−ヒドロキシスクシンイミドまたはＮ−ヒドロキシピリドンの存在下にて、非プロトン性溶媒（例えば、ピリジン、ＤＭＦまたはジクロロメタン）中で、このアミンと反応されて、このアミドが得られる。

Dienone 190.1, where the 20-ketone is protected as dimethylhydrazone, is reacted with 2-carboxyethylhydroxylamine 195.1 (J. Med. Chem., 1990, 33, 1423). The oxime 195.2. The reaction of steroidal 1,4-dien-3-one with hydroxylamine is described in J. Am. Steroid Bioch. 1976, 7, 795; this reaction is carried out in a polar organic solvent (eg pyridine or methanol), optionally in the presence of acetic acid or sodium acetate, and equimolar amounts of the reactants. Executed between. The product 195.2 is then reacted with dialkyl 4-aminophenyl 195.3 (Epsilon) phosphonate and dicyclohexylcarbodiimide to yield the amide oxime 195.4 after deprotection. Preparation of amides from carboxylic acids and derivatives is described, for example, in S.H. R. Sandler and W.W. Karo, Organic Functional Group Preparations 274 (Academic Press, 1968) and R.A. C. Larock, Comprehensive Organic Transformations, 972ff (VCH, 1989). The carboxylic acid can be used in the presence of an activator (e.g., dicyclohexylcarbodiimide or diisopropylcarbodiimide), optionally in the presence of, for example, hydroxybenzotriazole, N-hydroxysuccinimide, or N-hydroxypyridone. Reaction with the amine in a protic solvent such as pyridine, DMF or dichloromethane provides the amide.

  Alternatively, the carboxylic acid can be first converted to an activated derivative (eg, its acid chloride, anhydride, mixed anhydride, imidazolide, etc.) and then in the presence of an organic base (eg, pyridine), Reaction with the amine provides the amide.

  Conversion of the carboxylic acid to the corresponding acid chloride can be accomplished by reacting the carboxylic acid in an inert organic solvent (eg, dichloromethane), optionally in the presence of a catalytic amount of dimethylformamide, (eg, Can be caused by treatment with thionyl chloride or oxalyl chloride).

  Using the above procedure, but using a different carboxy-substituted hydroxylamine and / or a different amino-substituted phosphonate instead of carboxy-substituted hydroxylamine 195.1, a product similar to 195.4 is obtained.

  (Example 196)

ジエノン１９０Ａは、還元されて、１，２−ジヒドロ生成物１９６．１が得られる。この触媒水素化反応は、例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００１，４４，６０２で記述されているように、塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を使用することにより、引き起こされる。次いで、この生成物は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、不活性溶媒（例えば、トルエンまたはジメチルホルムアミド）中にて、ギ酸エチルおよび塩基（例えば、水素化ナトリウム）と反応されて、２−ホルミル生成物１９６．２が得られる。次いで、この化合物は、アルキル、アラルキル、アリールまたはヘテロアリールヒドラジン１９６．３（ここで、置換基Ｘは、ホスホネート基または引き続いてホスホネート含有置換基に変換される基のいずれかである）と反応される。例えば、Ｘは、ジアルキルホスホノ、ブロモ、ヒドロキシ、アミノ、カルボキシルなどである。この反応により、異性体２’−アリールピラゾール１９６．４および１’−アリールピラゾール１９６．５が生じる。このピラゾール形成反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されているように、酸性溶媒（例えば、酢酸）中にて、等モル量の反応物の間で実行される。次いで、ピラゾール１９６．４および１９６．５は、例えば、実施例１９２および１９３で記述された手順により、ホスホネート１９６．６および１９６．７に変換される。必要に応じて、これらの還元およびホルミル化反応は、基質１９０．１（ここで、その２０−ケトンは、環状エチレンケタールとして、保護されている）で、実行される。

Dienone 190A is reduced to give the 1,2-dihydro product 196.1. This catalytic hydrogenation reaction is described, for example, in J. Org. Med. Chem. , 2001, 44, 602 by using tris (triphenylphosphine) rhodium (I) chloride. The product is then Am. Chem. Soc. , 1964, 86, 1520, reacted with ethyl formate and a base (eg, sodium hydride) in an inert solvent (eg, toluene or dimethylformamide) to give the 2-formyl product. 196.2 is obtained. This compound is then reacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 196.3, where substituent X is either a phosphonate group or a group that is subsequently converted to a phosphonate-containing substituent. The For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomers 2'-arylpyrazole 196.4 and 1'-arylpyrazole 196.5. This pyrazole formation reaction is described in J. Am. Am. Chem. Soc. 1964, 86, 1520, carried out between equimolar amounts of the reactants in an acidic solvent (eg acetic acid). Pyrazoles 196.4 and 196.5 are then converted to phosphonates 196.6 and 196.7, for example, by the procedure described in Examples 192 and 193. If necessary, these reduction and formylation reactions are carried out with the substrate 190.1, where the 20-ketone is protected as a cyclic ethylene ketal.

  (Example 197)

ケトアルデヒド１９６．２は、上記のように、３−ヒドロキシフェニルヒドラジン１９７．１（ＪＰ ０３０１１０８１）と反応されて、ピラゾール１９７．２および１９７．３が得られる。次いで、２’−置換異性体１９７．２は、ジメチルホルムアミド溶液中にて、７０°で、１モル当量のホスホン酸ジアルキル２−ブロモエチル１９７．４（Ａｌｄｒｉｃｈ）および炭酸カリウムと反応されて、エトキシホスホネート１９７．５が生じる。

Ketoaldehyde 196.2 is reacted with 3-hydroxyphenylhydrazine 197.1 (JP 03011081) as described above to give pyrazoles 197.2 and 197.3. The 2′-substituted isomer 197.2 was then reacted with 1 molar equivalent of dialkyl 2-bromoethyl phosphonate 197.4 (Aldrich) and potassium carbonate in dimethylformamide solution at 70 ° to give ethoxyphosphonate. 197.5 results.

  Isomeric pyrazole 197.3 was reacted with 1 molar equivalent of dialkyl 3-hydroxypropyl phosphonate 197.6 (Zh. Obschei. Khim., 1974, 44, 1834) in Mitsunobu reaction to give phosphonate 197.7. Arise. Preparation of aromatic ethers by Mitsunobu reaction is described in, for example, R.A. C. Larock, Comprehensive Organic Transformations 448 (VCH, 1989), and F.R. A. Carey and R.C. J. et al. Sundberg, Advanced Organic Chemistry, Part B, 153-4 (Plenum, 2001) and Org. React. 1992, 42, 335. The phenol and alcohol or thiol component are reacted together in the presence of a dialkyl azodicarboxylate and a triarylphosphine in an aprotic solvent (eg, tetrahydrofuran) to give their ether or thioether product. . This procedure is also described in Org. React. 1992, 42, 335-656.

  Using the above procedure, but using different hydroxy substituted hydrazines and / or different bromo substituted or hydroxy substituted phosphonates, products similar to 195.5 and 197.6 are obtained.

  (Example 198)

ケトアルデヒド１９６．２は、上記のように、４−アミノフェニルヒドラジン１９８．１（Ｓｙｎ．Ｃｏｍｍ．，１９７４，４，５７）と反応されて、ピラゾール１９８．２および１９８．３が生成される。次いで、２’−置換異性体１９８．２は、ジメチルホルムアミド溶液中にて、７０°で、１モル当量のホスホン酸ジアルキル３−ブロモプロピル１９８．４（Ｊ．Ａｍｅｒ．Ｃｈｅｍ．Ｓｏｃ．，２０００，１２２，１５５４）および炭酸セシウムと反応されて、アミンホスホネート１９８．５が得られる。

Ketoaldehyde 196.2 is reacted with 4-aminophenylhydrazine 198.1 (Syn. Comm., 1974, 4, 57) as described above to produce pyrazoles 198.2 and 198.3. The 2'-substituted isomer 198.2 was then obtained in a dimethylformamide solution at 70 ° with 1 molar equivalent of a dialkyl 3-bromopropyl phosphonate 198.4 (J. Amer. Chem. Soc., 2000, 122, 1554) and cesium carbonate to give the amine phosphonate 198.5.

  Alternatively, 1′-substituted pyrazole 198.3 is reacted with dialkyl 4-hydroxymethylphenyl phosphonate 198.6 (US Pat. No. 5,569,664) and carbonyldiimidazole to prepare carbamate phosphonate 198.7. Is done. The preparation of carbamate is described in Comprehensive Organic Functional Group Transformations, A.M. R. Katritzky, Pergamon, 1995, Vol. 6, page 416ff and Organic Functional Group Preparations, S.A. R. Sandler and W.W. Karo, Academic Press, 1986, pp. 260ff. In this procedure, the amine is reacted with phosgene or a functional equivalent thereof (eg, carbonyldiimidazole, triphosgene, pentafluorophenyl carbonate, etc.) in an inert aprotic solvent (eg, dichloromethane or tetrahydrofuran). To obtain the corresponding activated acylamine. The latter compound is then reacted with an alcohol to produce its carbamate.

  Using the above procedure, but using a different amino substituted hydrazine and / or a different dialkyl bromo or hydroxy substituted phosphonate instead of aminophenyl hydrazine 198.1, products similar to 198.5 and 198.7 are obtained. can get.

  (Example 199)

ケトアルデヒド１９６．２は、ヒドラジンと反応されて、ピラゾール誘導体１９９．１が得られる。ステロイド性２−ホルミル−３−ケトンとヒドラジンとの反応は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６４，８６，１５２０で記述されている。この反応は、酢酸中にて、周囲温度で実行される。次いで、このピラゾール生成物は、ブロモメチル化合物１９９．２（ここで、Ｒ^２およびＸは、上で定義したとおりである）または反応性ブロモヘテロ芳香族試薬と反応されて、アルキル化生成物１９９．３および１９９．４が生成される。置換ピラゾールのアルキル化は、例えば、Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ，Ｔ．Ｌ．Ｇｉｌｃｈｒｉｓｔ，Ｌｏｎｇｍａｎ，１９９２，３０９頁で記述されている。この反応は、極性溶媒（例えば、ジメチルホルムアミドまたはテトラヒドロフラン）中で、塩基（例えば、ジメチルアミノピリジン、リチウムヘキサメチルジシラジドなど）の存在下にて、等モル量のこれらの基質の間で、実行される。生成物１９９．３および１９９．４は、Ｘがジアルキルホスホノである場合以外は、本明細書中で記述された手順を使用して、ホスホネート１９９．５および１９９．６に変換される。

Ketoaldehyde 196.2 is reacted with hydrazine to give the pyrazole derivative 199.1. The reaction of steroidal 2-formyl-3-ketone with hydrazine is described in J. Am. Am. Chem. Soc. 1964, 86, 1520. This reaction is carried out in acetic acid at ambient temperature. The pyrazole product is then reacted with a bromomethyl compound 199.2 (where R ² and X are as defined above) or a reactive bromoheteroaromatic reagent to yield the alkylated product 199.3. And 199.4 are generated. Alkylation of substituted pyrazoles is described, for example, in Heterocyclic Chemistry, T .; L. Gilchrist, Longman, 1992, page 309. This reaction is carried out between equimolar amounts of these substrates in a polar solvent (eg, dimethylformamide or tetrahydrofuran) in the presence of a base (eg, dimethylaminopyridine, lithium hexamethyldisilazide, etc.) Executed. Products 199.3 and 199.4 are converted to phosphonates 199.5 and 199.6 using the procedures described herein except when X is a dialkylphosphono.

  (Example 200)

ピラゾール１９９．１は、ジメチルホルムアミド溶液中にて、７０℃で、１モル当量のホスホン酸ジアルキル４−ブロモブテニル２００．１（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１３７１）およびリチウムヘキサメチルジシラジドと反応されて、ピラゾール２００．２および２００．３が得られる。

Pyrazole 199.1 was dissolved in dimethylformamide solution at 70 ° C. with 1 molar equivalent of dialkyl 4-bromobutenyl phosphonate 200.1 (J. Med. Chem., 1992, 35, 1371) and lithium hexamethyldisila. Reaction with the zide gives pyrazoles 200.2 and 200.3.

  Using the above procedure, but using different bromo-substituted phosphonates, products similar to 200.2 and 200.3 are obtained.

  (Example 201)

ピラゾール１９９．１は、テトラヒドロフラン溶液中にて、２，５−ビス（ブロモメチル）フラン２０１．１（Ｔｅｔ．，１９９９，５５，４７０９）およびカリウムヘキサメチルジシラジドと反応されて、アルキル化生成物２０１．２および２０１．３が得られる。次いで、２’−置換異性体２０１．２は、Ａｒｂｕｚｏｖ反応において、亜リン酸トリアルキルと反応されて、ホスホネート２０１．４が生じる。このＡｒｂｕｚｏｖ反応は、Ｈａｎｄｂ．Ｏｒｇａｎｏｐｈｏｓｐｈｏｒｕｓ Ｃｈｅｍ．，１９９２，１１５で記述されている。この手順（ここで、ブロモ置換基は、対応するホスホネートに変換される）では、その基質は、約６０℃〜約１６０℃で、５〜５０倍モル過剰の亜リン酸トリアルキルと共に加熱されて、この変換が引き起こされる。

Pyrazole 199.1 is reacted with 2,5-bis (bromomethyl) furan 201.1 (Tet., 1999, 55, 4709) and potassium hexamethyldisilazide in tetrahydrofuran solution to give the alkylated product. 201.2 and 201.3 are obtained. The 2'-substituted isomer 201.2 is then reacted with a trialkyl phosphite in an Arbuzov reaction to give the phosphonate 201.4. This Arbuzov reaction is described in Handb. Organophosphorus Chem. 1992, 115. In this procedure, where the bromo substituent is converted to the corresponding phosphonate, the substrate is heated at about 60 ° C. to about 160 ° C. with a 5-50 fold molar excess of trialkyl phosphite. This conversion is caused.

  1'-Substituted pyrazole 201.3 was prepared by adding 1 molar equivalent of dialkylmercaptomethyl phosphonate 201.5 (J. Med. Chem., 1985, 26, 1688) and cesium carbonate in dimethylformamide solution at ambient temperature. To give thioether phosphonate 201.6.

  Using the above procedure, but using different dihalides and / or different mercapto substituted phosphonates, products similar to 201.4 and 201.6 are obtained.

  (Example 202)

２０２．１型のＣ−２１第一級水酸基の誘導体は、図示したように、トリアムシノロンアセトニド２０２Ａを適当なホスホネートでアルキル化することにより、容易に調製される。

Derivatives of the C-21 primary hydroxyl group of type 202.1 are readily prepared by alkylating triamcinolone acetonide 202A with an appropriate phosphonate as shown.

  (Example 203)

１当量の水素化ナトリウムを使用して、化合物２０２Ａにある第一級ヒドロキシプロトンを化学選択的に抽出した後、このホスホネートトリフレートが加えられて、エーテル２０３．１が得られる。

After chemoselective extraction of the primary hydroxy proton in compound 202A using 1 equivalent of sodium hydride, the phosphonate triflate is added to give ether 203.1.

  (Example 204)

この第一級水酸基は、適当な保護基でマスクされる。２０４．１の第二級水酸基を脱離基結合ホスホネートでアルキル化し、引き続いて、脱保護した後、所望のアナログ２０４．２が得られる。

This primary hydroxyl group is masked with a suitable protecting group. After alkylating the secondary hydroxyl group of 204.1 with a leaving group-bound phosphonate followed by deprotection, the desired analog 204.2 is obtained.

  (Example 205)

トリアムシノロンアセトニド２０２Ａは、標準的なＴＢＳＣｌおよびイミダゾール条件を使用して、そのシリルエーテルとして、化学選択的に保護される（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．１９７２，９４，６１９０）。露出された第二級水酸基にて、水素化ナトリウムおよびこのホスホネートトリフレートでアルキル化すると、中間体２０５．６が得られる。このシリルエーテルを最後にＴＢＡＦで保護すると、所望の生成物２０５．７が得られる。

Triamcinolone acetonide 202A is chemoselectively protected as its silyl ether using standard TBSCl and imidazole conditions (J. Am. Chem. Soc. 1972, 94, 6190). Alkylation with sodium hydride and the phosphonate triflate at the exposed secondary hydroxyl group gives intermediate 205.6. The silyl ether is finally protected with TBAF to give the desired product 205.7.

  (Example 206)

このアセタールのホスホネート誘導体は、スキーム３．１に示されるようにトリアムシノロンアセトニド２０２Ａをジオール２０６．１に酸性加水分解することから、容易に調製される。このジオールをホスホネートアルデヒドでアセチル化すると、所望のアセタール２０６．２が得られる。本発明の特定の化合物は、以下で図示するように、調製できる。

This acetal phosphonate derivative is readily prepared from the acidic hydrolysis of triamcinolone acetonide 202A to the diol 206.1 as shown in Scheme 3.1. Acetylation of this diol with phosphonate aldehyde provides the desired acetal 206.2. Certain compounds of the invention can be prepared as illustrated below.

  (Example 207)

トリアムシノロンアセトニド２０２Ａは、まず、酢酸水溶液中にて、加水分解される（Ｃａｎ．Ｊ．Ｃｈｅｍ．１９８３，６１，６３４）。得られたジオール２０７．１は、このホスホネートアルデヒドおよび過塩素酸でアセタール化されて、アセタール２０７．２が得られる（Ｊ．Ｍｅｄ．Ｃｈｅｍ．１９９６，３９，４８８８−４８９６）。

Triamcinolone acetonide 202A is first hydrolyzed in an aqueous acetic acid solution (Can. J. Chem. 1983, 61, 634). The resulting diol 207.1 is acetalized with this phosphonate aldehyde and perchloric acid to give acetal 207.2 (J. Med. Chem. 1996, 39, 4888-4896).

  (Example 208)

Ｃ−１１水酸基での誘導体化は、リメキソロン２０８Ａを適当なホスホネートでアルキル化することによって達成され、２０８．１型のアナログが得られる。

Derivatization at the C-11 hydroxyl group is accomplished by alkylating rimexolone 208A with the appropriate phosphonate, resulting in an analog of type 208.1.

２０８Ａのヒドロキシプロトンを水素化ナトリウムで抽出した後、ホスホン酸トリフリト酸ジエチルが加えられて、エーテル２０８．２が得られる。

After extracting the hydroxy proton of 208A with sodium hydride, diethyl phosphonate triflate is added to give ether 208.2.

  (Example 209)

Ｃ−１７でのカルボニルの誘導体は、フルチカゾン２０９Ａをカルボン酸２０９．１にケン化することから、容易に調製される。このカルボン酸を活性化することに続いて、チオホスホネートまたはアミノホスホネート求核試薬と反応させると、それぞれ、所望のチオエステル２０９．２およびアミド２０９．３が得られる。

Derivatives of carbonyl at C-17 are readily prepared from saponification of fluticasone 209A to carboxylic acid 209.1. Following activation of the carboxylic acid, reaction with a thiophosphonate or aminophosphonate nucleophile provides the desired thioester 209.2 and amide 209.3, respectively.

  (Example 210)

フルチカゾン２０９Ａは、まず、アセトン中にて、水酸化カリウムでケン化される（Ｓｙｎｔｈｅｓｉｓ ２００２，９２１−９２７）。得られたカルボン酸２０９．１は、１，１’−カルボニルジイミダゾール（ＣＤＩ）を加えることにより、カルボン酸イミダゾールに活性化される（Ｊ．Ｍｅｄ．Ｃｈｅｍ．１９９４，３７，３７１７−３７２９）。このチオホスホネートで処理すると、チオエステル２１０．１が得られる。その反応性を向上させるために、マグネシウムエトキシドが加えられ得る（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．１９８１，２２，３２４５−３２４６）。あるいは、２０９．１から誘導されたカルボイミダゾール中間体は、このアミノホスホネートと反応でき、アミド２１０．２が生成される。

Fluticasone 209A is first saponified with potassium hydroxide in acetone (Synthesis 2002, 921-927). The resulting carboxylic acid 209.1 is activated to imidazole carboxylic acid by adding 1,1′-carbonyldiimidazole (CDI) (J. Med. Chem. 1994, 37, 3717-3729). Treatment with this thiophosphonate gives the thioester 210.1. Magnesium ethoxide can be added to improve its reactivity (Tetrahedron Lett. 1981, 22, 3245-3246). Alternatively, a carboimidazole intermediate derived from 209.1 can be reacted with this aminophosphonate to produce amide 210.2.

  (Example 211)

この立体的に障害が少ないＣ−１１水酸基は、適当なホスホネートで選択的にアルキル化されて、式２１１．１のアナログが得られる。

This sterically hindered C-11 hydroxyl group is selectively alkylated with a suitable phosphonate to give an analog of formula 211.1.

  (Example 212)

１当量の水素化ナトリウムを使用して、２０９ＡにあるＣ−１１ヒドロキシプロトンを位置選択的に抽出した後、このホスホネートトリフレートが加えられて、エーテル２１２．１が得られる。

After regioselective extraction of the C-11 hydroxy proton at 209A using 1 equivalent of sodium hydride, the phosphonate triflate is added to give ether 212.1.

  (Example 213)

このＣ−１１水酸基は、適当な保護基でマスクされる。２１３．１のＣ−１７ヒドロキシ部分を脱離基結合ホスホネートでアルキル化し、引き続いて、脱保護した後、所望のアナログ２１３．３が得られる。

The C-11 hydroxyl group is masked with a suitable protecting group. After alkylating the C-17 hydroxy moiety of 213.1 with a leaving group-linked phosphonate followed by deprotection, the desired analog 213.3 is obtained.

  (Example 214)

フルチカゾン２０９Ａは、標準的な無水酢酸およびＤＭＡＰ条件を使用して、そのＣ−１１酢酸エステルとして、位置選択的に保護される（Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９９８，６３，２３４２−２３４７）。露出されたＣ−１７水酸基にて、水素化ナトリウムおよびこのホスホネートトリフレートでアルキル化すると、中間体２１４．２が得られる。このアセテートを最後にアンモニア脱保護すると、所望のエーテル２１４．３が得られる。

Fluticasone 209A is regioselectively protected as its C-11 acetate using standard acetic anhydride and DMAP conditions (J. Org. Chem. 1998, 63, 2342-2347). Alkylation with sodium hydride and the phosphonate triflate at the exposed C-17 hydroxyl group gives intermediate 214.2. The acetate is finally ammonia deprotected to give the desired ether 214.3.

  (Example 215)

このＣ−１１水酸基での誘導体化は、モメタゾンフオレート２１５Ａを適当なホスホネートでアルキル化することによって達成され、２１５．１型のアナログが得られる。

This derivatization at the C-11 hydroxyl group is accomplished by alkylating mometasone forate 215A with an appropriate phosphonate, resulting in 215.1 type analogs.

  (Example 216)

２１５Ａのヒドロキシプロトンを水素化ナトリウムで抽出した後、ホスホン酸トリフリト酸ジエチルが加えられて、エーテル２１６．１が得られる。

After extracting the 215A hydroxy proton with sodium hydride, diethyl phosphonate triflate is added to give ether 216.1.

  (Example 217)

モメタゾンフオレート２１５Ａにある唯一の露出した水酸基を保護することに続いて、中間体２１７．１がケン化されて、アルコール２１７．３が得られる。Ｃ−１７水酸基にて、適当なホスホネートでアルキル化し、引き続いて、脱保護すると、所望の生成物２１７．４が得られる。

Following protection of the only exposed hydroxyl group on mometasone folate 215A, intermediate 217.1 is saponified to give alcohol 217.3. Alkylation with a suitable phosphonate at the C-17 hydroxyl group followed by deprotection yields the desired product 217.4.

  (Example 218)

モメタゾンフオレート２１５Ａは、標準的なＴＢＳＣｌおよびイミダゾール条件を使用して、そのシリルエーテルとして、保護される（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．１９７２，９４，６１９０）。水酸化ナトリウム水溶液を使用して、そのフオリルエステル部分をケン化すると、アルコール２１８．１が得られる（Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｐｅｒｋｉｎ Ｔｒａｎｓ．１，１９９３，１２，１３５９−１３６６）。この第三級水酸基は、水酸化ナトリウムおよびこのホスホネートトリフレートを加えることにより、アルキル化される。中間体２１８．３にあるシリルエーテルをＴＢＡＦで脱保護した後、ホスホネートジエチル２１８．４が得られる。

Mometasone phosphate 215A is protected as its silyl ether using standard TBSCl and imidazole conditions (J. Am. Chem. Soc. 1972, 94, 6190). Saponification of the fluoryl ester moiety using aqueous sodium hydroxide provides alcohol 218.1 (J. Chem. Soc. Perkin Trans. 1, 1993, 12, 1359-1366). The tertiary hydroxyl group is alkylated by adding sodium hydroxide and the phosphonate triflate. After deprotecting the silyl ether in intermediate 218.3 with TBAF, phosphonate diethyl 218.4 is obtained.

  (Example 219)

Ｃ−１１水酸基での誘導体化は、アセポン酸メチルプレドニゾロン（２１９Ａ）を適当なホスホネートでアルキル化することによって達成され、例２１９．１のアナログが得られる。

Derivatization at the C-11 hydroxyl group is accomplished by alkylating methyl prednisolone aceponate (219A) with the appropriate phosphonate to give the analog of Example 219.1.

  (Example 220)

２１９Ａのヒドロキシプロトンを水素化ナトリウムで抽出した後、ホスホン酸トリフリト酸ジエチルが加えられて、エーテル２２０．１が得られる。

After extracting the 219A hydroxy proton with sodium hydride, diethyl phosphonate triflate is added to give ether 220.1.

  (Example 221)

２１９Ａにある唯一の露出した水酸基の保護に続いて、中間体２２１．１は、ケン化されて、ジオール２２１．２が得られる。この第一級水酸基を適当なホスホネートでアルキル化し、引き続いて、アシル化すると、プロピオン酸エステル２２１．４が得られる。脱保護後、所望の生成物２２１．５が得られる。

Following protection of the only exposed hydroxyl group at 219A, intermediate 221.1 is saponified to give diol 221.2. Alkylation of this primary hydroxyl group with a suitable phosphonate followed by acylation yields propionate ester 221.4. After deprotection, the desired product 221.5 is obtained.

  (Example 222)

アセポン酸メチルプレドニゾロン２１９Ａは、標準的なＴＢＳＣｌおよびイミダゾール条件を使用して、そのシリルエーテルとして、保護される（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．１９７２，９４，６１９０）。水酸化ナトリウム水溶液を使用して、両方のエステル部分をケン化すると、ジオール２２２．２が得られる。立体的に障害が少ない第一級水酸基は、水酸化ナトリウムおよびホスホネートトリフレートを加えることにより、アルキル化される。中間体２２２．３をピリジン中の無水プロピオン酸で処理した後、先に加水分解したＣ−１７プロピオン酸エステルが置換される（Ｊ．Ｍｅｄ．Ｃｈｅｍ．１９８０，２３，４３０−４３７）。このシリルエーテルのＴＢＡＦ脱保護により、ホスホン酸ジエチル２２２．５が得られる。

Methylprednisolone aceponate 219A is protected as its silyl ether using standard TBSCl and imidazole conditions (J. Am. Chem. Soc. 1972, 94, 6190). Saponification of both ester moieties using aqueous sodium hydroxide provides diol 222.2. The sterically hindered primary hydroxyl group is alkylated by adding sodium hydroxide and phosphonate triflate. After treatment of intermediate 222.3 with propionic anhydride in pyridine, the previously hydrolyzed C-17 propionic acid ester is replaced (J. Med. Chem. 1980, 23, 430-437). TBAF deprotection of this silyl ether gives diethyl phosphonate 222.5.

  (Example 223)

ジオール２２１．２の２個の水酸基は、その第一級部位にて保護することにより、位置選択的に区別されて、それにより、この第三級水酸基でのアルキル化が可能となる。次いで、得られたホスホネート中間体２２３．１は、脱保護されて、ジオール２２３．３が得られる。再度、さらにアクセスし易い第一級水酸基は、アシル化されて、所望のアナログ２２３．４が生成される。

The two hydroxyl groups of diol 221.2 are regioselectively distinguished by protecting at their primary sites, thereby allowing alkylation at this tertiary hydroxyl group. The resulting phosphonate intermediate 223.1 is then deprotected to give the diol 223.3. Again, the more accessible primary hydroxyl group is acylated to produce the desired analog 223.4.

  (Example 224)

ジオール２２２．２は、のホスホン酸トリフリト酸ジエチルでアルキル化され、得られた中間体２２４．２は、ＴＢＡＦで処理されて、ジオール２２４．３が得られる。無水酢酸およびピリジンが使用されて、最終生成物２２４．４が産生される（Ｊ．Ｍｏｌ．Ｂｉｏｌ．１９７２，７２，２１９）。

Diol 222.2 is alkylated with diethyl phosphonate triflate and the resulting intermediate 224.2 is treated with TBAF to give diol 224.3. Acetic anhydride and pyridine are used to produce the final product 224.4 (J. Mol. Biol. 1972, 72, 219).

  (Example 225)

２２５．１のような化合物は、以下で概説する一般経路に従って、製造できる。

Compounds such as 225.1 can be prepared according to the general route outlined below.

ＰＮＰ−４０５（２２５Ａ）は、Ｌｉｔｔｌｅｒ，Ｂ．Ｊ．ら，第７版Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｃｏｎｆｅｒｅｎｃｅ ｏｎ Ｏｒｇａｎｉｃ Ｐｒｏｃｅｓｓ Ｒｅｓｅａｒｃｈ ａｎｄ Ｄｅｖｅｌｏｐｍｅｎｔ，Ｎｅｗ Ｏｒｌｅａｎｓ，ＬＡ，Ｍａｒｃｈ ２００３年３月１６−１９日の方法に従って、調製される。ＰＮＰ−４０５は、溶媒（例えば、テトラヒドロフランまたはジメチルホルムアミド）中にて、塩基（例えば、水素化ナトリウム）で処理される。泡立ちが止まると、トリフリト酸ジエチルホスホノメチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）が加えられて、所望生成物として、化合物２２６．１が得られる。

PNP-405 (225A) is disclosed in Littler, B. et al. J. et al. Et al., 7th Edition, International Conference on Organic Process Research and Development, New Orleans, LA, March, March 16-19, 2003. PNP-405 is treated with a base (eg, sodium hydride) in a solvent (eg, tetrahydrofuran or dimethylformamide). When bubbling ceases, diethylphosphonomethyl trifritrate (prepared according to Tetrahedron Lett., 1986, 27, 1477) is added to give compound 226.1 as the desired product.

  (Example 227)

２２７．１のような化合物（ここで、Ｘ＝Ｏであり、Ｚ＝ＣＨ_２ＯＨである）は、Ｌｉｔｔｌｅｒ，Ｂ．Ｊ．ら，第７版Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｃｏｎｆｅｒｅｎｃｅ ｏｎ Ｏｒｇａｎｉｃ Ｐｒｏｃｅｓｓ Ｒｅｓｅａｒｃｈ ａｎｄ Ｄｅｖｅｌｏｐｍｅｎｔ，Ｎｅｗ Ｏｒｌｅａｎｓ，ＬＡ，Ｍａｒｃｈ １６−１９，２００３で記述されたものと類似の手順を使用して、調製できる（スキーム３および４）。出発物質である２−ベンジルオキシフェニル酢酸２２７．１（これは、Ａｖｏｃａｄｏから得られる）は、８０〜８５℃で現れるオキサゾリジノンとの混合無水物を経由して、塩基としてのトリエチルアミンでアシル化でき、化合物２２７．２が得られる。ブロモアセトニトリルで低温アルキル化すると、良好なジアステレオマー比を有する化合物２２７．３が形成される。還元条件下にてキラル補助を除くと、ラセミ化なしで、化合物２２７．４が生じる。得られたアルコールをトリチル基で保護すると、化合物２２７．５が得られる。引き続いたピロール環の作成およびシクロ−グアニジニル化反応により６員の２−アミノピリミドン環を調製することは、化合物２２８．９について実施例２２８で記述されているように実行され、化合物２２７．６が得られる。

Compounds such as 227.1 (where X = O and Z = CH ₂ OH) are described by Littler, B .; J. et al. Et al., 7th edition, International Conference on Organic Process Research and Development, New Orleans, LA, March 16-19, 2003, can be used to prepare (Schemes 3 and 4). The starting material 2-benzyloxyphenylacetic acid 227.1 (obtained from Avocado) can be acylated with triethylamine as base via a mixed anhydride with oxazolidinone appearing at 80-85 ° C., Compound 227.2 is obtained. Low temperature alkylation with bromoacetonitrile forms compound 227.3 with a good diastereomeric ratio. Removal of the chiral aid under reducing conditions gives compound 227.4 without racemization. Protection of the resulting alcohol with a trityl group provides compound 227.5. Preparation of the 6-membered 2-aminopyrimidone ring by subsequent pyrrole ring creation and cyclo-guanidinylation reaction was performed as described in Example 228 for compound 228.9 and compound 227.6. Is obtained.

  (Example 228)

化合物２２８．１（ここで、Ｘ＝Ｏであり、Ｚ＝Ｈである）は、上で概説した一般経路に従って、調製できる。出発物質である３−（２−ベンジルオキシ−フェニル）−プロピオニトリル２２８．１は、米国特許第２，７８９，９９５号（これは、１９５４年に公開された）に従って、フェノールとアクリロニトリルとのルイス酸媒介反応により、入手可能である。中間体２２７．５は、ここで概説したものと同じ合成工程に従って、化合物２２７．１を得ることができる。

Compound 228.1 (where X = O and Z = H) can be prepared according to the general route outlined above. The starting material, 3- (2-benzyloxy-phenyl) -propionitrile 228.1, was prepared according to U.S. Pat. Available by Lewis acid mediated reaction. Intermediate 227.5 can be obtained according to the same synthetic steps outlined herein to give compound 227.1.

  The creation of the pyrrole ring can be completed in 3 steps from 3- (2-benzyloxy-phenyl) -propionitrile 228.1. The formation of 3-hydroxy-acrylonitrile 228.2 can be achieved by exposing 228.1 to LDA and ethyl formate. Condensation of this product with 2-amino-malonic acid diethyl ester (in EtOH) and sodium acetate yielded compound 228.3, which was decarboxylated cyclized in a basic medium of NaOH and EtOH. In this way, pyrrole 228.4 is obtained. In the case of the synthesis of compound 227.1, the trityl protecting group on the benzyl alcohol is removed at this stage. Subsequent guanidinylation reaction using cyanamide gives compound 228.5, which cyclizes to form this 2-aminopyrimidone ring (compound 228.6) upon treatment with sodium hydroxide. . Removal of the phenolic protecting group under hydrogenolysis conditions yields the free phenol, which is used as the binding site for the prodrug group. Various linkers can be utilized to attach the phosphonate-containing moiety to the backbone molecule. A specific example using diethylphosphonomethyl trifritate as starting material is given above. Accordingly, compound 228.7 is treated with a base (eg, sodium hydride or cesium carbonate) in a solvent (eg, tetrahydrofuran or dimethylformamide). When bubbling ceases, diethylphosphonomethyl trifritate (prepared according to Tetrahedron Lett., 1986, 27, 1477) is added to give compound 228.2 as the desired product.

  (Example 229)

２２９．１のような化合物（ここで、Ｘ＝Ｏであり、Ｙ＝Ｈであり、そしてＺ＝ＣＨ_２ＯＨである）は、４−ベンジルオキシフェニル酢酸（これは、Ａｌｄｒｉｃｈから入手できる）から調製できる。上で示したものと類似の手順に従って、中間体２２９．５が調製できる。上で示した手順と共に進行して、２２９．５は、所望生成物２２９．１に変換できる。

Compounds such as 229.1, where X = O, Y = H and Z = CH ₂ OH are obtained from 4-benzyloxyphenylacetic acid (which is available from Aldrich) Can be prepared. Intermediate 229.5 can be prepared following procedures similar to those shown above. Proceeding with the procedure shown above, 229.5 can be converted to the desired product 229.1.

上で概説した一般経路に従って、２３０Ａのような化合物が製造できる。

Compounds such as 230A can be prepared following the general route outlined above.

  (Example 231)

ＤＡＤＭｅ−ＩｍｍＧの調製は、Ｌｅｗａｎｄｏｗｉｃｓ Ａ．ら、Ｂｉｏｃｈｅｍｉｓｔｒｙ，２００３，４２，６０５７で報告されている。その環の第三級窒素は、この第二級アルコールのアルキル化を妨害し得ず、その場合、保護する必要はないが、もし必要なら、Ｇｒｅｅｎｅ，Ｔ．Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ，Ｗｉｌｅｙ−Ｉｎｔｅｒｓｃｉｅｎｃｅ，１９９９で記述された標準的な保護および脱保護プロトコルが使用され得る。第一級アルコール２３１．１を塩基と反応させることに続いて、適当に活性化したホスホネートを加えると、保護した生成物が生じる。全体的に脱保護すると、所望のホスホネート２３１．２が生じる。

The preparation of DADMe-ImmG was prepared by the method described in Lewandowics A.D. Et al., Biochemistry, 2003, 42, 6057. The tertiary nitrogen of the ring cannot interfere with the alkylation of the secondary alcohol, in which case it need not be protected, but if necessary, Greene, T .; Standard protection and deprotection protocols described in Protective Groups in Organic Synthesis, Wiley-Interscience, 1999 may be used. Subsequent reaction of the primary alcohol 231.1 with a base followed by the addition of a suitably activated phosphonate gives the protected product. Overall deprotection yields the desired phosphonate 231.2.

  (Example 232)

２３２．１のような化合物は、上で概説した一般経路に従って、製造できる。

Compounds such as 232.1 can be prepared according to the general route outlined above.

  (Example 233)

保護したＤＡＤＭｅ誘導体は、溶媒（例えば、テトラヒドロフランまたはジメチルホルムアミド）中にて、塩基（例えば、水素化ナトリウム）で処理できる。泡立ちが止まると、トリフリト酸ジエチルホスホノメチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）を加えて、所望生成物として、化合物ホスホン酸エステルが得られる。その保護基の除去は、Ｇｒｅｅｎｅ，Ｔ．，Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ，Ｗｉｌｅｙ−Ｉｎｔｅｒｓｃｉｅｎｃｅ，１９９９で記述されているように実行でき、所望のホスホン酸エステル２３３．１が得られる。

The protected DADMe derivative can be treated with a base (eg, sodium hydride) in a solvent (eg, tetrahydrofuran or dimethylformamide). When bubbling ceases, diethylphosphonomethyl trifritate (prepared according to Tetrahedron Lett., 1986, 27, 1477) is added to give the compound phosphonate as the desired product. Removal of the protecting group is described in Greene, T .; , Protective Groups in Organic Synthesis, Wiley-Interscience, 1999, to give the desired phosphonate ester 233.1.

  (Example 234)

２３４．２のような化合物は、上で概説した一般経路に従って、製造できる。

Compounds such as 234.2 can be prepared according to the general route outlined above.

ＣＰ−６９０，５５０である３−｛４−メチル−３−［メチル−（７Ｈ−ピロロ［２，３−ｄ］ピリミジン−４−イル）−アミノ］−ピペリジン−１−イル｝−３−オキソ−プロピオニトリル２３４．１は、ＷＯ ０２０９６９０９およびＷＯ ０３０４８１６２で記述されているように、調製できる。２当量の塩基を使用してα−シアノアミド位置でエノラートを形成することに続いて、ホスホノメチルトリフリト酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）を加えると、所望化合物２３４．３が得られる。この反応には、ＴＨＦ、ＤＭＦのような溶媒または他の無水溶媒が使用され得る。そのピロールの窒素が所望のアルキル化を妨害する場合、このアルキル化反応の前に、保護基（例えば、ＢＯＣ）が導入され得る。このＢＯＣ基の除去は、Ｇｒｅｅｎｅ，Ｔ．，「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｗｉｌｅｙ−Ｉｎｔｅｒｓｃｉｅｎｃｅ，１９９９で記述されているように、その反応生成物をＴＦＡに晒すことにより、達成できる。

3- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo which is CP-690,550 -Propionitrile 234.1 can be prepared as described in WO02096909 and WO03048162. Following formation of the enolate at the α-cyanoamide position using 2 equivalents of base, diethyl phosphonomethyltriflate (which was prepared according to Tetrahedron Lett., 1986, 27, 1477) was added. The desired compound 234.3 is obtained. For this reaction, solvents such as THF, DMF or other anhydrous solvents may be used. If the pyrrole nitrogen interferes with the desired alkylation, a protecting group (eg, BOC) can be introduced prior to the alkylation reaction. Removal of this BOC group is described in Greene, T .; , "Protective Groups in Organic Synthesis", Wiley-Interscience, 1999, which can be achieved by exposing the reaction product to TFA.

  (Example 235)

化合物２３５．１は、ＷＯ ０２０９６９０９に従って、調製される。そのピロール窒素のトシル基での保護は、Ｓａｋａｍｏｔｏ，Ｔ．ら、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．１９９４，３５，１８，２９１９で記述されているように、達成される。上記参考文献だけでなく、Ｓｅｅｌａ，Ｆ．ら、Ｃｈｅｍ．Ｂｅｒ．，１９７７，１１０，４，１４６２で記述されているように、ｔ−ＢｕＬｉを使用するオルトリチエーション（Ｏｒｔｈｏ ｌｉｔｈｉａｔｉｏｎ）およびホルムアルデヒドでのクエンチにより、必要な部位で置換基を導入する。そのように形成された第一級アルコールは、塩基およびホスホノメチルトリフリト酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）を使用して、無水溶媒中で、エーテル形成を介して、このホスホネート部分の結合に使用され得る。そのベンジル保護基の除去は、水素化分解条件を使用して、達成される。次いで、このピペリジン窒素を、シアノ酢酸２，５−ジオキソ−ピロリジン−１−イルエステルとカップリングして、化合物２３５．５が得られる。このトシル保護基の除去は、塩基性条件を使用して達成でき、所望生成物２３５．６が得られる。

Compound 235.1 is prepared according to WO 02096909. Protection of the pyrrole nitrogen with the tosyl group is described by Sakamoto, T .; Et al., Tetrahedron Lett. This is accomplished as described in 1994, 35, 18, 2919. In addition to the above references, Seela, F. et al. Et al., Chem. Ber. , 1977, 110, 4, 1462, substituents are introduced at the required sites by ortho-lithiation using t-BuLi and quenching with formaldehyde. The primary alcohol so formed was prepared using ether and diethyl phosphonomethyltriflate (which was prepared according to Tetrahedron Lett., 1986, 27, 1477) in an anhydrous solvent. It can be used to attach this phosphonate moiety through formation. Removal of the benzyl protecting group is accomplished using hydrogenolysis conditions. This piperidine nitrogen is then coupled with cyanoacetic acid 2,5-dioxo-pyrrolidin-1-yl ester to give compound 235.5. Removal of this tosyl protecting group can be accomplished using basic conditions to give the desired product 235.6.

  (Example 236)

具体的には、（１−ベンジル−４−メチル−ピペリジン−３−イル）−メチル−（７Ｈ−ピロロ［２，３−ｄ］ピリミジン−４−イル）−アミンである化合物２３６．１（これは、ＷＯ ０２，０９６，９０９で記述されてようにして、調製した）を、まず、トシル基を使用して、そのピロール窒素にて保護する。Ｓａｋａｍｏｔｏ，Ｔ．ら、（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９９４，３５，２９１９）で報告された手順を使用する引き続いたホルミル化により、化合物２３６．３が得られる。次いで、この第一級アルコールを、溶媒（例えば、テトラヒドロフランまたはジメチルホルムアミド）中にて、塩基（例えば、水素化ナトリウム）で処理する。泡立ちが止まると、ホスホノメチルトリフリト酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）を加えて、所望生成物２３６．４が得られる。このピペリジン窒素のジベンジル化に続いて、シアノ−酢酸２，５−ジオキソ−ピロリジン−１−イルエステルにカップリングすると、化合物２３６．５が得られる。このトシル保護基を除去すると、所望のプロドラッグ２３６．６が得られる。

Specifically, compound 236.1 (this is (1-benzyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine) Was prepared as described in WO 02,096,909) first protected with its pyrrole nitrogen using the tosyl group. Sakamoto, T .; Et al. (Tetrahedron Lett., 1994, 35, 2919) followed by formylation using the procedure reported gives compound 236.3. The primary alcohol is then treated with a base (eg, sodium hydride) in a solvent (eg, tetrahydrofuran or dimethylformamide). When bubbling ceases, diethyl phosphonomethyltrifritate (prepared according to Tetrahedron Lett., 1986, 27, 1477) is added to give the desired product 236.4. This dibenzylation of the piperidine nitrogen, followed by coupling to cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester gives compound 236.5. Removal of this tosyl protecting group provides the desired prodrug 236.6.

  (Example 237)

本発明のホスホネート化合物およびそれらの合成に必要な中間体化合物の合成は、ここで図示している。

The synthesis of the phosphonate compounds of the invention and the intermediate compounds required for their synthesis is illustrated here.

  (Example 238)

本発明のホスホネート化合物のホスホネートの調製は、上で図示している。５−ヒドロキシ−１−β−Ｄ−リボフラノシル−１Ｈ−イミダゾール−４−カルボキサミド２３８．１（これは、米国特許第３，８８８，８４３号に従って、調製した）は、溶媒（例えば、テトラヒドロフランまたはジメチルホルムアミド）中にて、塩基（例えば、水素化ナトリウム）で処理され得る。泡立ちが止まると、トリフリト酸ジエチルホスホノメチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）を加えて、所望のホスホン酸ジエステル２３８．２が生じる。

The preparation of phosphonates of the phosphonate compounds of the present invention is illustrated above. 5-Hydroxy-1-β-D-ribofuranosyl-1H-imidazole-4-carboxamide 238.1 (prepared according to US Pat. No. 3,888,843) is used in a solvent (eg, tetrahydrofuran or dimethylformamide). ) Can be treated with a base such as sodium hydride. When bubbling ceases, diethylphosphonomethyl triflate (which was prepared according to Tetrahedron Lett., 1986, 27, 1477) is added to give the desired phosphonic acid diester 238.2.

  (Example 239)

本発明のホスホン酸エステルの調製は、上で図示している。化合物２３９．１である５−ヒドロキシ−１−（４−ヒドロキシ−５−ヒドロキシメチル−テトラヒドロフラン−２−イルメチル）−１Ｈ−イミダゾール−４−カルボン酸アミド（これは、イミダゾール塩基（日本公開公報７６ ８８９６５）を３，５−ビス−保護２−デオキシ−Ｄ−エリトロ−ペントフラノシルクロライド（Ｈａｙａｓｈｉ，Ｍ．ら、Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，１９７５，２３，１，２４５；Ｍｏｎｔｇｏｍｅｒｙ，Ｊ．Ａ．ら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９６９，１２，３，４９８；およびＩｗａｍｏｔｏ，Ｒ．Ｈ．ら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９６３，６，６８４）に付加することにより、調製される）は、イミダゾール−４−オールにて、保護される。その５’−ＯＨを酸化することに続いて、脱離すると、グリカール２３９．２が得られる（Ｚｅｍｌｉｃｋａ Ｊ．ら、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９７２，９４，９，３２１３の手順を参照）。セレノエーテル化すると、保護ホスホネート２３９．３（Ｋｉｍ，Ｃ．ら、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９１，５６，２６４２）が得られる。このフェニルセレニドを（Ｋｉｍ，Ｃ．ら、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９１，５６，２６４２で記述されているように）酸化脱離し、続いて、立体選択的にジヒドロキシル化すると、ジオール２３９．４が得られる。最後に、その保護基が除去されて、化合物２３９．５が得られる。

The preparation of the phosphonate esters of the present invention is illustrated above. Compound 239.1, 5-hydroxy-1- (4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-ylmethyl) -1H-imidazole-4-carboxylic acid amide (this is imidazole base (Japan Publication 76 88965) ) 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))) Protected with imidazol-4-ol. Following oxidation of the 5′-OH, elimination yields glycal 239.2 (see the procedure of Zemlicka J. et al., J. Am. Chem. Soc., 1972, 94, 9, 3213). ). Selenoetherification provides the protected phosphonate 239.3 (Kim, C. et al., J. Org. Chem., 1991, 56, 2642). The phenyl selenide was oxidatively desorbed (as described in Kim, C. et al., J. Org. Chem., 1991, 56, 2642) followed by stereoselective dihydroxylation to give diol 239 .4 is obtained. Finally, the protecting group is removed to give compound 239.5.

  (Example 240)

ホスホネートシス（ｐｈｏｓｐｈｏｎａｔｅｓｉｓ）の調製は、上で図示している。具体的には、化合物２３９．１である５−ヒドロキシ−１−（４−ヒドロキシ−５−ヒドロキシメチル−テトラヒドロフラン−２−イルメチル）−１Ｈ−イミダゾール−４−カルボン酸アミドを、まず、ＴＢＳ基を使用して、保護する。ＰｔＯ_２での引き続いた酸化が進行して、カルボン酸２４０．１が得られる。脱炭酸脱離は、ＤＭＦ中にて、高温で、ジメチルホルムアミドジネオペンチルアセタールを使用して、達成される（Ｚｅｍｌｉｃｋａ Ｊ．ら、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９７２，９４，９，３２１３）。一旦、フラノイドグリカール２４０．２が手に入ると、それを、ジエチル（ヒドロキシルメチル）ホスホネート（Ｐｈｉｌｌｉｏｎ，Ｄ．ら、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７）の存在下にて、過塩素酸銀で処理して、ホスホネート２４０．３が得られる（Ｋｉｍ，Ｃ．ら、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９１，５６，２６４２）。このセレン化物を酸化脱離することに続いて、四酸化オスミウムを使用してジヒドロキシル化すると、所望の立体配置を備えたジオール２４０．５が得られる。そのＴＢＳ基の脱保護は、ＴＢＡＦを使用して達成でき、化合物２４０．６が得られる。

The preparation of phosphonatesis is illustrated above. Specifically, 5-hydroxy-1- (4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-ylmethyl) -1H-imidazole-4-carboxylic acid amide, which is the compound 239.1, is first converted to a TBS group. Use and protect. Subsequent oxidation with PtO ₂ proceeds to give carboxylic acid 240.1. Decarboxylization is accomplished using dimethylformamide dineopentyl acetal in DMF at elevated temperature (Zemlicka J. et al., J. Am. Chem. Soc., 1972, 94, 9, 3213). ). Once the furanoid glycal 240.2 is obtained, it is perchloric acid in the presence of diethyl (hydroxylmethyl) phosphonate (Philion, D. et al., Tetrahedron Lett., 1986, 27, 1477). Treatment with silver gives phosphonate 240.3 (Kim, C. et al., J. Org. Chem., 1991, 56, 2642). Following oxidative desorption of the selenide, dihydroxylation using osmium tetroxide provides the diol 240.5 with the desired configuration. The deprotection of the TBS group can be achieved using TBAF to give compound 240.6.

(Example 241)
The synthesis of compound 241A of the present invention, which is an analog of CsA (and similar cyclosporine), is illustrated here.

（実施例２４２）

(Example 242)

本発明のホスホネート化合物およびそれらの合成に必要な中間体化合物の合成は、ここで図示されている。そのオレフィン複分解の方法論は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００３，４６，６７４で記述されている。

The synthesis of the phosphonate compounds of the present invention and the intermediate compounds required for their synthesis is illustrated here. The olefin metathesis methodology is described in J. Am. Med. Chem. 2003, 46, 674.

  (Example 243)

ホスホネート基を有する本発明の化合物およびそれらの合成に有用な中間体化合物の調製は、ここで図示されている。

The preparation of the compounds of the invention having phosphonate groups and intermediate compounds useful for their synthesis are illustrated here.

  (Example 244)

ホスホネート基を有する本発明の化合物およびそれらの合成に有用な中間体化合物の調製は、ここで図示されている。

The preparation of the compounds of the invention having phosphonate groups and intermediate compounds useful for their synthesis are illustrated here.

  (Example 245)

種々の置換基のリンク−Ｐ（Ｏ）（ＯＲ^１）_２基（ここで、Ｒ^１は、上で定義されている）または実際に上で定義したような最終段階のＰ（Ｏ）ＲＲ^０への変換は、この合成手順の任意の好都合な段階または最終工程で、引き起こされ得る。このホスホネート置換基を導入するのに適当な工程の選択は、必要な化学手順およびこれらの手順に対する基質の安定性を考慮した後、行う。リンク−Ｐ（Ｏ）（ＯＲ^１）_２またはＰ（Ｏ）ＲＲ^０基の導入中において、反応性基（例えば、ヒドロキシル、アミノ）を保護する必要があり得る。式２４５．５〜２４５．８を有する本発明の化合物の特定の例は、ここで図示している。

Link of various substituents —P (O) (OR ¹ ) ₂ groups (where R ¹ is defined above) or indeed the final stage P (O) RR ⁰ as defined above. Conversion to can be triggered at any convenient stage or final step of the synthesis procedure. The selection of the appropriate process for introducing the phosphonate substituent is made after considering the necessary chemical procedures and the stability of the substrate to these procedures. During the introduction of the link-P (O) (OR ¹ ) ₂ or P (O) RR ⁰ group, it may be necessary to protect reactive groups (eg hydroxyl, amino). Particular examples of compounds of the invention having the formula 245.5 to 245.8 are illustrated here.

本発明の化合物を、ここで記述した方法に従って、合成する。代表的な中間体ホスホン酸エステルが示されており、ここで、Ｒ^１は、水素、アルキル、アリール、ハロアルキル、アルケニル、アラルキルまたはアリールである。これらの化合物は、置換ホスホネートを合成する公知方法を使用して、当業者により、本発明の化合物（例えば、ここで図示したもの）を調製するのに使用できる。これらの方法は、アミドの合成について記述されたものと類似している。カルボン酸および誘導体からのアミドの調製は、例えば、「Ｏｒｇａｎｉｃ Ｆｕｎｃｔｉｏｎａｌ Ｇｒｏｕｐ Ｐｒｅｐａｒａｔｉｏｎｓ」、ｂｙ Ｓ．Ｒ．Ｓａｎｄｌｅｒ ａｎｄ Ｗ．Ｋａｒｏ，Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ，１９６８，ｐ．２７４で記述されている。以下の実施例では、ホスホン酸ジエステルを合成するさらに別の方法が記述されており、ある場合には、ホスホラミドの合成に適用できる。

The compounds of the invention are synthesized according to the methods described herein. Representative intermediate phosphonates are shown, wherein R ¹ is hydrogen, alkyl, aryl, haloalkyl, alkenyl, aralkyl or aryl. These compounds can be used by those skilled in the art to prepare compounds of the invention (eg, those illustrated herein) using known methods of synthesizing substituted phosphonates. These methods are similar to those described for the synthesis of amides. Preparation of amides from carboxylic acids and derivatives is described, for example, in “Organic Functional Group Preparations”, by S. B. R. Sandler and W.M. Karo, Academic Press, 1968, p. 274. The following examples describe additional methods for synthesizing phosphonic acid diesters and, in some cases, can be applied to the synthesis of phosphoramides.

  The phosphonates 245.1 to 245.4 involved in the conversion to phosphonate moieties with amino acids or lactates are shown here. Cyclosporine A (CsA) 245.10 can be purchased and synthesized from Sigma Aldrich (see US Pat. No. 4,396,542) or as described in US Pat. No. 4,117,118. Can be obtained from biological sources. Other cyclosporine derivatives can be synthetic in nature (see US Pat. No. 4,396,542) or can be isolated to CsA by similar means (US Pat. No. 6,410,696 B1). See).

アミノ酸１の水酸基を介してＣｓＡへのホスホネート連鎖を調製して式２４５．１の化合物を得ることは、ここで図示されている。ＣｓＡ（２４５．１０）は、適当な溶媒（例えば、ＤＭＦまたは他の非プロトン性溶媒）に溶解され、次いで、適当な有機塩基または無機塩基の存在下にて、ホスホネート試薬２４５．９（これは、脱離基（例えば、臭素、メシル、トシルまたはトリフルオロメタンスルホニル）を有する）で処理される。

Illustrated here is the preparation of the phosphonate linkage to CsA via the hydroxyl group of amino acid 1 to give the compound of formula 245.1. CsA (245.10) is dissolved in a suitable solvent (eg, DMF or other aprotic solvent) and then in the presence of a suitable organic or inorganic base, the phosphonate reagent 245.9 (which is , With a leaving group (eg bromine, mesyl, tosyl or trifluoromethanesulfonyl).

例えば、２４５．１０（これは、ＤＭＦに溶解した）を、１当量の水素化ナトリウムおよび１当量の（トルエン−４−スルホニルメチル）−ホスホン酸ジベンジルエステル２４５．１１（これは、Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９９６，６１，７６９７の手順に従って、調製した）で処理して、ＣｓＡホスホネート２４５．５が得られる。上記手順を使用するが、２４５．１１に代えて、異なるホスホネート試薬２４５．９を使用して、異なる連結基を有する本発明の対応する生成物２４５．１が得られる。

For example, 245.10 (dissolved in DMF) is converted to 1 equivalent of sodium hydride and 1 equivalent of (toluene-4-sulfonylmethyl) -phosphonic acid dibenzyl ester 245.11 (which is J. Org Chem. 1996, 61, 7697) to give CsA phosphonate 245.5. Using the above procedure, but instead of 245.11, using a different phosphonate reagent 245.9, the corresponding product 245.1 of the present invention with a different linking group is obtained.

  (Example 246)

ＣｓＡ−ホスホネート抱合体の調製は、上で図示している。アミノ酸１の水酸基は、まず、ＧｒｅｅｎｅおよびＷｕｔｓ、「Ｐｒｏｔｅｃｔｉｎｇ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、第３版、Ｊｏｈｎ Ｗｉｌｅｙ ａｎｄ Ｓｏｎｓ，Ｉｎｃ．で記述されているように、適当な保護基（例えば、シリルエーテル、ベンジルエーテル、トリチルエーテルなど）で保護される。次いで、保護生成物２４６．１は、酸化剤（その例の多くは、「Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ」、Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ、第２版、Ｒ．Ｃ．Ｌａｒｏｃｋ，ｐ １２１１−１２１５で記述されている）で処理されて、アルデヒド２４６．２が得られる。

The preparation of CsA-phosphonate conjugates is illustrated above. The hydroxyl group of amino acid 1 is first described in Green and Wuts, “Protecting Groups in Organic Synthesis”, 3rd edition, John Wiley and Sons, Inc. Protected with a suitable protecting group (eg, silyl ether, benzyl ether, trityl ether, etc.). The protected product 246.1 is then oxidised (many examples of which are described in “Comprehensive Organic Transformations”, John Wiley & Sons, 2nd edition, RC Larock, p 1211-1215). To give aldehyde 246.2.

  Aldehyde 246.2 is then treated with an amine phosphonate of general formula 246.3 under reductive amination conditions to give amine 246.4. Preparation of amines by reductive amination procedures is described, for example, in “Comprehensive Organic Transformations”, by R.A. C. Larock, 2nd edition, p. 835. In this procedure, the amine and aldehyde components are reacted together in the presence of a reducing agent (eg, borane, sodium cyanoborohydride or diisobutylaluminum hydride). Finally, Greene and Wuts, “Protecting Groups in Organic Synthesis”, 3rd edition, John Wiley and Sons, Inc. Deprotection of the hydroxyl group according to the procedure established at p116-121 provides the phosphonate 246.5.

  (Example 247)

例えば、２４５．１０は、米国特許第６，４１０，６９６ Ｂ１号で記述されているように、ピリジンおよびジクロロメタン中にて、塩化トリメチルシリルで処理されて、シリルエーテル２４７．１が得られる。次いで、シリルエーテル２４７．１を、オゾンで処理し、続いて、ジメチルスルフィドでワークアップして、アルデヒド２４７．２が得られる。アルデヒド２４７．２を、そのイミンが形成されるまで、１当量の（２−アミノ−エチル）−ホスホン酸エステルジエチルエステル２４７．３の塩酸塩（これは、Ｊ．Ｍｅｄ．Ｃｈｅｍ．１９９８，４１，２３，ｐ４４３９に従って、調製した）および適当な塩基（例えば、ヒューニッヒ塩基、トリエチルアミンなど）で処理する。次いで、この中間体イミン溶液を、シアノホウ水素化ナトリウムで処理して、アミン２４７．４が得られる。次いで、アミン２４７．４は、非プロトン性溶媒（例えば、ＴＨＦまたはジオキサン）中にてＴＢＡＦで処理することにより脱保護されて、ホスホネート２４７．５が得られる。上記手順を使用するが、ホスホネート２４６．３に代えて、異なるホスホネート試薬２４７．３を使用して、異なる連結基を有する対応する生成物２４６．５が得られる。

For example, 245.10 is treated with trimethylsilyl chloride in pyridine and dichloromethane as described in US Pat. No. 6,410,696 B1 to give silyl ether 247.1. The silyl ether 247.1 is then treated with ozone followed by work-up with dimethyl sulfide to give the aldehyde 247.2. Aldehyde 247.2 was converted to one equivalent of (2-amino-ethyl) -phosphonic acid ester diethyl ester 247.3 hydrochloride until its imine was formed (see J. Med. Chem. 1998, 41, 23, p4439) and a suitable base (eg Hunig base, triethylamine, etc.). This intermediate imine solution is then treated with sodium cyanoborohydride to give amine 247.4. The amine 247.4 is then deprotected by treatment with TBAF in an aprotic solvent such as THF or dioxane to give the phosphonate 247.5. Using the above procedure, but using phosphonate reagent 247.3 instead of phosphonate 246.3, the corresponding product 246.5 with different linking groups is obtained.

  (Example 248)

ＣｓＡホスホネート抱合体の調製（この場合、このホスホネートは、アミノ酸７および８（化合物２４５．３および２４５．４）中のアラニン窒素に連結される）は、ここで図示している。保護ＣｓＡ２４６．１（実施例２４６）を、まず、そのアミド部分を除去するのに十分に塩基性である塩基（例えば、金属水素化物、金属アミド）で処理する。次いで、この生成物を、ホスホネート試薬２４５．９（これは、脱離基（例えば、臭素、メシル、トシルまたはトリフルオロメタンスルホニルホスホネート）を有する）で処理して、２４８．１および２４８．２が得られる。次いで、アルキル化生成物を、クロマトグラフィーで分離して、そして別個に、ＧｒｅｅｎｅおよびＷｕｔｓ、「Ｐｒｏｔｅｃｔｉｎｇ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、第３版、Ｊｏｈｎ Ｗｉｌｅｙ ａｎｄ Ｓｏｎｓ Ｉｎｃ．ｐ１１６−１２１で記述されている通常の条件を使用して脱保護されて、式２４５．３および２４５．４を有する化合物が得られる。

The preparation of the CsA phosphonate conjugate, in which case this phosphonate is linked to the alanine nitrogen in amino acids 7 and 8 (compounds 245.3 and 245.4) is illustrated here. Protected CsA246.1 (Example 246) is first treated with a base (eg, metal hydride, metal amide) that is sufficiently basic to remove its amide moiety. This product is then treated with phosphonate reagent 245.9, which has a leaving group (eg, bromine, mesyl, tosyl or trifluoromethanesulfonyl phosphonate) to give 248.1 and 248.2. It is done. The alkylated product is then chromatographed and separately separated by Greene and Wuts, “Protecting Groups in Organic Synthesis”, 3rd edition, John Wiley and Sons Inc. Deprotection using the usual conditions described in p116-121 gives compounds having the formulas 245.3 and 245.4.

  (Example 249)

シリルエーテル２４７．１を、トルエン中にて、水素化ナトリウムおよび１５−クラウン−５−エーテルで処理し、続いて、１当量のブロモメチルホスホン酸ジアリルエーテル２４９．１（Ｌａｎｃａｓｔｅｒ）で処理して、それぞれ、ホスホネート２４９．２および２４９．３が得られる。ホスホネート２４９．２および２４９．３は、非プロトン性溶媒（例えば、ＴＨＦまたはジオキサン）中にて、ＴＢＡＦで処理することにより脱保護されて、それぞれ、２４９．４および２４９．５が得られ、ここで、その連鎖は、メチレン基である。上記手順を使用するが、２４９．１に代えて、異なるホスホネート試薬２４５．９を使用して、異なる連結基を備えた式２４５．３および２４５．４を有する対応する生成物が得られる。

Silyl ether 247.1 was treated with sodium hydride and 15-crown-5-ether in toluene, followed by 1 equivalent of bromomethylphosphonic acid diallyl ether 249.1 (Lancaster), respectively. The phosphonates 249.2 and 249.3 are obtained. Phosphonates 249.2 and 249.3 are deprotected by treatment with TBAF in an aprotic solvent (eg THF or dioxane) to give 249.4 and 249.5, respectively, where And the chain is a methylene group. Using the above procedure, but replacing 249.1, using a different phosphonate reagent 245.9, the corresponding products having formulas 245.3 and 245.4 with different linking groups are obtained.

(Example 250)
The preparation of the compounds of the invention having phosphonate groups and intermediate compounds useful for their synthesis are illustrated here. The structure on the right is meant to represent cyclosporin A in the following examples.

（実施例２５１）
（シクロ−［［（２Ｓ，３Ｒ，４Ｒ，６Ｅ）−７−（４−アセトキシフェニル）−４−メチル−３−ヒドロキシ−２−（メチルアミノ）−６−ヘプテノイル］−Ｌ−２−アミノブチリル−サルコシル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−バリル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−アラニル−Ｄ−アラニル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−バリル］）

(Example 251)
(Cyclo-[[(2S, 3R, 4R, 6E) -7- (4-acetoxyphenyl) -4-methyl-3-hydroxy-2- (methylamino) -6-heptenoyl] -L-2-aminobutyryl- Sarkosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl- L-Baryl])

ジクロロメタン（１ｍＬ）中のシクロスポリンＡ（３６０ｍｇ、０．３ｍｍｏｌ）、４−アセトキシスチレン（７３０ｍｇ、４．５ｍｍｏｌ）および（１，３−ビス−（２，４，６−トリメチルフェニル）−２−イミダゾリデン）ジクロロ（Ｏ−イソプロポキシフェニルメチレン）ルテニウム（Ｈｏｖｅｙｄａ−Ｇｒｕｂｂｓ触媒、２０ｍｇ、０．０３２ｍｍｏｌ）の混合物を窒素でパージし、そして還流下にて、１６時間攪拌した。冷却した後、その反応混合物をシリカゲルカラムクロマトグラフィー（これは、ＭｅＯＨ−ＣＨ_２Ｃｌ_２を使用する）で精製して、固形物（３９５ｍｇ、９９％）として、この生成物を得た。

Cyclosporin A (360 mg, 0.3 mmol), 4-acetoxystyrene (730 mg, 4.5 mmol) and (1,3-bis- (2,4,6-trimethylphenyl) -2-imidazolidene in dichloromethane (1 mL) A mixture of) dichloro (O-isopropoxyphenylmethylene) ruthenium (Hoveyda-Grubbs catalyst, 20 mg, 0.032 mmol) was purged with nitrogen and stirred at reflux for 16 hours. After cooling, the reaction mixture was purified by silica gel column chromatography (which uses MeOH—CH ₂ Cl ₂ ) to give the product as a solid (395 mg, 99%).

MS (m / z) 1322.9 [M + H] ⁺ , 1344.9 [M + Na] ⁺ ; HPLC retention time 3.3 minutes. (For 4.1 minutes of cyclosporin A; Phenominex Synergi 4 micron hydro-RP 80A 50 × 4.6 mm; solvent, 35% water and 65% acetonitrile; flow rate 2 mL / min; column temperature 60 ° C.).

(Example 252)
(Cyclo-[[(2S, 3R, 4R, 6E) -7- (4-hydroxyphenyl) -4-methyl-3-hydroxy-2- (methylamino) -6-heptenoyl] -L-2-aminobutyryl- Sarkosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl- L-Baryl])

シクロ−［［（２Ｓ，３Ｒ，４Ｒ，６Ｅ）−７−（４−アセトキシフェニル）−４−メチル−３−ヒドロキシ−２−（メチルアミノ）−６−ヘプテノイル］−Ｌ−２−アミノブチリル−サルコシル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−バリル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−アラニル−Ｄ−アラニル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−バリル］（３８５ｍｇ、０．２９ｍｍｏｌ）およびトリエチルアミン（１ｍＬ）のＭｅＯＨ（１０ｍＬ）溶液を、室温で、１６時間攪拌した。この反応混合物を真空中で濃縮し、その残留物をシリカゲルカラムクロマトグラフィー（これは、ＭｅＯＨ−ＣＨ_２Ｃｌ_２を使用する）で精製して、所望生成物（３１０ｍｇ、８３％）を得た。

Cyclo-[[(2S, 3R, 4R, 6E) -7- (4-acetoxyphenyl) -4-methyl-3-hydroxy-2- (methylamino) -6-heptenoyl] -L-2-aminobutyryl-sarcosyl -N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L -Valyl] (385 mg, 0.29 mmol) and triethylamine (1 mL) in MeOH (10 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (using MeOH—CH ₂ Cl ₂ ) to give the desired product (310 mg, 83%).

^{MS (m / z) 1280.9 [} M + H] +, 1278.8 [M-H] -; HPLC retention time 1.6 minutes. (For 4.0 minutes of cyclosporin A; Phenominex Synergi 4 micron hydro-RP 80A 50 × 4.6 mm; solvent, 35% water and 65% acetonitrile; flow rate 2 mL / min; column temperature 60 ° C.).

(Example 253)
(Cyclo-[[(2S, 3R, 4R, 6E) -7- (4- (diethoxyphosphoryl-methoxy) phenyl) -4-methyl-3-hydroxy-2- (methylamino) -6-heptenoyl]- L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L- Leucyl-N-methyl-L-valyl])

ＤＭＦ（１ｍＬ）中のシクロ−［［（２Ｓ，３Ｒ，４Ｒ，６Ｅ）−７−（４−ヒドロキシフェニル）−４−メチル−３−ヒドロキシ−２−（メチルアミノ）−６−ヘプテノイル］−Ｌ−２−アミノブチリル−サルコシル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−バリル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−アラニル−Ｄ−アラニル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−バリル］（１１３ｍｇ、０．０８８ｍｍｏｌ）および炭酸セシウム（３３ｍｇ、０．１ｍｍｏｌ）の混合物に、トリフルオロメタンスルホン酸ジエトキシホスホリルメチルエステル（６０ｍｇ、０．２ｍｍｏｌ）を加えた。この混合物を、室温で、１６時間攪拌した。その反応を２％塩化リチウム水溶液でクエンチし、この混合物を酢酸エチルで抽出した。その酢酸エチル抽出物を真空中で濃縮した。その残留物をシリカゲルクロマトグラフィーで精製して、所望生成物（３１０ｍｇ、８３％）（これには、未反応の出発物質が混入している）が得られ、これを、ＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ−ＣＨ_３ＣＮの溶離液と共に、Ｐｈｅｎｏｍｅｎｅｘ Ｓｙｎｅｒｇｉ ５μ Ｈｙｄｒｏ ＲＰ ８０Ａカラム（５０×２１．２ｍｍ）を使用する）でさらに精製した。所望生成物を含有する画分をプールし、そして乾燥状態まで濃縮した（６２ｍｇ、４９％）。

Cyclo-[[(2S, 3R, 4R, 6E) -7- (4-hydroxyphenyl) -4-methyl-3-hydroxy-2- (methylamino) -6-heptenoyl] -L in DMF (1 mL) -2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl To a mixture of -N-methyl-L-valyl] (113 mg, 0.088 mmol) and cesium carbonate (33 mg, 0.1 mmol) was added trifluoromethanesulfonic acid diethoxyphosphoryl methyl ester (60 mg, 0.2 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with 2% aqueous lithium chloride and the mixture was extracted with ethyl acetate. The ethyl acetate extract was concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired product (310 mg, 83%), which was contaminated with unreacted starting material, which was analyzed by RP HPLC (which was Further purification on a Phenomenex Synergi 5μ Hydro RP 80A column (50 × 21.2 mm) with eluent of H ₂ O—CH ₃ CN. Fractions containing the desired product were pooled and concentrated to dryness (62 mg, 49%).

MS (m / Z) 1431.0 [M + H] ⁺ ; 1428.7 [M−H] ⁻ ; ³¹ P (121.4 MHz, CDCl ₃ ) δ 19.5.

(Example 254)
(Cyclo-[[(2S, 3R, 4R, 6E) -7- (4- (dibenzyloxy-phosphorylmethoxy) phenyl) -4-methyl-3-hydroxy-2- (methylamino) -6-heptenoyl] -L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L -Leucyl-N-methyl-L-valyl])

ＤＭＦ（２ｍＬ）中のシクロ−［［（２Ｓ，３Ｒ，４Ｒ，６Ｅ）−７−（４−ヒドロキシフェニル）−４−メチル−３−ヒドロキシ−２−（メチルアミノ）−６−ヘプテノイル］−Ｌ−２−アミノブチリル−サルコシル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−バリル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−アラニル−Ｄ−アラニル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−バリル］（３００ｍｇ、０．２３４ｍｍｏｌ）および炭酸セシウム（３２６ｍｇ、１ｍｍｏｌ）の混合物に、トリフルオロメタンスルホン酸ジベンジルオキシホスホリルメチルエステル（６０ｍｇ、０．２ｍｍｏｌ）を加えた。この混合物を、室温で、１６時間攪拌した。その反応混合物をＡｃｒｏｄｉｓｃ（１３ｍｍの注射器フィルターであり、これは、０．４５ミクロンのナイロン膜を備えている）で濾過し、そしてＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ−ＣＨ_３ＣＮの溶離液と共に、Ｐｈｅｎｏｍｅｎｅｘ Ｓｙｎｅｒｇｉ ５μ Ｈｙｄｒｏ ＲＰ ８０Ａカラム（５０×２１．２ｍｍ）を使用する）でさらに精製した。所望生成物を含有する画分をプールし、そして乾燥状態まで濃縮すると、白色固形物（１１５ｍｇ、３２％）が得られた。

Cyclo-[[(2S, 3R, 4R, 6E) -7- (4-hydroxyphenyl) -4-methyl-3-hydroxy-2- (methylamino) -6-heptenoyl] -L in DMF (2 mL) -2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl To a mixture of -N-methyl-L-valyl] (300 mg, 0.234 mmol) and cesium carbonate (326 mg, 1 mmol) was added trifluoromethanesulfonic acid dibenzyloxyphosphoryl methyl ester (60 mg, 0.2 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered on an Acrodisc (13 mm syringe filter, equipped with a 0.45 micron nylon membrane) and RP HPLC (which was eluted with H ₂ O—CH ₃ CN eluent). , Using a Phenomenex Synergi 5μ Hydro RP 80A column (50 × 21.2 mm). Fractions containing the desired product were pooled and concentrated to dryness to give a white solid (115 mg, 32%).

MS (m / z) 1554.9 [M + H] ⁺ , 1552.7 [M−H] ⁻ ; ³¹ P (121.4 MHz, CDCl ₃ ) δ 20.5.

(Example 255)
(Cyclo-[[(2S, 3R, 4R, 6E) -7- (4- (dihydroxyphosphorylmethoxy) phenyl) -4-methyl-3-hydroxy-2- (methylamino) -6-heptenoyl] -L- 2-Aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl- N-methyl-L-valyl])

ジクロロメタン（２ｍＬ）中のシクロ−［［（２Ｓ，３Ｒ，４Ｒ，６Ｅ）−７−（４−（ジベンジルオキシホスホリル−メトキシ）フェニル）−４−メチル−３−ヒドロキシ−２−（メチルアミノ）−６−ヘプテノイル］−Ｌ−２−アミノブチリル−サルコシル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−バリル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−アラニル−Ｄ−アラニル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−バリル］（１１５ｍｇ、０．０７４ｍｍｏｌ）および２，６−ルチジン（４０μＬ、０．３５ｍｍｏｌ）の混合物に、臭化トリメチルシリル（５０μＬ、０．３５ｍｍｏｌ）を加えた。この混合物を、室温で、２時間攪拌した。その反応をメタノール（１ｍＬ）でクエンチし、その混合物を濃縮した。その残留物をフッ化アンモニア溶液（０．５Ｍ、２ｍＬ）で処理し、１時間攪拌し、濃縮し、そしてジクロロメタンと１Ｎ ＨＣｌとの間で分配した。このジクロロメタン層を濃縮し、その粗生成物をＲＰ ＨＰＬＣ（これは、０．１％ＴＦＡ Ｈ_２Ｏ−０．１％ＴＦＡ ＣＨ_３ＣＮの溶離液と共に、Ｐｈｅｎｏｍｅｎｅｘ Ｓｙｎｅｒｇｉ ５μ Ｈｙｄｒｏ ＲＰ ８０Ａカラム（５０×２１．２ｍｍ）を使用する）で精製した。所望生成物を含有する画分をプールし、そして乾燥状態まで濃縮すると、吸湿性固形物（６８ｍｇ、６３％）が得られた。

Cyclo-[[(2S, 3R, 4R, 6E) -7- (4- (dibenzyloxyphosphoryl-methoxy) phenyl) -4-methyl-3-hydroxy-2- (methylamino) in dichloromethane (2 mL) -6-heptenoyl] -L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl- N-methyl-L-leucyl-N-methyl-L-valyl] (115 mg, 0.074 mmol) and 2,6-lutidine (40 μL, 0.35 mmol) were added to trimethylsilyl bromide (50 μL, 0.35 mmol). Was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with methanol (1 mL) and the mixture was concentrated. The residue was treated with ammonia fluoride solution (0.5 M, 2 mL), stirred for 1 h, concentrated, and partitioned between dichloromethane and 1 N HCl. The dichloromethane layer was concentrated and the crude product was purified using RP HPLC (Phenomenex Synergi 5μ Hydro RP 80A column (50 × with 0.1% TFA H ₂ O—0.1% TFA CH ₃ CN eluent). 21.2 mm)). Fractions containing the desired product were pooled and concentrated to dryness to give a hygroscopic solid (68 mg, 63%).

^{MS (m / z) 1374.9 [} M + H] +, 1373.1 [M-H] -; HPLC retention time 0.3 minutes. (For 4.0 minutes of cyclosporin A; Phenominex Synergi 4 micron hydro-RP 80A 50 × 4.6 mm; solvent, 35% water and 65% acetonitrile; flow rate 2 mL / min; column temperature 60 ° C.).

(Example 256)
(Cyclo-[[(2S, 3R, 4R, 6E) -7- (4- (1- (S) -ethoxycarbonylethoxy) -phenoxyphosphorylmethoxy) phenyl) -4-methyl-3-hydroxy-2- ( Methylamino) -6-heptenoyl] -L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L -Leucyl-N-methyl-L-leucyl-N-methyl-L-valyl])

ＤＭＦ（２ｍＬ）中のシクロ−［［（２Ｓ，３Ｒ，４Ｒ，６Ｅ）−７−（４−（ジヒドロキシホスホリルメトキシ）フェニル）−４−メチル−３−ヒドロキシ−２−（メチルアミノ）−６−ヘプテノイル］−Ｌ−２−アミノブチリル−サルコシル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−バリル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−アラニル−Ｄ−アラニル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−バリル］（３４ｍｇ、０．０２３ｍｍｏｌ）、フェノール（２２ｍｇ、０．２３ｍｍｏｌ）、ジシクロヘキシルカルボジイミド（４７ｍｇ、０．２３ｍｍｏｌ）および４−（Ｎ、Ｎ−ジメチルアミノ）ピリジン（５．６ｍｇ、０．０４６ｍｍｏｌ）の混合物を、１４０℃で、２０分間攪拌した。冷却した後、そのモノフェニルモノホスホン酸生成物をＲＰ ＨＰＬＣ（これは、０．１％ＴＦＡ Ｈ_２Ｏ−０．１％ＴＦＡ ＣＨ_３ＣＮの溶離液と共に、Ｐｈｅｎｏｍｅｎｅｘ Ｓｙｎｅｒｇｉ ５μ Ｈｙｄｒｏ ＲＰ ８０Ａカラム（５０×２１．２ｍｍ）を使用する）で精製した。ＭＳ（ｍ／ｚ）１４５０．９［Ｍ＋Ｈ］^＋、１４４９．１［Ｍ−Ｈ］⁻；^３１Ｐ（１２１．４ＭＨｚ、ＣＤＣｌ_３）δ１４．９。この中間体を（Ｓ）−（−）−乳酸エチル（４０ｍｇ、０．３４ｍｍｏｌ）、ＰｙＢＯＰ（８０ｍｇ、０．１５ｍｍｏｌ）、ジイソプロピルエチルアミン（４５μＬ、０．２６ｍｍｏｌ）およびＤＭＦ（１．７ｍＬ）と混合した。得られた混合物を、室温で、２時間攪拌した。不溶性不純物を除去した後、その粗生成物をＲＰ ＨＰＬＣ（これは、０．１％ＴＦＡ Ｈ_２Ｏ−０．１％ＴＦＡ ＣＨ_３ＣＮの溶離液と共に、Ｐｈｅｎｏｍｅｎｅｘ Ｓｙｎｅｒｇｉ ５μ Ｈｙｄｒｏ ＲＰ ８０Ａカラム（５０×２１．２ｍｍ）を使用する）で精製した。所望の画分をプールし、そしてアセトニトリルと炭酸水素ナトリウム飽和水溶液との間で分配した。その有機層を濃縮して、固形物（１２ｍｇ、３４％）として、この生成物を得た。

Cyclo-[[(2S, 3R, 4R, 6E) -7- (4- (dihydroxyphosphorylmethoxy) phenyl) -4-methyl-3-hydroxy-2- (methylamino) -6-] in DMF (2 mL) Heptenoyl] -L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl -L-Leucyl-N-methyl-L-valyl] (34 mg, 0.023 mmol), phenol (22 mg, 0.23 mmol), dicyclohexylcarbodiimide (47 mg, 0.23 mmol) and 4- (N, N-dimethylamino) A mixture of pyridine (5.6 mg, 0.046 mmol) was stirred at 140 ° C. for 20 minutes. After cooling, the monophenyl mono acid product RP HPLC (which, together with the eluent _{0.1% TFA H 2 O-0.1} % TFA CH 3 CN, Phenomenex Synergi 5μ Hydro RP 80A column (50 X 21.2 mm)). MS (m / z) 1450.9 [M + H] ⁺ , 1449.1 [M−H] ⁻ ; ³¹ P (121.4 MHz, CDCl ₃ ) δ 14.9. This intermediate was mixed with (S)-(−)-ethyl lactate (40 mg, 0.34 mmol), PyBOP (80 mg, 0.15 mmol), diisopropylethylamine (45 μL, 0.26 mmol) and DMF (1.7 mL). . The resulting mixture was stirred at room temperature for 2 hours. After removal of insoluble impurities, the crude product was purified by RP HPLC (this was a Phenomenex Synergi 5μ Hydro RP 80A column (50 × with 0.1% TFA H ₂ O—0.1% TFA CH ₃ CN eluent). 21.2 mm)). Desired fractions were pooled and partitioned between acetonitrile and saturated aqueous sodium bicarbonate. The organic layer was concentrated to give the product as a solid (12 mg, 34%).

MS (m / z) 1573.1 [M + Na] ⁺ , 1548.8 [M−H] ⁻ ; ³¹ P (121.4 MHz, CDCl ₃ ) d 15.3 and 17.4.

(Example 257)
(Cyclo-[[(2S, 3R, 4R, 6E) -7- (4- (1- (S) -hydroxycarbonylethoxy) -hydroxyphosphorylmethoxy) phenyl) -4-methyl-3-hydroxy-2- ( Methylamino) -6-heptenoyl] -L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L -Leucyl-N-methyl-L-leucyl-N-methyl-L-valyl])

水およびアセトニトリルの混合溶媒（０．５ｍＬおよび４．５ｍＬ）中のシクロ−［［（２Ｓ，３Ｒ，４Ｒ，６Ｅ）−７−（４−（１−（Ｓ）−エトキシカルボニル−エトキシ）フェノキシホスホリルメトキシ）フェニル）−４−メチル−３−ヒドロキシ−２−（メチルアミノ）−６−ヘプテノイル］−Ｌ−２−アミノブチリル−サルコシル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−バリル−Ｎ−メチル−Ｌ−ロイシル−Ｌ−アラニル−Ｄ−アラニル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−ロイシル−Ｎ−メチル−Ｌ−バリル］（５ｍｇ、３．２μｍｏｌ）の溶液に、１Ｎ ＮａＯＨ（４０μＬ）を加えた。その溶液を、室温で、２時間攪拌した。得られた反応混合物を濃縮し、そしてＲＰ ＨＰＬＣ（これは、０．１％ＴＦＡ Ｈ_２Ｏ−０．１％ＴＦＡ ＣＨ_３ＣＮの溶離液と共に、Ｐｈｅｎｏｍｅｎｅｘ Ｓｙｎｅｒｇｉ ５μ Ｈｙｄｒｏ ＲＰ ８０Ａカラム（５０×２１．２ｍｍ）を使用する）で精製した。所望の画分を乾燥状態まで濃縮すると、固形物（１．５ｍｇ、３２％）として、この生成物が得られた。

Cyclo-[[(2S, 3R, 4R, 6E) -7- (4- (1- (S) -ethoxycarbonyl-ethoxy) phenoxyphosphoryl in a mixed solvent of water and acetonitrile (0.5 mL and 4.5 mL) Methoxy) phenyl) -4-methyl-3-hydroxy-2- (methylamino) -6-heptenoyl] -L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L -Leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl] (5 mg, 3.2 μmol) in a solution of 1N NaOH (40 μL ) Was added. The solution was stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated and RP HPLC (this was a Phenomenex Synergi 5μ Hydro RP 80A column (50 × 21. 5 with 0.1% TFA H ₂ O—0.1% TFA CH ₃ CN eluent). 2 mm)). The desired fraction was concentrated to dryness to give the product as a solid (1.5 mg, 32%).

MS (m / z) 1446.9 [M + H] ⁺ , 1444.9 [M−H] ⁻ ; HPLC retention time 0.2 min. (For 4.0 minutes of cyclosporin A; Phenominex Synergi 4 micron hydro-RP 80A 50 × 4.6 mm; solvent, 35% water and 65% acetonitrile; flow rate 2 mL / min; column temperature 60 ° C.).

(Example 258)
The synthesis of a compound of the invention that is an analog of BCX-1777 is illustrated here.

本発明の化合物（例えば、２５８．１）は、ここで概説する一般経路に従って、製造できる。

The compounds of the invention (eg, 258.1) can be prepared according to the general routes outlined herein.

（実施例２５９）

(Example 259)

このＢｏｃ−保護（１Ｓ）−１−（９−デアザグアニン−９−イル）−１，４−ジデオキシ−１，４−イミノ−Ｄ−リビトール（化合物２５９．１）を、Ｇｒｅｅｎｅ，Ｔ．，「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｗｉｌｅｙ−Ｉｎｔｅｒｓｃｉｅｎｃｅ，１９９９で記述されているように、（１Ｓ）−１−（９−デアザグアニン−９−イル）−１，４−ジデオキシ−１，４−イミノ−Ｄ−リビトール（ＷＯ ９，９１９，３３８およびＥｖａｎｓ，Ｇ．Ｂ．ら、Ｔｅｔｒａｈｅｄｒｏｎ，２０００，５６，３０５３；これはまた、Ｅｖａｎｓ，Ｇ．Ｂ．ら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．２００３，４６，３４１２でも報告されている）をＢＯＣ無水物と共に攪拌することにより、調製する。次いで、化合物２５９．１を、溶媒（例えば、テトラヒドロフランまたはジメチルホルムアミド）中にて、塩基（例えば、水素化ナトリウム）で処理する。泡立ちが止まると、ホスホノメチルトリフリト酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）を加え、トリフルオロ酢酸（ＴＦＡ）を使用してＢＯＣ基を脱保護した後、所望のホスホネート２５９．２が得られる。

This Boc-protected (1S) -1- (9-deazaguanine-9-yl) -1,4-dideoxy-1,4-imino-D-ribitol (compound 259.1) was prepared according to Greene, T .; , “Protective Groups in Organic Synthesis”, Wiley-Interscience, 1999, (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; this is also Evans, GB et al., J. Med. Chem. 2003, 46, 3412. But also reported) with BOC anhydride. Compound 259.1 is then treated with a base (eg, sodium hydride) in a solvent (eg, tetrahydrofuran or dimethylformamide). When bubbling ceased, after adding diethyl phosphonomethyltriflate (which was prepared according to Tetrahedron Lett., 1986, 27, 1477) and deprotecting the BOC group using trifluoroacetic acid (TFA) The desired phosphonate 259.2 is obtained.

  (Example 260)

２６０．１および２６０．２のような化合物は、ここで概説する一般経路に従って、製造できる。

Compounds such as 260.1 and 260.2 can be made according to the general route outlined herein.

  (Example 261)

このＢｏｃ−保護（１Ｓ）−１−（９−デアザグアニン−９−イル）−１，４−ジデオキシ−１，４−イミノ−Ｄ−リビトール（化合物２５９．１）を、Ｇｒｅｅｎｅ，Ｔ．，「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｗｉｌｅｙ−Ｉｎｔｅｒｓｃｉｅｎｃｅ，１９９９で記述されているように、（１Ｓ）−１−（９−デアザグアニン−９−イル）−１，４−ジデオキシ−１，４−イミノ−Ｄ−リビトール（ＷＯ ９，９１９，３３８およびＥｖａｎｓ，Ｇ．Ｂ．ら、Ｔｅｔｒａｈｅｄｒｏｎ，２０００，５６，３０５３；これはまた、Ｅｖａｎｓ，Ｇ．Ｂ．ら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．２００３，４６，３４１２でも報告されている）をＢＯＣ無水物と共に攪拌することにより、調製する。ＴＢＳ基を使用するこの第一級アルコールの引き続いた保護は、Ｇｒｅｅｎｅ、Ｔ．「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、Ｗｉｌｅｙ−Ｉｎｔｅｒｓｃｉｅｎｃｅ、１９９９で記述されているように、溶媒（例えば、ＣＨ_２Ｃｌ_２）中にて、ＴＢＳＣｌおよびイミダゾールを使用して達成でき、化合物２６１．１が得られる。次いで、化合物２６１．１を、溶媒（テトラヒドロフランまたはジメチルホルムアミド）中にて、塩基（例えば、水素化ナトリウム）で処理する。泡立ちが止まると、ホスホノメチルトリフリト酸ジエチル（これは、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７に従って、調製した）を加え、トリフルオロ酢酸（ＴＦＡ）を使用してＢＯＣ基を脱保護した後、所望のホスホン酸ジエステル２６１．２および２６１．３の混合物が得られる。化合物２６１．２および２６１．３はまた、２６１．１のさらに複雑な２’ＯＨ保護類似物を経由し、続いて、トリフリト酸ジエチルホスホノメチルを使用してアルキル化されて、全く化合物２６１．２のみが得られる。化合物２６１．３はまた、３’ＯＨ位置に異なる保護基を導入することに続いて、２’ＯＨの脱保護および２’中心におけるトリフリト酸ジエチルホスホノメチルでのアルキル化により、続いて、全体的な脱保護により、調製できる。

This Boc-protected (1S) -1- (9-deazaguanine-9-yl) -1,4-dideoxy-1,4-imino-D-ribitol (compound 259.1) was prepared according to Greene, T .; , “Protective Groups in Organic Synthesis”, Wiley-Interscience, 1999, (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; this is also Evans, GB et al., J. Med. Chem. 2003, 46, 3412. But also reported) with BOC anhydride. The subsequent protection of this primary alcohol using the TBS group is described in Greene, T .; This can be achieved using TBSCl and imidazole in a solvent (eg, CH ₂ Cl ₂ ) as described in “Protective Groups in Organic Synthesis”, Wiley-Interscience, 1999, to give compound 261.1. It is done. Compound 261.1 is then treated with a base (eg, sodium hydride) in a solvent (tetrahydrofuran or dimethylformamide). When bubbling ceased, after adding diethyl phosphonomethyltriflate (which was prepared according to Tetrahedron Lett., 1986, 27, 1477) and deprotecting the BOC group using trifluoroacetic acid (TFA) A mixture of the desired phosphonic acid diesters 261.2 and 261.3 is obtained. Compounds 261.2 and 261.3 were also routed through the more complex 2'OH protected analog of 261.1, followed by alkylation using diethylphosphonomethyl trifritate to give compound 261. Only 2 is obtained. Compound 261.3 was also prepared by introducing a different protecting group at the 3′OH position, followed by deprotection of 2′OH and alkylation with diethylphosphonomethyl trifritate at the 2 ′ center, followed by Can be prepared by selective deprotection.

  (Example 262)

本発明の代表的な化合物は、上で図示したように、調製できる。Ｃ−１１水酸基での誘導体化は、アセポン酸メチルプレドニゾロン２６２．１を適当なホスホネートでアルキル化することによって達成され、式２６２．２の類似物が得られる。本発明の特定の化合物は、以下のようにして、調製できる。

Representative compounds of the present invention can be prepared as illustrated above. Derivatization at the C-11 hydroxyl group is accomplished by alkylating methylprednisolone 262.1 aceponate with the appropriate phosphonate to give an analog of formula 262.2. Certain compounds of the invention can be prepared as follows.

２６２．１のヒドロキシプロトンを水素化ナトリウムで抽出した後、ホスホン酸トリフリト酸ジエチルを加えて、エーテル２６２．３が得られる。

After extracting the 262.1 hydroxy protons with sodium hydride, diethyl phosphonate triflate is added to give ether 262.3.

  (Example 263)

本発明の代表的な化合物は、アセポン酸メチルプレドニゾロン２６２．１を完全に加水分解したときに利用可能な３個の水酸基の間の反応性の差を利用することにより、上で図示したように、調製できる。２６２．１にある唯一の露出した水酸基の保護に続いて、中間体２６３．１を、ケン化して、ジオール２６３．２が得られる。この第一級水酸基を適当なホスホネートでアルキル化し、引き続いて、アシル化すると、プロピオン酸エステル２６３．４が得られる。脱保護後、所望の生成物２６３．５が得られる。

Representative compounds of the present invention, as illustrated above, take advantage of the difference in reactivity between the three hydroxyl groups available when methylprednisolone aceponate 262.1 is fully hydrolyzed. Can be prepared. Following protection of the only exposed hydroxyl group at 262.1, intermediate 263.1 is saponified to give diol 263.2. Alkylation of this primary hydroxyl group with a suitable phosphonate followed by acylation provides the propionate ester 263.4. After deprotection, the desired product 263.5 is obtained.

  (Example 264)

アセポン酸メチルプレドニゾロン２６２．１は、標準的なＴＢＳＣｌおよびイミダゾール条件を使用して、そのシリルエーテルとして、保護される（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．１９７２，９４，６１９０）。水酸化ナトリウム水溶液を使用して、両方のエステル部分をケン化すると、ジオール２６４．２が得られる。立体的に障害が少ない第一級水酸基は、水酸化ナトリウムおよびホスホネートトリフレートを加えることにより、アルキル化される。中間体２６４．３をピリジン中の無水プロピオン酸で処理した後、先に加水分解したＣ−１７プロピオン酸エステルを置換する（Ｊ．Ｍｅｄ．Ｃｈｅｍ．１９８０，２３，４３０−４３７）。このシリルエーテルのＴＢＡＦ保護により、ホスホン酸ジエチル２６４．５が得られる。

Methylprednisolone aceponate 262.1 is protected as its silyl ether using standard TBSCl and imidazole conditions (J. Am. Chem. Soc. 1972, 94, 6190). Saponification of both ester moieties using aqueous sodium hydroxide gives the diol 264.2. The sterically hindered primary hydroxyl group is alkylated by adding sodium hydroxide and phosphonate triflate. After treating intermediate 264.3 with propionic anhydride in pyridine, the previously hydrolyzed C-17 propionic acid ester is replaced (J. Med. Chem. 1980, 23, 430-437). This TBAF protection of the silyl ether provides diethyl phosphonate 264.5.

  (Example 265)

本発明の代表的な化合物は、上で図示したように、調製できる。ジオール２６３．２の２個の水酸基は、その第一級部位にて保護することにより、位置選択的に区別されて、それにより、この第三級水酸基でのアルキル化が可能となる。次いで、得られたホスホネート中間体２６５．２は、脱保護されて、ジオール２６５．３が得られる。再度、さらにアクセスし易い第一級水酸基は、アシル化されて、所望の類似物２６５．４が生成される。

Representative compounds of the present invention can be prepared as illustrated above. The two hydroxyl groups of diol 263.2 are regioselectively distinguished by protecting at their primary site, thereby allowing alkylation at this tertiary hydroxyl group. The resulting phosphonate intermediate 265.2 is then deprotected to give the diol 265.3. Again, the more accessible primary hydroxyl group is acylated to produce the desired analog 265.4.

  (Example 266)

ジオール２６４．２（実施例２６４を参照）は、この第一級部位にて、そのシリルエーテル２６６．１として、保護される。このホスホン酸トリフリト酸ジエチルでアルキル化することに続いて、得られた中間体２６６．２を、ＴＢＡＦで処理して、ジオール２６６．３が得られる。無水酢酸およびピリジンを使用して、最終生成物２６６．４が産生される（Ｊ．Ｍｏｌ．Ｂｉｏｌ．１９７２，７２，２１９）。

The diol 264.2 (see Example 264) is protected at this primary site as its silyl ether 266.1. Following alkylation with this diethyl phosphonate triflate, the resulting intermediate 266.2 is treated with TBAF to give the diol 266.3. The final product 266.4 is produced using acetic anhydride and pyridine (J. Mol. Biol. 1972, 72, 219).

  (Example 267)

本発明の代表的な化合物は、上で図示したように、調製できる。リン含有メリメポディブ（ｍｅｒｉｍｅｐｏｄｉｂ）類似物２６７．２を、アルキル化により、親化合物から合成する。メリメポディブ２６７．１は、米国特許第６，０５４，４７２号および米国特許第６，３４４，４６５号で記述された手順により、得られる。メリメポディブ２６７．１のメトキシ基を、適当な試薬（例えば、三臭化ホウ素）を使用して、フェノール性ＯＨに脱メチル化する。このホスホネート部分を、適当な溶媒（例えば、ＤＭＦ）中にて、このフェノール性ＯＨに導入し、次いで、適当な有機塩基または無機塩基の存在下にて、脱離基（例えば、臭素、メシル、トシルまたはトリフルオロメタンスルホニル）を有するホスホネート試薬で処理する。本発明の特定の化合物は、以下のようにして、調製できる。

Representative compounds of the present invention can be prepared as illustrated above. The phosphorus-containing merimepodib analog 267.2 is synthesized from the parent compound by alkylation. Merimepodib 267.1 is obtained by the procedures described in US Pat. No. 6,054,472 and US Pat. No. 6,344,465. The methoxy group of Merimepodibu 267.1 is demethylated to phenolic OH using a suitable reagent (eg, boron tribromide). The phosphonate moiety is introduced into the phenolic OH in a suitable solvent (eg, DMF) and then in the presence of a suitable organic or inorganic base (eg bromine, mesyl, Treatment with a phosphonate reagent having tosyl or trifluoromethanesulfonyl). Certain compounds of the invention can be prepared as follows.

２６７．１のジクロロメタン溶液を、三臭化ホウ素で処理して、脱メチル化化合物２６７．８が得られる。次いで、化合物２６７．８を、炭酸セシウムおよび１当量の（トリフルオロメタンスルホニルオキシ）−メチルホスホン酸ジエチルエステル２６７．９で処理して、メリメポディブ−ホスホネート２６７．１０が得られる。上記手順を使用するが、異なるホスホネート試薬を使用して、異なる連結基を有する対応する生成物２６７．２を得ることができる。

Treatment of a solution of 267.1 in dichloromethane with boron tribromide gives the demethylated compound 267.8. Compound 267.8 is then treated with cesium carbonate and 1 equivalent of (trifluoromethanesulfonyloxy) -methylphosphonic acid diethyl ester 267.9 to give merimepodibu-phosphonate 267.10. Using the above procedure, but using different phosphonate reagents, the corresponding product 267.2 with different linking groups can be obtained.

  (Example 268)

本発明の代表的な化合物は、上で図示したように、調製できる。イミダゾール含有中間体２６８．１３を、Ｓｈｉｈの手順（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．１９９３，３４，５９５）により、アルデヒド２６８．１２から合成する。化合物２６８．１２を、米国特許第５，８０７，８７６号、米国特許第６，０５４，４７２号および米国特許第６，３４４，４６５号で記述された２段階手順により、調製する。このイミダゾールを、適当な試薬（例えば、塩化２−（トリメチルシリル）エトキシメチル（ＳＥＭ））を使用して保護され、化合物２６８．１４は、米国特許第６，０５４，４７２号および米国特許第６，３４４，４６５号において１９７．１の合成について記述されたものと類似の手順により、２６８．１５に転換する。２６８．１５のイミダゾール上の保護基を除去した後、このホスホネート含有部分を、このイミダゾールに導入して、本発明の化合物が得られる。本発明の特定の化合物は、以下のようにして、調製できる。

Representative compounds of the present invention can be prepared as illustrated above. The imidazole-containing intermediate 268.13 is synthesized from the aldehyde 268.12 by Shih's procedure (Tetrahedron Lett. 1993, 34, 595). Compound 268.12 is prepared by the two-step procedure described in US Pat. No. 5,807,876, US Pat. No. 6,054,472 and US Pat. No. 6,344,465. The imidazole is protected using a suitable reagent such as 2- (trimethylsilyl) ethoxymethyl chloride (SEM) and compound 268.14 is described in US Pat. No. 6,054,472 and US Pat. Convert to 268.15 by a procedure similar to that described for the synthesis of 197.1 in 344,465. After removal of the protecting group on the imidazole at 268.15, the phosphonate containing moiety is introduced into the imidazole to give the compounds of the invention. Certain compounds of the invention can be prepared as follows.

化合物２６８．１５を、ＴＨＦ中にて、還流条件で、フッ化テトラブチルアンモニウムで処理し、得られた２６８．１６は、塩基として水素化ナトリウムを使用して、２６８．９でアルキル化して、２種の異性体２６８．１７および２６８．１８が得られ、これらを、クロマトグラフィーで分離する。

Compound 268.15 was treated with tetrabutylammonium fluoride in THF under reflux conditions and the resulting 268.16 was alkylated with 268.9 using sodium hydride as the base, Two isomers 268.17 and 268.18 are obtained, which are separated by chromatography.

  (Example 269)

本発明の代表的な化合物は、上で図示したように、調製できる。四置換ベンゼン誘導体は、文献手順（ＩｃｈｉｋａｗａおよびＩｃｈｉｂａｇａｓｅ Ｙａｋｕｇａｋｕ Ｚａｓｓｈｉ １９６３，８３，１０３；Ｎｏｒｉｏ，Ａ．ら、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．１９９２，３３（３７），５４０３）により、得られる。このフェノール性ＯＨを適当な保護基（例えば、ベンジル基）で保護した後、化合物２６９．２１を、米国特許第６，０５４，４７２号および米国特許第６，３４４，４６５号で記述されたものと同じ手順により、合成する。この保護基を除去した後、このホスホネート含有部分を、ホスホネート試薬２６９．７（これは、適当な脱離基を有する）を使用して、このフェノール性ＯＨに導入する。本発明の特定の化合物は、以下のようにして、調製できる。

Representative compounds of the present invention can be prepared as illustrated above. Tetrasubstituted benzene derivatives are obtained by literature procedures (Ichikawa and Ichibagase Yakugaku Zashishi 1963, 83, 103; Norio, A. et al., Tetrahedron Lett. 1992, 33 (37), 5403). After protecting the phenolic OH with a suitable protecting group (eg, a benzyl group), compound 269.21 was prepared as described in US Pat. No. 6,054,472 and US Pat. No. 6,344,465. The same procedure is used for synthesis. After removal of the protecting group, the phosphonate containing moiety is introduced into the phenolic OH using phosphonate reagent 269.7 (which has an appropriate leaving group). Certain compounds of the invention can be prepared as follows.

例えば、２６９．２２の溶液（これは、Ｎｏｒｉｏらの手順（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．１９９２，３３（３７），５４０３）により、得られる）を、水素化ナトリウムおよび１当量の臭化ベンジル（ＤＭＦ中）で処理して、２６９．２３が得られる。化合物２６９．２３を、一連の工程（例えば、米国特許第６，０５４，４７２号および米国特許第６，３４４，４６５号で報告されたもの）により、２６９．２４に転換する。２６９．２４のベンジル保護基を触媒水素化で除去した後、ホスホネート保持部分を、ＤＭＦ中にて、水素化ナトリウムおよび１当量の（トリフルオロメタンスルホニルオキシ）メチルホスホン酸ジエチルエステル２６９．９を使用して、得られたフェノールをアルキル化することにより結合して、２６９．２５が得られる。

For example, a solution of 269.22 (obtained by the procedure of Norio et al. (Tetrahedron Lett. 1992, 33 (37), 5403)) with sodium hydride and 1 equivalent of benzyl bromide (in DMF). Processing gives 269.23. Compound 269.23 is converted to 269.24 by a series of steps (eg, those reported in US Pat. No. 6,054,472 and US Pat. No. 6,344,465). After removal of the benzyl protecting group at 269.24 by catalytic hydrogenation, the phosphonate retention moiety was used in DMF using sodium hydride and 1 equivalent of (trifluoromethanesulfonyloxy) methylphosphonic acid diethyl ester 269.9. The resulting phenol is coupled by alkylation to give 269.25.

  (Example 270)

本発明の代表的な化合物は、上で図示したように、調製できる。化合物２７０．２６を、カルボニルジイミダゾールまたはトリホスゲンに続いて化合物２７０．２７（これは、ホスホネート部分を結合するハンドルを有する）で処理する。余分な置換基を有する化合物２７０．２７を、シアノ基およびニトロ基を有する三置換フェノール（これは、市販されているか、または文献手順（Ｚｏｌｆｉｇｏｌ，Ｍ．Ａ．ら、Ｉｎｄｉａｎ Ｊ．Ｃｈｅｍ．Ｓｅｃｔ．Ｂ ２００１，４０，１１９１；Ｄｅ Ｊｏｎｇｈ，Ｒ．Ｏ．ら、Ｒｅｃｌ．Ｔｒａｖ．Ｃｈｉｍ．Ｐａｙｓ−Ｂａｓ １９６８，８７，１３２７）によるか、いずれかである）から合成する。得られた２７０．２８を、米国特許第６，０５４，４７２号および米国特許第６，３４４，４６５号で記述されたものと類似の手順を使用して、２７０．２９に転換する。２７０．６のホスホネート部分を、２７０．２９のベンジル基を脱保護した後、結合する。

Representative compounds of the present invention can be prepared as illustrated above. Compound 270.26 is treated with carbonyldiimidazole or triphosgene followed by compound 270.27, which has a handle that attaches the phosphonate moiety. Compounds 270.27 with extra substituents can be converted to trisubstituted phenols with cyano and nitro groups, which are either commercially available or are described in literature procedures (Zolfigor, MA et al., Indian J. Chem. Sect. B 2001, 40, 1191; De Jong, RO, et al., Recl. Trav. Chim. Pays-Bas 1968, 87, 1327). The resulting 270.28 is converted to 270.29 using procedures similar to those described in US Pat. No. 6,054,472 and US Pat. No. 6,344,465. The phosphonate moiety at 270.6 is coupled after deprotecting the benzyl group at 270.29.

例えば、化合物２７０．３０の臭素置換基を、Ｄｅ Ｊｏｎｇｈ，Ｒ．Ｏ．らの手順（Ｒｅｃｌ．Ｔｒａｖ．Ｃｈｉｍ．Ｐａｙｓ−Ｂａｓ １９６８，８７，１３２７）により、シアノ基で置換し、そのメトキシ基を、保護基として、ベンジルオキシ基に変換し、これにより、化合物２７０．３１が得られる。ボランによりシアノをアミノメチル基に選択的に還元した後、このアミノ基を、Ｂｏｃ基で保護し、次いで、塩化スズ（ＩＩ）を使用して、このニトロ基を還元すると、化合物２７０．３２が産生される。次いで、この置換アニリン２７０．３２を、米国特許第６，０５４，４７２号および米国特許第６，３４４，４６５号で記述されているように、化合物２７０．２６およびカルボニルジイミダゾールの反応混合物で処理して、尿素２７０．３３を形成する。化合物２７０．３３を、２７０．３４に転換する。触媒水素化を使用してこのベンジル基を脱保護することに続いて、炭酸セシウムの存在下にて、２７０．９を使用して、ホスホネート部分を結合すると、化合物２７０．３５が生成される。

For example, the bromine substituent of compound 270.30 can be obtained from De Jong, R. O. And the like (Recl. Trav. Chim. Pays-Bas 1968, 87, 1327), and the methoxy group was converted to a benzyloxy group as a protecting group, thereby converting the compound 270.31 Is obtained. After selective reduction of cyano to an aminomethyl group with borane, the amino group is protected with a Boc group and then the nitro group is reduced using tin (II) chloride to give compound 270.32. Produced. This substituted aniline 270.32 is then treated with a reaction mixture of compound 270.26 and carbonyldiimidazole as described in US Pat. No. 6,054,472 and US Pat. No. 6,344,465. Thus, urea 270.33 is formed. Compound 270.33 is converted to 270.34. Following deprotection of this benzyl group using catalytic hydrogenation, coupling of the phosphonate moiety using 270.9 in the presence of cesium carbonate produces compound 270.35.

(Example 271)
The synthesis of the phosphonate compounds of the invention and the intermediate compounds required for their synthesis is illustrated here. Its derivatization at the C-21 hydroxyl group is accomplished by alkylating dexamethasone 271A with the appropriate phosphonate, resulting in the analog shown here.

そのＣ−２１水酸基での誘導体化は、デキサメタゾン２７１Ａを適当なホスホネートでアルキル化することによって達成され、２７１．２型の類似物が得られる。

Its derivatization at the C-21 hydroxyl group is accomplished by alkylating dexamethasone 271A with the appropriate phosphonate to give an analog of type 271.2.

２７１Ａの第一級ヒドロキシプロトンを水素化ナトリウムで抽出した後、ホスホン酸トリフリト酸ジエチルを加えて、エーテル２７１．５が得られる。

After extracting the primary hydroxy proton of 271A with sodium hydride, diethyl phosphonate triflate is added to give ether 271.5.

  (Example 272)

式２７１．４を有するＣ−２１ホスホネート類似物の合成は、ここで図示している。立体障害がより少ない部位でデキサメタゾン２７１Ａを保護すると、このとき、アルコール２７１．５が得られ、これは、その唯一の露出した水酸基にて、適当なホスホネートでアルキル化される。その保護基を除去すると、類似物２７１．４の作成が完結する。

The synthesis of a C-21 phosphonate analog having formula 271.4 is illustrated here. Protection of dexamethasone 271A at a site with less steric hindrance yields alcohol 271.5, which is alkylated with the appropriate phosphonate at its only exposed hydroxyl group. Removal of the protecting group completes the creation of analog 271.4.

  (Example 272)

デキサメタゾン２７１Ａを、標準的なＴＢＳＣｌおよびイミダゾール条件を使用して、そのシリルエーテルとして、保護する（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．１９７２，９４，６１９０）；しかしながら、ビス−保護には、さらに厳しい条件が許容できるはずである。ホスホン酸トリフリト酸ジエチルでアルキル化した後、得られた中間体２７１．９を、ＴＢＡＦで処理して、所望のホスホネート２７１．１０が得られる。

Dexamethasone 271A is protected as its silyl ether using standard TBSCl and imidazole conditions (J. Am. Chem. Soc. 1972, 94, 6190); Should be acceptable. After alkylation with diethyl phosphonate triflate, the resulting intermediate 271.9 is treated with TBAF to give the desired phosphonate 271.10.

(Example 273)
A number of compounds having the general structure 273A can either be prepared using procedures described in the literature or can be purchased from companies. The following is a good source of information on techniques for preparing various compounds of general structure 273A: Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994; and Vorbrugen and Ruh-Pohlens & Sons, Inc. , 2001.

  In the examples of the compounds of the invention described herein, the substituent has the following general formula 273A:

ここで、１個またはそれ以上の置換基Ｚは、Ａ^０基で置換されている；ここで：
Ｚ_１およびＺ_２は、別個に、水素、またはＣ_１〜Ｃ_１８アシルから選択され、そしてＺ_３は、Ｈ、Ｃ_１〜Ｃ_１８アシル、または

Wherein one or more substituents Z are substituted with an A ⁰ group; where:
Z ₁ and Z ₂ are independently selected from hydrogen or C ₁ -C ₁₈ acyl, and Z ₃ is H, C ₁ -C ₁₈ acyl, or

であるか、またはＺ_１は、水素であり、そしてＺ_２およびＺ_３は、共に、

Or Z ₁ is hydrogen and Z ₂ and Z ₃ are both

である；
塩基は、以下である：

Is
The base is:

ここで、ＸおよびＹは、別個に、ＯまたはＳである；Ｚ_４は、水素、アミノ、ヒドロキシまたはハロゲンであり、このハロゲンは、ＣｌおよびＢｒから選択される。

Wherein X and Y are independently O or S; Z ₄ is hydrogen, amino, hydroxy or halogen, wherein the halogen is selected from Cl and Br.

さらに具体的には、一般構造２７３Ａの調製は、Ｎａｇａｈａｒａら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．；３３；１９９０；４０７−４１５で記述されている。構造２７３．２は、Ｋｉｎｉら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．；３４；１９９１；３００６−３０１０で記述されている。上で列挙した２つの特許もまた、化合物２７３Ａの合成の例を提供した。

More specifically, the preparation of general structure 273A is described in Nagahara et al. Med. Chem. 33; 1990; 407-415. Structure 273.2 is described in Kini et al. Med. Chem. 34; 1991; 3006-3010. The two patents listed above also provided examples of the synthesis of compound 273A.

The core element of this reaction procedure is the conversion of the compound from 273.3 to 273.6. A suitable oxidizing agent can convert the primary alcohol (5′-hydroxy) illustrated at 273.3 to a carboxylic acid or its corresponding ester. In the case of an ester, an additional deprotection step provides the carboxylic acid 273.4. Various oxidation procedures exist in this document and are available here. This includes, but is not limited to, the following methods: (i) The t-butyl ester is formed from Ac ₂ O, t-BuOH and pyridinium dichromate in dichloromethane, followed by reagents. (E.g., trifluoroacetic acid) and converted to the corresponding carboxylic acid (Classson et al., Acta Chem. Scand. Ser. B; 1985, 39, 501-504. Cristalli et al., J. Med. Chem., 1988, 31, 1179-1183); (ii) from iodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) in acetonitrile (Epp et al .; J. Org. Chem. 64; 1999; 293- J. Org. Chem .; 66; 2001; 2624-2635); (iii) sodium periodate in chloroform, ruthenium (III) chloride, to produce their carboxylic acids (Kim J Med. Chem. 37; 1994; 4020-4030. Hamma et al .; J. Med. Chem. 35; 1992; 2881-2890); (iv) the carboxylic acid from chromium trioxide in acetic acid. (See Olsson et al .; J. Med. Chem .; 29; 1986; 1683-1689. Gallo-Rodriguez et al .; J. Med. Chem .; 37; 1994; 636-646); (v) hydroxylation The carboxylic acid is produced from potassium permanganate in an aqueous potassium solution (Ha ; J.Med.Chem;. 29; 1986; 1683-1689.Franchetti et; J.Med.Chem;. 41; 1998; see 1708-1715) (vi) S. The carboxylic acid is produced from a nucleoside oxidase derived from maltophilia (see Mahmudian et al .; Tetrahedron; 54; 1998; 8171-8182).

  The preparation of compound 273.5 (Lv = OAc) using lead (IV) tetraacetate starting with compound 273.4 is 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 in combination with lithium chloride (see Kochi et al .; J. Am. Chem. Soc .; 87; 1965; 2052), the corresponding chloride is obtained (273.5, Lv = Cl ). When lead (IV) tetraacetate is used in combination with N-chlorosuccinimide, the same product (273.5, Lv = Cl) can be produced (Wang et al .; Tet. Asym .; 1; 1990; 527 and Wilson et al .; Tet. Asym.; 1; 1990; 525). Alternatively, the acetate leaving group (Lv) can also be converted to other leaving groups (eg, bromide) by treatment with trimethylsilyl bromide to give 273.5 ((Spencer et al .; J. Org Chem .; 64; 1999; 3987-3955).

Coupling of 273.5 (Lv = OAc) with various nucleophiles is described by Teng et al .; Synlett; 1996; 346-348 and US Pat. No. 6,087,482; column 54, lines 64-55, It is described in 20 lines. Specifically, the coupling between 273.5 and diethyl hydroxymethylphosphonate in the presence of trimethylsilyl trifluoromethanesulfonate (TMS-OTf) has been described. It can be envisaged that other compounds having the general structure of HO-linker-POR ^P1 R ^P2 can also be used as long as the functional groups in these compounds are compatible with the coupling reaction conditions. There are many examples in the published literature describing the coupling of 273.5 (Lv = halogen) with various alcohols. These reactions can be facilitated, for example, using a number of reagents: Silver (I) salts (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) salt (Veenman et al .; Recl.Trav.Chim.Pays-Bas; 106; 1987; 129-131), three Boron bromide diethyl etherate (Kunz et al .; see Hel. Chim Acta; 68; 1985; 283-287), tin (II) chloride (O'Leary et al .; J. Org. Chem .; 59; 1994; 6629-6636 ), Alkoxides (Shortacy-Fowler et al .; Nucleosi). es Nucleotides; 20; 2001; see 1583-1598) and iodine (Kartha et al; see 770-772); J.Chem.Soc.Perkins Trans.1; 2001. These methods can be selectively combined with different methods of forming 273.5 using various leaving groups (Lv) to produce 273.6.

The conversion from 273.1 to 273.2, the conversion from 273.2 to 273.3 and the conversion from 273.6 to 273.7 maintain the functional groups already present in their compound structure. However, it is intended to give rise to a core element of transformation (from 273.3 to 273.6). Therefore, these syntheses may require the introduction and removal of protecting groups from the compound, a method commonly practiced in organic synthesis. It should be understood that in the conversion from 273.6 to 273.7, R ^P1 and R ^P2 need not remain unchanged. The final shape of R ^P1 and R ^P2 can be selected from a variety of possible shapes.

  (Example 274)

化合物２７４．１を、特許出願ＷＯ ０１／９０１２１（１１５ページの表）で記述された方法を使用して、調製する。２７４．１中の５’−ヒドロキシルを、第三級ブチルジメチルシリル（ＴＢＤＭＳ）エーテルとして、保護する。それらの２’−および３’−水酸基は、ベンゾイル（Ｂｚ）エステルとして保護でき、２７４．２が得られる。次いで、この５’−ヒドロキシルは、脱保護でき、２７４．３が得られる。二酢酸ヨードベンゼンおよび２，２，６，６−テトラメチル−１−ピペリジニルオキシ遊離ラジカル（ＴＥＭＰＯ）を使用して酸化すると、この第一級アルコールは、対応する酸２７４．４に転換される。四酢酸鉛を使用して２７４．４をさらに酸化すると、２７４．５が生成できる。ＴＭＳ−ＯＴｆにより引き起こされる２７４．５とヒドロキシメチルホスホン酸ジエチル（これは、Ｓｉｇｍａ−Ａｌｄｒｉｃｈ，Ｃａｔ．Ｎｏ．３９，２６２−６から入手できる）との間のカップリングにより、２７４．６を得ることができる。２７４．６をＴＭＳ−Ｂｒで処理すると、このホスホジエステルは、対応するホスホン酸２７４．７に変換される。その２’−および３’−ヒドロキシルを脱保護すると、一般構造Ａの一例として、２７４．８が得られ、この場合、塩基は、７−チア−８−オキソ−グアノシンであり、Ｒ^１、Ｒ^２、Ｒ^Ｐ１およびＲ^Ｐ２は、水素であり、リンカーは、メチレン基である。

Compound 274.1 is prepared using the method described in patent application WO 01/90121 (table on page 115). The 5'-hydroxyl in 274.1 is protected as tertiary butyldimethylsilyl (TBDMS) ether. Their 2'- and 3'-hydroxyl groups can be protected as benzoyl (Bz) esters to give 274.2. This 5'-hydroxyl can then be deprotected to give 274.3. Upon oxidation using iodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO), this primary alcohol is converted to the corresponding acid 274.4. The Further oxidation of 274.4 using lead tetraacetate can produce 274.5. Coupling between 274.5 caused by TMS-OTf and diethyl hydroxymethylphosphonate (which is available from Sigma-Aldrich, Cat. No. 39, 262-6) can yield 274.6. it can. Treatment of 274.6 with TMS-Br converts this phosphodiester to the corresponding phosphonic acid 274.7. Deprotection of the 2′- and 3′-hydroxyls yields 274.8 as an example of general structure A, where the base is 7-thia-8-oxo-guanosine, R ¹ , R ² , R ^P1 and R ^P2 are hydrogen and the linker is a methylene group.

  The phosphonic acids in 274.7 and 274.8 are used as examples for illustrative purposes. Other forms of phosphonates can be accessed through their phosphonic acid or other forms (eg, the corresponding diesters as described herein).

(Example 275)
Leflunomide (along with its active metabolite, the following structure) (see US Pat. No. 4,284,786) is a derivative of isoxazole. Representative compounds of the present invention are described in J. Org. Med. Chem. A procedure similar to that described in 1996, 39, 4608 can be used and prepared as illustrated above. These structures are shown below.

これらのような化合物の合成方法論は、以下で概説した一般経路に従って、Ｗｅｓｔｗｏｏｄら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９６，３９，４６０８−４６２１で記述されている。

Synthetic methodologies for compounds such as these are described in Westwood et al., J. Mol. Med. Chem. 1996, 39, 4608-4621.

（実施例２７５Ａ）
適当なホスホネート含有アニリンの合成は、以下で図示している。

(Example 275A)
The synthesis of a suitable phosphonate-containing aniline is illustrated below.

（実施例２７５Ｂ）

(Example 275B)

（実施例２７６）

(Example 276)

本発明の代表的な化合物は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．１９９６，３９，４６０８で記述されたものと類似の手順を使用して、上で図示したように、調製できる。本発明の化合物２７６．１を塩基で処理すると、化合物２７６．２が得られ、これはまた、本発明の化合物である。

Representative compounds of the present invention are described in J. Org. Med. Chem. It can be prepared as illustrated above using procedures similar to those described in 1996, 39, 4608. Treatment of compound 276.1 of the present invention with a base provides compound 276.2, which is also a compound of the present invention.

  (Example 277)

本発明の代表的な化合物は、上で図示したように、調製できる。本発明の化合物２７７．１を塩基で処理すると、化合物２７７．２が得られ、これはまた、本発明の化合物である。

Representative compounds of the present invention can be prepared as illustrated above. Treatment of compound 277.1 of the present invention with a base yields compound 277.2, which is also a compound of the present invention.

  (Example 278)

（実施例２７８Ａ）
（Ｋ−１０５−４４の合成）
２−メチル−５−ニトロフェノール（２．００ｇ、１３．０５ｍｍｏｌ）を、アルゴン雰囲気下にて、無水ＤＭＦ（１０ｍＬ）に溶解し、そして０℃まで冷却した。ジメチルホスホノメチル−Ｏ−トリフレート（４．７０ｇｍ、１５．６６ｍｍｏｌ）および炭酸セシウム（６．３８ｇｍ、１９．５８ｍｍｏｌ）を連続的に加えた。その反応混合物を、０℃で、４時間攪拌した。ＴＬＣ（シクロヘキサン／ＥｔＯＡｃ、１：１）により、反応が完結していることが明らかとなった。脱イオン水（１５ｍＬ）を加え、その混合物をＥｔＯＡＣ（２×５０ｍＬ）で抽出した。その有機層を１Ｎ ＨＣｌ（２０ｍＬ）で洗浄し、続いて、水（２×２０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、そして半固形物になるまで濃縮した。シリカゲルカラムクロマトグラフィー（シクロヘキサン／ＥｔＯＡｃ、１：１）で精製すると、オイル（３．８６ｇ、９７％）として、純粋な化合物Ｋ−１０５−４４が得られた。

(Example 278A)
(Synthesis of K-105-44)
2-Methyl-5-nitrophenol (2.00 g, 13.05 mmol) was dissolved in anhydrous DMF (10 mL) under an argon atmosphere and cooled to 0 ° C. Dimethylphosphonomethyl-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) revealed that the reaction was complete. Deionized water (15 mL) was added and the mixture was extracted with EtOAC (2 × 50 mL). The organic layer was washed with 1N HCl (20 mL) followed by water (2 × 20 mL), dried over Na ₂ SO ₄ and concentrated to a semi-solid. Purification by silica gel column chromatography (cyclohexane / EtOAc, 1: 1) gave pure compound K-105-44 as an oil (3.86 g, 97%).

ESI-MS m / z 304 [M + H] ^< +>.

(Example 278B)
(Synthesis of K-105-48)
Compound K-105-44 (2.8 g, 9.24 mmol) was dissolved in absolute ethanol 15 mL (15 mL) and 6N HCl (2 mL) under an argon atmosphere. Following 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) revealed that the reaction was complete. The mixture was concentrated to a semi-solid and dissolved in ethyl acetate (30 mL). The ethyl acetate layer was washed with deionized water (10 mL) and saturated NaHCO ₃ (10 mL) and dried over Na ₂ SO ₄ . Concentration gave a solid that was used without further purification.

ESI-MS m / z 274 [M + H] ^< +>.

(Example 278C)
(Synthesis of K-105-49-3)
Crude compound K-105-48 (900 mg, 3.38 mmol) was dissolved in 15 mL anhydrous THF (15 mL) under an argon atmosphere. Following 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) revealed that the reaction was complete. 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 K-105- as a pale yellow solid (680 mg, 55%). 49-3 was obtained.

^３１Ｐ ＮＭＲ（１２１．７ＭＨｚ、ＤＭＳＯ−ｄ_６／外部Ｈ_３ＰＯ_４）δｐｐｍ １９．７−２０．０（ｍ）。

³¹ P NMR (121.7 MHz, DMSO-d ₆ / external H ₃ PO ₄ ) δ ppm 19.7-20.0 (m).

HPLC: 98% purity (Sphereclone 5 μL, H ₂ O: MeCN, 20 min linear from 10-90% MeCN, 1.0 mL / min).

(Example 278D)
(Synthesis of K-105-54-1)
Compound K-105-54-1 (250 mg, 0.65 mmol) was dissolved in 10 mL (15 mL) of absolute ethanol under an argon atmosphere. Following the addition of NaOH (29 mg, 0.72 mmol), the reaction mixture was stirred at room temperature overnight. TLC (CHCl ₃ / MeOH, 9: 1) revealed that the reaction was complete. 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 pure compound K-105-54-1 as a solid (188 mg, 75%). was gotten.

^３１Ｐ ＮＭＲ（１２１．７ＭＨｚ、ＤＭＳＯ−ｄ_６／外部Ｈ_３ＰＯ_４）δｐｐｍ ２０．０−２０．４（ｍ）
ＨＰＬＣ：９３％純度（Ｓｐｈｅｒｅｃｌｏｎｅ ５μＬ、Ｈ_２Ｏ：ＭｅＣＮ、１０〜９０％ＭｅＣＮからの２０分間の線形、１．０ｍＬ／分）。

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, 20 min linear from 10-90% MeCN, 1.0 mL / min).

  (Example 279)

本発明の代表的な化合物は、上で図示したようにして、調製できる。本発明の特定の化合物は、以下のようにして、調製できる。

Representative compounds of the present invention can be prepared as illustrated above. Certain compounds of the invention can be prepared as follows.

および

and

（実施例２８０）

(Example 280)

本発明の代表的なマクロライド化合物（ここで、構造２８０．１は、化合物タクロリムス、アスコマイシンまたはシロリムスであることが分かる）は、例えば、アリールビスマス試薬（例えば、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ，１９９５，５，１０３５で記述されたもの）を使用して、上で図示したように、調製できる。さらに、このような免疫抑制性マクロライドでのアルキル化を媒介するために、銀塩が使用されている：Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９８，４１，１７６４を参照。本発明の特定の化合物は、以下で図示するように、調製できる。

Representative macrolide compounds of the present invention (where structure 280.1 is known to be the compound tacrolimus, ascomycin or sirolimus) are, for example, aryl bismuth reagents (eg, Bioorg. Med. Chem. Lett, 1995,5,1035) and can be prepared as illustrated above. In addition, silver salts have been used to mediate alkylation with such immunosuppressive macrolides: Med. Chem. 1998, 41, 1764. Certain compounds of the invention can be prepared as illustrated below.

  (Example 281)

本発明の代表的なマクロライド化合物（ここで、構造２１２．１は、化合物タクロリムス、アスコマイシンまたはシロリムスであることが分かる）は、例えば、アリールビスマス試薬（例えば、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ，１９９５，５，１０３５で記述されたもの）を使用して、上で図示したように、調製できる。さらに、このような免疫抑制性マクロライドでのアルキル化を媒介するために、銀塩が使用されている：Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９８，４１，１７６４を参照。本発明の特定の化合物は、以下で図示するように、調製できる。

Representative macrolide compounds of the present invention (where structure 212.1 is found to be the compound tacrolimus, ascomycin or sirolimus) are for example aryl bismuth reagents (eg, Bioorg. Med. Chem. Lett, 1995,5,1035) can be used as illustrated above. In addition, silver salts have been used to mediate alkylation with such immunosuppressive macrolides: Med. Chem. 1998, 41, 1764. Certain compounds of the invention can be prepared as illustrated below.

（実施例２８２）

(Example 282)

本発明の代表的な化合物は、上で図示したようにして、調製できる。本発明の特定の化合物は、以下のようにして、調製できる。そのＣ−２１水酸基での誘導体化は、プレドニゾン２８２．１を適当なホスホネートでアルキル化することによって達成され、本発明の化合物２８２．２が得られる。本発明の特定の化合物は、以下のようにして、調製できる。

Representative compounds of the present invention can be prepared as illustrated above. Certain compounds of the invention can be prepared as follows. Its derivatization at the C-21 hydroxyl group is accomplished by alkylating prednisone 282.1 with the appropriate phosphonate to give compound 282.2 of the present invention. Certain compounds of the invention can be prepared as follows.

２８２．１の第一級ヒドロキシプロトンを水素化ナトリウムで抽出した後、ホスホン酸ジエチルトリフラートが加えられて、エーテル２８２．４が得られる。

After extraction of the primary hydroxy proton of 282.1 with sodium hydride, diethyl phosphonate triflate is added to give ether 282.4.

  (Example 283)

本発明の代表的な化合物２８３．３は、上で図示したようにして、調製できる。プレドニゾン２８３．１を、障害が少ない第一級部位で保護すると、アルコール２８３．５が得られ、これは、その露出した水酸基にて、適当なホスホネートでアルキル化されて、２８３．６が得られる。その保護基を除去すると、類似物２８３．３の作成が完結する。特定の化合物は、以下のようにして、調製できる。

Representative compounds 283.3 of the present invention can be prepared as illustrated above. Protection of prednisone 283.1 at a less hindered primary site gives alcohol 283.5, which is alkylated at the exposed hydroxyl group with an appropriate phosphonate to give 283.6. . Removal of the protecting group completes the creation of analog 283.3. Specific compounds can be prepared as follows.

プレドニゾン２８３．１は、そのＴＢＳエーテル２８３．７として、モノ保護される。このホスホン酸ジエチルトリフラートでアルキル化した後、得られた中間体２８３．８は、ＴＢＡＦで処理されて、所望のホスホネート２８３．９が得られる。

Prednisone 283.1 is mono-protected as its TBS ether 283.7. After alkylation with this phosphonic acid diethyl triflate, the resulting intermediate 283.8 is treated with TBAF to give the desired phosphonate 283.9.

  The synthesis of the phosphonate compounds of the present invention and intermediate compounds necessary for their synthesis is illustrated here. Its derivatization at the C-21 hydroxyl group is accomplished by alkylating dexamethasone 1 with a suitable phosphonate to give the analogs illustrated here.

(Example 284)
Representative compounds of the present invention can be prepared as illustrated above. Its derivatization at the C-11 hydroxyl group is accomplished by alkylating rimexolone 284.1 with the appropriate phosphonate to give an analog of formula 284.2. Certain compounds of the invention can be prepared as follows.

２８４．１のヒドロキシプロトンを水素化ナトリウムで抽出した後、ホスホン酸ジエチルトリフラートが加えられて、エーテル２８４．５が得られる。

After extracting 284.1 hydroxy protons with sodium hydride, diethyl phosphonate triflate is added to give ether 284.5.

（実施例２８５）

(Example 285)

二酸（１００ｍｇ、０．３０４ｍｍｏｌ）、アミノ酸（１００ｍｇ、０．６５１ｍｍｏｌ）、フェノール（１４５ｍｇ、１．５４ｍｍｏｌ）およびトリエチルアミン（５１０μＬ、３．６６ｍｍｏｌ）をピリジン（５ｍＬ）に溶解した。その混合物を、５分間にわたって、６０℃まで加熱した。この反応混合物に、トリフェニルホスフィン（５６０ｍｇ、２．１４ｍｍｏｌ）およびＡｌｄｒｉｔｈｉｏｌ（２）（４７０ｍｇ、２．１３ｍｍｏｌ）をピリジン（５ｍＬ）に溶解した溶液を加えた。次いで、その反応物を、６０℃で、１２時間加熱した。その反応混合物をＥｔＯＡｃで希釈し、Ｈ_２Ｏで洗浄し、飽和ＮａＨＣＯ_３（水溶液）およびブラインで洗浄した。その有機層を乾燥し（ＭｇＳＯ_４）、濃縮し、そしてシリカゲルクロマトグラフィー（１％ＭｅＯＨ／ＣＨ_２Ｃｌ_２→１０％ＭｅＯＨ／ＣＨ_２Ｃｌ_２）で精製して、モノアミデート１３０−１（５ｍｇ、３％）およびビスアミデート１３０−２（５ｍｇ、３％）を得た。
130-1について: ¹H NMR (300 MHz,CD₃OD) 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); ³¹PNMR (121 MHz, CD₃OD) δ 36.3, 35.3; LC-MS (方法: 0.5 分間 95% H₂O/5%MeCN → 5 分間 0% H₂O/100% MeCN, 溶出時間 = 2.18 分。 MS C₂₃H₃₄N₆O₅P(MH⁺)に対する計算値: 505.2. 実測値 505.2.
130-2について: ¹H NMR (300 MHz,CD₃OD) 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); ³¹PNMR (121 MHz, CD₃OD) δ 33.9; LC-MS (方法: 0.5 分間 95% H₂O/5%MeCN → 5 分間 0% H₂O/100% MeCN, 溶出時間 = 1.79 分。 MS C₂₂H₃₉N₇O₆P(MH⁺)に対する計算値: 528.3. 実測値 528.3.
（実施例２８６）

Diacid (100 mg, 0.304 mmol), amino acid (100 mg, 0.651 mmol), phenol (145 mg, 1.54 mmol) and triethylamine (510 μL, 3.66 mmol) were dissolved in pyridine (5 mL). The mixture was heated to 60 ° C. for 5 minutes. To this reaction mixture was added a solution of 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, washed with H ₂ O, washed with saturated NaHCO ₃ (aq) and brine. The organic layer was dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (1% MeOH / CH ₂ Cl ₂ → 10% MeOH / CH ₂ Cl ₂ ) to give monoamidate 130-1 (5 mg 3%) and bisamidate 130-2 (5 mg, 3%).
About 130-1: 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 PNMR (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, elution time = 2.18 min Calculated for MS C ₂₃ H ₃₄ N ₆ O ₅ P (MH ⁺ ): Measured value 505.2.
About 130-2: 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 PNMR (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, elution time = 1.79 min. Calculated for MS C ₂₂ H ₃₉ N ₇ O ₆ P (MH ⁺ ) : 528.3.
(Example 286)

二酸（２５ｍｇ、０．０７２ｍｍｏｌ）、アミノ酸（２５ｍｇ、０．１６ｍｍｏｌ）、フェノール（３８ｍｇ、０．４０ｍｍｏｌ）およびトリエチルアミン（１２７μＬ、０．９１１ｍｍｏｌ）をピリジン（１．２５ｍＬ）に溶解した。その混合物を、５分間にわたって、６０℃まで加熱した。この反応混合物に、トリフェニルホスフィン（１４０ｍｇ、０．５３４ｍｍｏｌ）およびＡｌｄｒｉｔｈｉｏｌ（２）（１１９ｍｇ、０．５４０ｍｍｏｌ）をピリジン（１．２５ｍＬ）に溶解した溶液を加えた。次いで、その反応物を、６０℃で、１２時間加熱した。別のバッチの二酸（１２ｍｇ、０．０３５ｍｍｏｌ）を、上記のようにして処理した。両方のバッチからの反応混合物を合わせ、ＥｔＯＡｃで希釈し、Ｈ_２Ｏで洗浄し、飽和ＮａＨＣＯ_３（水溶液）およびブラインで洗浄した。その有機層を乾燥し（ＭｇＳＯ_４）、濃縮し、そしてシリカゲルクロマトグラフィー（１％ＭｅＯＨ／ＣＨ_２Ｃｌ_２→１０％ＭｅＯＨ／ＣＨ_２Ｃｌ_２）で精製して、モノアミデート１３３−１（３ｍｇ、８％）およびビスアミデート１３３−２（８ｍｇ、２０％）を得た。
133-1について: ¹H NMR (300 MHz,CD₃OD) 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); ³¹P NMR (121 MHz, CD₃OD) δ 21.5,20.2; LC-MS (方法: 0.5 分間 95% H₂O/5% MeCN → 5 分間 0% H₂O/100%MeCN, 溶出時間 = 1.98 分。 MS C₂₅H₂₈N₆O₅P(MH⁺)に対する計算値: 523.2. 実測値 523.2.
133-2について: ¹H NMR (300 MHz,CD₃OD) δ 8.15 (1H, dd), 7.72 (1H, s), 7.67 (1H, m), 7.39 (2H, m),7.28 (1H, m), 6.44 (1H, dd), 5.40 (2H, s), 4.23-3.90 (6H, m), 1.42 (6H, m),1.27 (3H, t), 1.18 (3H, t); ³¹P NMR (121 MHz, CD₃OD) δ 19.7;LC-MS (方法: 0.5 分間 95% H₂O/5% MeCN → 5 分間 0% H₂O/100%MeCN, 溶出時間 = 1.86 分。 MS C₂₄H₃₃N₇O₆P(MH⁺)に対する計算値: 546.2. 実測値 546.2。

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) were dissolved in pyridine (1.25 mL). The mixture was heated to 60 ° C. for 5 minutes. To this reaction mixture was added a solution of triphenylphosphine (140 mg, 0.534 mmol) and Aldrithiol (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, washed with saturated NaHCO ₃ (aq) and brine. The organic layer was dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (1% MeOH / CH ₂ Cl ₂ → 10% MeOH / CH ₂ Cl ₂ ) to give monoamidate 133-1 (3 mg 8%) and bisamidate 133-2 (8 mg, 20%).
About 133-1: 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, elution time = 1.98 min. MS C ₂₅ H ₂₈ N Calculated for ₆ O ₅ P (MH ⁺ ): 523.2.
About 133-2: ¹ H NMR (300 MHz, CD ₃ OD) δ 8.15 (1H, dd), 7.72 (1H, s), 7.67 (1H, m), 7.39 (2H, m), 7.28 (1H, m ), 6.44 (1H, dd), 5.40 (2H, s), 4.23-3.90 (6H, m), 1.42 (6H, m), 1.27 (3H, t), 1.18 (3H, t); ³¹ P NMR ( 121 MHz, CD ₃ OD) δ 19.7; LC-MS (Method: 0.5 min 95% H ₂ O / 5% MeCN → 5 min 0% H ₂ O / 100% MeCN, elution time = 1.86 min. MS C ₂₄ H Calculated for ₃₃ N ₇ O ₆ P (MH ⁺ ): 546.2.

(Example 287)
(Prodrug cleavage assay)
(Isolation of PBMC extract)
Fresh human PBMCs were obtained from patients undergoing leukophoresis; cells were transported in plasma and processed within 26 hours of aspiration. Purification was accomplished using the Ficoll-Paque method: PBMC cells were harvested by centrifugation at 1200 × g for 5 minutes and RBC lysis buffer (155 mM NH ₄ Cl, 0.1 mM EDTA, 10 mM KHCO ₃ ). Washed 3 times by resuspending. Washed cells were suspended in lysis buffer (0.2 × 10 ⁹ cells per 1 ml of 10 mM Tris (pH 7.4), 150 mM NaCl, 20 mM CaCl ₂ , 1 mM DTT and 1% NP40) on ice And incubated for 20 minutes. The PBMC crude extract was centrifuged at 1000 × g for 30 minutes to remove undissolved cells, and the supernatant was centrifuged at 100,000 × g for 1 hour. This 100,000 × g supernatant (PMBC extract: P0) was collected, snap frozen in liquid nitrogen and stored at −70 ° C.

(Protocol for measurement of 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 enzymatic reaction was carried out at 37 ° C. for 10-120 minutes and was stopped by adding 180 μl ice-cold methanol at 3-4 individual time points. Samples were incubated at −20 ° C. for 30 minutes and centrifuged at 13,000 RPM for 30 minutes (at 4 ° C.). The supernatant was transferred to a 96-well plate and evaporated under reduced pressure using a speedvac. The precipitate was dissolved in 100 μl of 20 mM CH ₃ COONH ₄ + 5% AcCN. The disappearance of the prodrug was monitored by 260 nm and measured by HPLC. The specific activity of the PBMC extract relative to the prodrug tested is defined as v (cleavage rate) / μg protein = pmol / min / μg.

（実施例２８８）
次式を有する本発明の代表的な化合物は、ここで記述されているように、調製できる。

(Example 288)
Representative compounds of the present invention having the formula: can be prepared as described herein.

例えば、ミコフェノール酸モフェチルの３つの領域は、上で図示した化合物Ｄ、ＥおよびＧにより示されているように、このホスホネートプロドラッグの結合に利用できる。また、このカルボン酸は、化合物Ｆのように、ホスホン酸で置き換えることができる。

For example, the three regions of mycophenolate mofetil are available for conjugation of this phosphonate prodrug, as shown by compounds D, E, and G illustrated above. The carboxylic acid can be replaced with phosphonic acid as in compound F.

  (Example 288A)

本発明の代表的な化合物は、上で図示したように、調製できる。そのモルホリノエチル部分は、バイオアベイラビリティーを向上させるプロドラッグ官能性として役立ち得、そして上で示したように、このホスホネートプロドラッグハンドルで置き換えることができる。ミコフェノール酸は、例えば、Ｓｉｇｍａ Ｃｈｅｍｉｃａｌ Ｃｏｍｐａｎｙ，Ｓｔ．Ｌｏｕｉｓ，Ｍｏから市販されている。遊離フェノールの存在下にて、カルボン酸２８８．１を活性化することに続いて、このホスホネート基を備えたアルコールを加えると、所望の生成物２８８．３が形成される（米国特許第４，７８６，６３７号）。本発明の特定の化合物は、以下のようにして、調製できる。

Representative compounds of the present invention can be prepared as illustrated above. The morpholinoethyl moiety can serve as a prodrug functionality that improves bioavailability and can be replaced with this phosphonate prodrug handle, as indicated above. Mycophenolic acid is described in, for example, Sigma Chemical Company, St. Commercially available from Louis, Mo. Following activation of carboxylic acid 288.1 in the presence of free phenol, addition of an alcohol with this phosphonate group forms the desired product 288.3 (US Pat. 786, 637). Certain compounds of the invention can be prepared as follows.

ミコフェノール酸２８８．１は、ジクロロメタンに溶解される。塩化チオニルが加えられ、続いて、触媒量のＤＭＦが加えられる。その反応混合物は、室温で、３時間攪拌され、その後、真空下にて、揮発性物質が除去される。このホスホネート−アルコールは、ジクロロメタンに溶解され、そして氷浴にて、約４℃で冷却される。ミコフェノール酸塩化物２８８．２は、ジクロロメタンに溶解され、この冷却した溶液に加えられる。約４℃で９０分間攪拌した後、この反応混合物は、水で洗浄され、次いで、炭酸水素ナトリウム水溶液で洗浄される。その有機溶液は、乾燥され、そして蒸発されて、ホスホネート２８８．４が生じる。

Mycophenolic acid 288.1 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 volatiles are removed under vacuum. The phosphonate-alcohol is dissolved in dichloromethane and cooled at about 4 ° C. in an ice bath. Mycophenolic acid chloride 288.2 is dissolved in dichloromethane and added to this cooled solution. After stirring for 90 minutes at about 4 ° C., the reaction mixture is washed with water and then with aqueous sodium bicarbonate. The organic solution is dried and evaporated to give phosphonate 288.4.

  Example 289

本発明の代表的な化合物は、上で図示したように、調製できる。そのＣ−４フェノール位置は、上で図示したように、さらに他の類似物の反応性ハンドルを与える。一旦、２８９．１のカルボン酸がモルホリノエチル（例えば、化合物２８９．２中のもの）でブロックされると、このフェノールは、塩基性条件下にて、アルキル化できる。塩基（例えば、ピリジン、炭酸カリウムまたはトリエチルアミン）が利用される。このホスホネートプロドラッグには、脱離基（例えば、トリフルオロメタンスルホネート、メシレート、臭化物またはヨウ化物）が結合され、そして塩基の存在下にて、化合物２８９．２と反応される。化合物２８９．３は、直接的に、または塩の形状（化合物２８９．４）で、いずれかで使用できる。調製できる多数の塩のうちで、塩化物および硫酸水素塩は、本発明の特定の１実施形態である。本発明の特定の化合物は、以下のようにして、調製できる。

Representative compounds of the present invention can be prepared as illustrated above. The C-4 phenol position provides a reactive handle for yet other analogs, as illustrated above. Once the 289.1 carboxylic acid is blocked with morpholinoethyl (eg, in compound 289.2), the phenol can be alkylated under basic conditions. A base such as pyridine, potassium carbonate or triethylamine is utilized. To the phosphonate prodrug, a leaving group (eg, trifluoromethanesulfonate, mesylate, bromide or iodide) is attached and reacted with compound 289.2 in the presence of a base. Compound 289.3 can be used either directly or in salt form (compound 289.4). Of the many salts that can be prepared, chloride and hydrogen sulfate are one particular embodiment of the present invention. Certain compounds of the invention can be prepared as follows.

化合物２８９．５は、化合物２８８．２（これは、実施例２８８で記述されている）と同様に、調製される。モルホリノエタノールのジクロロメタン溶液は、約４℃まで冷却される。ミコフェノール酸塩化物２８９．５は、ジクロロメタンに溶解され、そしてこの冷却した溶液に加えられる。この溶液を約９０分間攪拌すると、化合物２８９．２が得られる。その反応混合物は、水で洗浄され、そして硫酸ナトリウムで乾燥される。溶媒を除去すると、単離した化合物２８９．２が得られる。この化合物をピリジンに懸濁することにより、２８９．２のフェノール部分でのアルキル化が達成される。この溶液には、トリフレート２８９．６が加えられ、その混合物は、室温で、約９０分間攪拌される。この反応混合物は、水に注がれ、その生成物は、酢酸エチルで抽出される。その有機層を除去すると、化合物２８９．７が得られる。必要に応じて、２８９．７の塩酸塩が調製できる。化合物２８９．７は、イソプロパノールに溶解され、その溶液は、イソプロパノール中の塩化水素の混合物に加えられる。濾過により塩酸塩２８９．８が集められ、そして真空下にて乾燥される。

Compound 289.5 is prepared similarly to compound 288.2, which is described in Example 288. The dichloromethane solution of morpholinoethanol is cooled to about 4 ° C. Mycophenolic acid chloride 289.5 is dissolved in dichloromethane and added to the cooled solution. This solution is stirred for about 90 minutes to give compound 289.2. The reaction mixture is washed with water and dried over sodium sulfate. Removal of the solvent gives isolated compound 289.2. By suspending this compound in pyridine, alkylation at the phenol moiety of 289.2 is achieved. To this solution is added triflate 289.6 and the mixture is stirred at room temperature for about 90 minutes. The reaction mixture is poured into water and the product is extracted with ethyl acetate. Removal of the organic layer gives compound 289.7. If necessary, 289.7 hydrochloride can be prepared. Compound 289.7 is dissolved in isopropanol and the solution is added to a mixture of hydrogen chloride in isopropanol. The hydrochloride 289.8 is collected by filtration and dried under vacuum.

  (Example 290)

本発明の代表的な化合物は、上で図示したように、調製できる。ミコフェノール酸のカルボン酸は、ホスホン酸（これもまた、プロドラッグハンドルとして、役立ち得る）で置き換えることができる。側鎖を含有するカルボン酸を除去するために、酸塩化物２８９．５（これは、実施例２８９で調製した）は、エステル２９０．１に変換される。このフェノールをシリル基で保護し、続いて、ジヒドロキシル化し、このジオールを開裂すると、アルデヒド２９０．３が産生される（Ｐａｎｋｉｅｗｉｃｚ，ら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００２，４５，７０３）、（Ｐａｔｔｅｒｓｏｎら、米国特許第５，４４４，０７２号）。適当に保護したホスホネートを備えたイリド２９０．４でウィッティヒ反応にかけると、所望の化合物２９０．５が得られる。最後に脱保護すると、化合物２９０．６が生じる。本発明の特定の化合物は、以下のようにして、調製できる。

Representative compounds of the present invention can be prepared as illustrated above. The carboxylic acid of mycophenolic acid can be replaced with phosphonic acid, which can also serve as a prodrug handle. To remove the carboxylic acid containing side chain, the acid chloride 289.5 (prepared in Example 289) is converted to the ester 290.1. Protection of the phenol with a silyl group followed by dihydroxylation and cleavage of the diol yields the aldehyde 290.3 (Pankiewicz, et al., J. Med. Chem., 2002, 45, 703), ( Patterson et al., US Pat. No. 5,444,072). A Wittig reaction with ylide 290.4 with an appropriately protected phosphonate gives the desired compound 290.5. Final deprotection yields compound 290.6. Certain compounds of the invention can be prepared as follows.

ミコフェノラートエステル２９０．８は、単に、酸塩化物２９０．７をＭｅＯＨと共に攪拌することにより、調製できる。次いで、ミコフェノラートエステルのフェノール位置は、シリル基（例えば、ＴＢＳ）で保護されて、化合物２９０．９が得られる。一旦、このフェノール位置が保護されると、四酸化オスミウムを使用するジヒドロキシル化に続いて、過ヨウ素化開裂により、アルデヒド２９０．１０が得られる。アルデヒド２９０．１０および過剰のイリド２９０．１１は、ベンゼン中にて、還流状態で、約２４時間加熱される。その反応混合物は、濃縮され、その残留物は、カラムクロマトグラフィーで精製されて、オレフィン２９０．１２が得られる（Ｐａｎｋｉｅｗｉｃｓら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００２，４５，７０３）。最後に、ＨＦ−ピリジンを使用して脱保護すると、最終生成物２９０．１３が生じる。

The mycophenolate ester 290.8 can be prepared simply by stirring the acid chloride 290.7 with MeOH. The phenol position of the mycophenolate ester is then protected with a silyl group (eg, TBS) to give compound 290.9. Once this phenolic position is protected, dihydroxylation using osmium tetroxide followed by periodate cleavage yields aldehyde 290.10. Aldehyde 290.10 and excess ylide 290.11 are heated in benzene at reflux for about 24 hours. The reaction mixture is concentrated and the residue is purified by column chromatography to give the olefin 290.12 (Pankieics et al., J. Med. Chem., 2002, 45, 703). Finally, deprotection using HF-pyridine yields the final product 290.13.

  (Example 291)

本発明の代表的な化合物は、上で図示したように、調製できる。この化合物の他の結合点は、上で図示したように、ミコフェノラートエステル２９１．２の脱メチル化後、アンマスクできる。この目的のために、その４−ＯＨは、保護基（Ｐ）（例えば、シリル基）でマスクする必要がある。一旦、その６−ＭｅＯが脱メチル化されアルキル化されると、４位置での保護基は、除去されて、最終生成物２９１．４が現れる。そのモルホニルエタノール基は、早期に導入され、これらのアルキル化工程にわたって、運ばれる。初期には、異なる保護基が導入され、後に、除去され得る。このような後者のタイプの合成では、最後の工程は、モルホリノエチルエステルプロドラッグの形成である。本発明の特定の化合物は、以下で記述するようにして、調製できる。

Representative compounds of the present invention can be prepared as illustrated above. Other points of attachment of this compound can be unmasked after demethylation of mycophenolate ester 291.2, as illustrated above. For this purpose, the 4-OH needs to be masked with a protecting group (P) (eg a silyl group). Once the 6-MeO is demethylated and alkylated, the protecting group at the 4 position is removed to reveal the final product 291.4. The morpholethanol group is introduced early and carried over these alkylation steps. Initially, different protecting groups can be introduced and later removed. In this latter type of synthesis, the last step is the formation of a morpholino ethyl ester prodrug. Certain compounds of the invention can be prepared as described below.

フェノール２９１．５は、ＣＨ_２Ｃｌ_２中にて、塩基としてイミダゾールを使用して、ＴＢＳ基で保護されて、２９１．６が生じる。脱メチル化は、チオラート求核試薬を使用して実行され、化合物２９１．７が産生される。種々の他の方法もまた、Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ ｂｙ Ｇｒｅｅｎｅ ａｎｄ Ｗｕｔｓで記述されているように、文献で入手できる。このホスホネートのトリフレートを使用する６−ＯＨのアルキル化は、Ｋ_２ＣＯ_３またはＴＥＡを使用してうまく進行し、２９１．８が得られる。最後に、ＴＢＳ基を除去するための脱保護すると、生成物２９１．９が得られる。

Phenol 291.5 is protected with TBS group in CH ₂ Cl ₂ using imidazole as base to give 291.6. Demethylation is performed using a thiolate nucleophile to produce compound 291.7. Various other methods are also available in the literature, as described in Protective Groups in Organic Synthesis by Greene and Wuts. The alkylation of 6-OH using the phosphonate triflate proceeds successfully using K ₂ CO ₃ or TEA to give 291.8. Finally, deprotection to remove the TBS group gives the product 291.9.

  (Example 292)

本発明の代表的な化合物は、上で図示したように、調製できる。

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. 1) in DMF (3 mL). 18 mmol, Pankiewicz et al., J. Med. Chem., 45,703), diisopropyl bromomethylphosphonate (93 mg, 0.36 mmol) and lithium t-butoxide (1M in THF, 0.54 mL) at 70 ° C. Heated for 5 hours. The reaction was quenched with 1N HCl. The mixture was poured into 5% aqueous lithium chloride, 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 ) 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) 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] -diisopropyl phosphonate To an acetonitrile solution of ester 1B (25 mg, 0.055 mmol) and 2,6-lutidine (0.18 mL, 1.65 mmol) at 0 ° C. was added trimethylsilyl bromide (0.126 mL, 1.1 mmol). 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 preparative reverse phase HPLC to remove the solvent and then [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1) as an oil (17 mg, 83%). , 3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid 1C; 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) and oil (2 mg, 7%) as [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl ) -2-methyl-but-2-enyloxymethyl] -phosphonic acid monoisopropyl ester 1D was obtained; ¹ HNMR (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 293)
Representative compounds of the present invention can be prepared as illustrated below.

（［５−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−３−メチル−ペンタ−１，３−ジエニル］−ホスホン酸ジメチルエステル）
テトラメチルメチレンジホスホネート（１０２ｍｇ、０．４４ｍｍｏｌ）のＴＨＦ（２．５ｍＬ）溶液に、ナトリウムビス（トリメチルシリル）アミド（１．０Ｍ、０．４４ｍＬ）のＴＨＦ溶液を加えた。３０分間攪拌した後、４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エナール２Ａ（３０ｍｇ、０．１１ｍｍｏｌ、Ｐａｎｋｉｅｗｉｃｚら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，４５，７０３）のＴＨＦ（２．５ｍＬ）溶液を加え、攪拌を、さらに１５分間継続した。その反応を、塩化アンモニウム飽和水溶液でクエンチした。この混合物を酢酸エチルで抽出した。溶媒を蒸発させた後、その残留物をシリカゲルクロマトグラフィー（これは、酢酸エチル（５０％〜１００％）／ヘキサンで溶出する）で精製して、オイルとして、［５−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−３−メチル−ペンタ−１，３−ジエニル］−ホスホン酸ジメチルエステル２Ｂ（３０ｍｇ、７１％）を得た；¹H NMR (300 MHz, CDCl₃) δ1.80 (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 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 was continued for an additional 15 minutes. The reaction was quenched with saturated aqueous ammonium chloride. This 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 as an oil. -Methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-penta-1,3-dienyl] -phosphonic acid dimethyl ester 2B (30 mg, 71%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.80 (s, 3H), 2.04 (s, 3H), 3.45 (d, J = 6.6 Hz, 2H), 3.76 (s, 3H), 3.88 ( d, 6H), 5.20 (s, 3H), 5.55 (m, 1H), 5.95 (m, 1H), 7.05 (m, 1H), 7.65 (s, 1H) ppm.

([5- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-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 2B (22 mg, 0.057 mmol) and 2,6-lutidine (0.22 mL, 1.71 mmol) at 0 ° C. was added trimethylsilyl bromide (0.183 mL, 1.71 mmol). 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 preparative reverse phase HPLC to remove the solvent and then [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-] as a solid (13 mg, 65%). 1,3-dihydro-isobenzofuran-5-yl) -3-methyl-penta-1,3-dienyl] -phosphonic acid 2C was obtained; ¹ H NMR (300 MHz, CD ₃ OD) δ1.91 (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 294)
Representative compounds of the present invention can be prepared as illustrated below.

（６−（４−ブロモ−３−メチル−ブタ−２−エニル）−７−ヒドロキシ−５−メトキシ−４−メチル−３Ｈ−イソベンゾフラン−１−オン）
重合体で支持したトリフェニルホスフィン（３ｍｍｏｌ／ｇ、０．５ｇ）を、１時間にわたって、ジクロロメタン（１０ｍＬ）に浸漬し、７−ヒドロキシ−６−（４−ヒドロキシ−３−メチル−ブタ−２−エニル）−５−メトキシ−４−メチル−３Ｈ−イソベンゾフラン−１−オン１Ａ（１００ｍｇ、０．３６ｍｍｏｌ）および四臭化炭素（１４３ｍｇ、０．４３ｍｍｏｌ）を順次加え、その混合物を、室温で、１時間振盪した。さらに多くの四臭化炭素（１４３ｍｇ、０．４３ｍｍｏｌ）を加え、この混合物を、さらに１時間振盪した。この混合物を濾過し、その濾液を濃縮した。その残留物をシリカゲルクロマトグラフィー（０％〜６０％酢酸エチル／ヘキサン）にかけて、オイル（５２ｍｇ、４２％）として、６−（４−ブロモ−３−メチル−ブタ−２−エニル）−７−ヒドロキシ−５−メトキシ−４−メチル−３Ｈ−イソベンゾフラン−１−オン３Ｂを得た；¹H NMR (300 MHz, CDCl₃) δ1.95 (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。

(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 soaked in dichloromethane (10 mL) for 1 hour to give 7-hydroxy-6- (4-hydroxy-3-methyl-but-2-ene). Enyl) -5-methoxy-4-methyl-3H-isobenzofuran-1-one 1A (100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) were added sequentially and the mixture was added at room temperature. Shake for 1 hour. More 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 / hexanes) to give 6- (4-bromo-3-methyl-but-2-enyl) -7-hydroxy as an oil (52 mg, 42%). -5-methoxy-4-methyl-3H-isobenzofuran-1-one 3B was obtained; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.95 (s, 3H), 2.16 (s, 3H), 3.44 ( d, J = 7.2 Hz, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2H), 5.68 (t, J = 7.2 Hz, 1H), 7.71 (brs, 1H) ppm .

([5- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -phosphonic acid diethyl ester )
n-Butyllithium (1.6 M in hexane, 1 mL) was added to an equal volume of THF at −20 ° C. Then, a solution of diethyl methylphosphonate (220 mg, 1.45 mmol) in THF (1 mL) was added dropwise and the solution was stirred for 30 minutes. After cooling at −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 transferred to −30 ° C. at 1 Stir for hours. 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) ) Solution was added and the mixture was allowed to warm to 0 ° C. over 2 h before adding saturated aqueous ammonium chloride. The reaction mixture was acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate extract was concentrated and the residue was chromatographed on silica gel (40% to 100% ethyl acetate / hexanes) as an oil (27 mg, contaminated with starting methyl diethylphosphonate) [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 is obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ1.32 (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 = 7.2Hz, 1H), 7.65 (s, 1H) ppm.

([5- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -monophosphonate 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 preparative 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) δ1.28 (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−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−３−メチル−ペンタ−３−エニル］−ホスホン酸）
｛５−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−ソベンゾフラン−５−イル］−３−メチル−ペンタ−３−エニル｝−ホスホン酸ジエチルエステル（２０ｍｇ、０．０３９ｍｍｏｌ）のＤＭＦ（０．５ｍＬ）およびＤＣＭ（０．５ｍＬ）溶液に、ＴＭＳＢｒ（５０．５μＬ、０．３９ｍｍｏｌ）を加え、続いて、２，６−ルチジン（４５．３μＬ、０．３９ｍｍｏｌ）を加えた。この反応は、ＬＣＭＳで判定したとき、１時間進行し、そのとき、完結した。その反応混合物をＭｅＯＨでクエンチし、そして乾燥状態まで濃縮した。その残留物を分取逆相ＨＰＬＣで精製した。所望生成物を含有する画分を濃縮し、そして５分間にわたって、１０％ＴＦＡ／ＤＣＭで処理した。濃縮した後、その残留物を分取逆相ＨＰＬＣで精製して、固形物として、７ｍｇ（５０％）の［５−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−３−メチル−ペンタ−３−エニル］−ホスホン酸を得た。¹H NMR (300 MHz, CD₃OD) δ1.66-1.78 (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; ³¹P(121.4 MHz, CD₃OD) δ 31.57 ppm; MS (m/z) 355 [M-H]^-,357 [M+H]⁺.
（実施例２９５）
本発明の代表的な化合物は、以下で図示するように、調製できる。

([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- To a solution of enyl} -phosphonic acid diethyl ester (20 mg, 0.039 mmol) in DMF (0.5 mL) and DCM (0.5 mL) was added TMSBr (50.5 μL, 0.39 mmol) followed by 2,6 -Lutidine (45.3 μL, 0.39 mmol) was added. The reaction proceeded for 1 hour as judged by LCMS, when it was complete. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by preparative reverse phase HPLC. Fractions containing the desired product were concentrated and treated with 10% TFA / DCM for 5 minutes. After concentration, the residue was purified by preparative reverse phase HPLC to yield 7 mg (50%) of [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1, 3-Dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -phosphonic acid was obtained. ¹ H NMR (300 MHz, CD ₃ OD) δ1.66-1.78 (m, 5H), 2.10 (s, 3H), 2.16-2.22 (m, 2H), 3.34 (d, J = 7.2 Hz, 2H), 3.72 (s, 3H), 5.16 (s, 2H), 5.20 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 31.57 ppm; MS (m / z) 355 (MH ] ^- , 357 [M + H] ⁺ .
(Example 295)
Representative compounds of the present invention can be prepared as illustrated below.

（２−（４−ブロモ−ブタ−２−エニル）−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸メチルエステル）
ミコフェノール酸メチルエステル４Ａ（１３８ｍｇ、０．４１ｍｍｏｌ）のＴＨＦ（２．５ｍＬ）冷却（−７８℃）溶液に、ナトリウムビス（トリメチルシリル）アミド（１．０Ｍ、０．９８ｍＬ）のＴＨＦ溶液を加えた。３０分間攪拌した後、１，４−ジブロモ−２−ブテン（９５０ｍｇ、４．１ｍｍｏｌ）のＴＨＦ（２．５ｍＬ）溶液を加え、そして攪拌を１０分間継続した。得られた混合物を−３０℃まで温め、この温度で、１６時間保存した。この反応を塩化アンモニウム飽和水溶液でクエンチした。その混合物を酢酸エチルで抽出し、溶媒を蒸発させた後、残留物を得、これを、シリカゲルクロマトグラフィー（これは、酢酸エチル（０％〜４０％）／ヘキサンで溶出する）で精製して、オイルとして、２−（４−ブロモ−ブタ−２−エニル）−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸メチルエステル４Ｂ（１５０ｍｇ、７８％）を得た；¹H NMR (300 MHz, CDCl₃) δ1.75 (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-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 THF (2.5 mL) cooled (−78 ° C.) solution of mycophenolic acid methyl ester 4A (138 mg, 0.41 mmol) was added sodium bis (trimethylsilyl) amide (1.0 M, 0.98 mL) in THF. . 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 stored at this temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride. After extracting the mixture with ethyl acetate and evaporating the solvent, a residue was obtained, which was purified by silica gel chromatography, which was eluted with ethyl acetate (0% to 40%) / hexane. 2- (4-Bromo-but-2-enyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) as an oil -4-methyl-hex-4-enoic acid methyl ester 4B (150 mg, 78%) was 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) 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 hexa-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 at reflux for 20 hours. The mixture was concentrated and subjected to silica gel chromatography (eluting with ethyl acetate (60% -100%) / hexane) to give 2- [4- (diethoxy-phosphoryl) as an oil (70 mg, 43%). -But-2-enyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-ene Acid methyl ester 4C 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) 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- in a mixture of THF (6 mL) and water (1 mL) A mixture of 1,3-dihydro-isobenzofuran-5-yl) -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. Stir. The organic solvent was removed and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate extract was concentrated to give 2- [4- (diethoxy-phosphoryl) -but-2-enyl] -6- (4-hydroxy-6-methoxy-7-) as an oil (30 mg, 100%). Methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid 4D 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) 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- in a mixture of methanol (3 mL) and water (1 mL) A mixture of 1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester 4C (25 mg, 0.048 mmol) and lithium hydroxide (200 mg) Stir for hours. The organic solvent was evaporated and the residue was acidified with 2N HCl and extracted with ethyl acetate / acetonitrile. The organic extract was concentrated and the residue was purified by preparative reverse phase HPLC (acetonitrile and 0.1% aqueous CF ₃ COOH) to give 2- [4- (ethoxy) as an oil (15 mg, 89%). -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 4E was obtained; ¹ H NMR (300 MHz, CD ₃ OD) δ1.25 (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−（ジメトキシ−ホスホリル）−ブタ−２−エニル］−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸メチルエステル）
Ｎ_２雰囲気下にて、２−（４−ブロモ−ブタ−２−エニル）−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸メチルエステル（４９０ｍｇ、１．０５ｍｍｏｌ）の亜リン酸トリメチル（２．５ｍＬ、２１．１ｍｍｏｌ）溶液を、１２０℃で、１時間加熱した。その反応物を室温まで冷却した。この反応混合物を、真空中で溶媒を除去することによりワークアップし、続いて、クロマトグラフィー（これは、ＥｔＯＡｃ−ヘキサンを使用する）にかけて、オイルとして、４６０ｍｇ（８８％）の生成物を得た。¹H NMR (300 MHz, CDCl₃) δ1.77 (s, 3H), 2.081- 2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H, J= 22 Hz),2.54 (d, 1H, J= 22 Hz), 2.55- 2.63 (m, 1H), 3.36 (d, 2H, J= 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) ppm; ³¹P (121.4MHz, CDCl₃) δ 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 methyl ester)
2- (4-Bromo-but-2-enyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5 under N ₂ atmosphere A solution of -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 hour. The reaction was cooled to room temperature. The reaction mixture was worked up by removing the solvent in vacuo, followed by chromatography (which uses EtOAc-hexane) to give 460 mg (88%) of product as an oil. . ¹ H NMR (300 MHz, CDCl ₃ ) δ1.77 (s, 3H), 2.081- 2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H, J = 22 Hz), 2.54 (d , 1H, J = 22 Hz), 2.55- 2.63 (m, 1H), 3.36 (d, 2H, J = 7 Hz), 3.57 (s, 3H), 3.72 (d, 6H, J = 11 Hz), 3.76 ( s, 3H), 5.20 (s, 2H), 5.20- 5.26 (m, 1H), 5.36- 5.56 (m, 2H), 7.69 (s, 1H) ppm; ³¹ P (121.4MHz, CDCl ₃ ) δ 30.1 ppm MS (m / z) 497.2 [M + H] ⁺ , 519.2 [M + Na] ⁺ .

（２−［４−（ジメトキシ−ホスホリル）−ブタ−２−エニル］−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸）
２−［４−（ジメトキシ−ホスホリル）−ブタ−２−エニル］−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸メチルエステル（４６０ｍｇ、０．９２７ｍｍｏｌ）を、１：１：２のＨ_２Ｏ、ＭｅＯＨ、ＴＨＦ（８ｍＬ）の溶液中にて、ＬｉＯＨ．Ｈ_２Ｏ（７８ｍｇ、１．８６ｍｍｏｌ）とともに、周囲温度で、１２時間攪拌した。第二バッチのＬｉＯＨ．Ｈ_２Ｏ（４０ｍｇ、０．９５２ｍｍｏｌ）を加えた。その反応混合物を、室温で、さらに１６時間攪拌し、その後、それ以上の進行は認められなかった。この反応を、ＮＨ_４Ｃｌの飽和水溶液を加えることにより、クエンチした。その有機層を真空中で除去し、その水層から生成物をＥｔＯＡｃで抽出し、これを、５滴の２Ｎ ＨＣｌを加えることにより、酸性化した。この生成物をクロマトグラフィーでさらに精製して、所望生成物を得た。¹H NMR (300 MHz, CDCl₃) δ1.79 (s, 3H), 2.08- 2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J= 22 Hz),2.60 (d, 1H, J= 22 Hz), 2.57- 2.64 (m, 1H), 3.38 (d, 2H, J= 7Hz), 3.72 (d, 6H, J= 11 Hz) 3.76 (s, 3H), 5.20 (s, 2H), 5.27 (t, 1H, J=6 Hz), 5.36- 5.63 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ30.5 ppm; MS (m/z) 481.2 [M-H]^-。

(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) was dissolved in 1: 1: 2 H ₂ O, MeOH, THF (8 mL) in LiOH. Stir with H ₂ O (78 mg, 1.86 mmol) at ambient temperature for 12 hours. A second batch of LiOH. H ₂ O (40 mg, 0.952 mmol) was added. The reaction mixture was stirred for an additional 16 hours at room temperature, after which no further progress was observed. The reaction was quenched by adding a saturated aqueous solution of NH ₄ Cl. The organic layer was removed in vacuo and the product was extracted from the aqueous layer with EtOAc, which was acidified by adding 5 drops of 2N HCl. The product was further purified by chromatography to give the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ1.79 (s, 3H), 2.08- 2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J = 22 Hz), 2.60 (d , 1H, J = 22 Hz), 2.57- 2.64 (m, 1H), 3.38 (d, 2H, J = 7Hz), 3.72 (d, 6H, J = 11 Hz) 3.76 (s, 3H), 5.20 (s , 2H), 5.27 (t, 1H, J = 6 Hz), 5.36- 5.63 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ30.5 ppm; MS (m / z) 481.2 [MH] ^-

（２−［４−（２−［４−（ジメトキシ−ホスホリル）−ブタ−２−エニル］−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸）
２−［４−（ジメトキシ−ホスホリル）−ブタ−２−エニル］−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸（２５ｍｇ、０．０５２ｍｍｏｌ）のアセトニトリル（２ｍＬ）溶液に、２，６−ルチジン（６０μＬ、０．５２ｍｍｏｌ）およびＴＭＳＢｒ（６７μＬ、０．５２ｍｍｏｌ）を加えた。この反応は、ＬＣＭＳで判定したとき、４５分間進行し、そのとき、完結した。その反応混合物を減圧下にて濃縮し、そしてＮａＯＨ水溶液（１ｍＬ）でクエンチした。その生成物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、固形物として、１４．２ｍｇ（６０％）の生成物を得た。¹H NMR (300 MHz, CD₃OD) δ1.81 (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= 7Hz), 3.77 (s, 3H), 5.25 (s, 2H), 5.20- 5.36 (m, 1H), 5.36- 5.56 (m, 2H) ppm; ³¹P(121.4 MHz, CD₃OD) δ 25.4 ppm; MS (m/z) 453 [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 μL, 0.52 mmol) and TMSBr (67 μL, 0.52 mmol). . The reaction proceeded for 45 minutes as judged by LCMS, when it was complete. The reaction mixture was concentrated under reduced pressure and quenched with aqueous NaOH (1 mL). The product was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) to give 14.2 mg ( 60%) of product was obtained. ¹ H NMR (300 MHz, CD ₃ OD) δ1.81 (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 = 7Hz), 3.77 (s, 3H), 5.25 (s, 2H), 5.20-5.36 (m, 1H), 5.36-5.56 (m, 2H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 25.4 ppm; MS (m / z) 453 [MH] ⁻ .

（２−［４−（ジメトキシ−ホスホリル）−ブタ−２−エニル］−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニル−エチルエステル）
２−［４−（ジメトキシ−ホスホリル）−ブタ−２−エニル］−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸（１６０ｍｇ、０．３３２ｍｍｏｌ）およびトリメチルシリルエタノール（１６０ｍｇ、１．３６ｍｍｏｌ）のＴＨＦ（８．００ｍＬ）溶液をトリフェニルホスフィン（３４５ｍｇ、１．３３ｍｍｏｌ）と共に攪拌した。この溶液に、０℃で、アジジカルボン酸ジエチル（２３０μＬ、１．３３ｍｍｏｌ）を加えた。その混合物を室温まで温め、そして１６時間攪拌した。さらなるトリフェニルホスフィン（１８０ｍｇ、０．６９２ｍｍｏｌ）、トリメチルシリルエタノール（１６０ｍｇ、１．３６ｍｍｏｌ）およびアゾジカルボン酸ジエチル（１１５μＬ、０．６６５ｍｍｏｌ）を追加し、この反応混合物を、室温で、さらに１日間攪拌した。真空中で溶媒を除去し、その残留物をシリカゲルクロマトグラフィーで精製することにより、この反応物をワークアップして、透明オイルとして、１９２ｍｇ（８５％）の生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.03 (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 (見かけ上 t, 2H, J= 8 Hz), 4.30(見かけ上 t, 2H, J= 8 Hz), 5.12 (s, 2H), 5.15- 5.25 (m, 1H), 5.36- 5.63 (m,2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 29.3 ppm; MS (m/z)705.3 [M+Na]⁺.。

(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). . To this solution was added diethyl azidicarboxylate (230 μL, 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 azodicarboxylate (115 μL, 0.665 mmol) were added and the reaction mixture was stirred at room temperature for an additional day. . The reaction was worked up by removing the solvent in vacuo and purifying the residue by silica gel chromatography to give 192 mg (85%) of product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.03 (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 (apparent t, 2H, J = 8 Hz), 4.30 (apparent t , 2H, J = 8 Hz), 5.12 (s, 2H), 5.15- 5.25 (m, 1H), 5.36- 5.63 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 29.3 ppm; MS ( m / z) 705.3 [M + Na] ^+.

（２−［４−（ヒドロキシ−メトキシ−ホスホリル）−ブタ−２−エニル］−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニル−エチルエステル）
第三級ブチルアミン（２．８ｍＬ、２７ｍｍｏｌ）中の２−［４−（ジメトキシ−ホスホリル）−ブタ−２−エニル］−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニル−エチルエステル（１８４ｍｇ、０．２７０ｍｍｏｌ）の混合物を、６０℃で、２４時間加熱した。その溶液を室温まで冷却し、そして濃縮した。その残留物をシリカゲルカラムクロマトグラフィー（これは、ＭｅＯＨ／ＣＨ_２Ｃｌ_２（０〜３０％）を使用する）で精製して、透明オイルとして、７５ｍｇの生成物を得た。

(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) in tert-butylamine (2.8 mL, 27 mmol) -Trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (184 mg, 0.270 mmol) And heated at 60 ° C. for 24 hours. The solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (which uses MeOH / CH ₂ Cl ₂ (0-30%)) to give 75 mg of product as a clear oil.

（２−｛４−［（１−エトキシカルボニル−エトキシ）−メトキシ−ホスホリル］−ブタ−２−エニル｝−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニル−エチルエステル）
２−［４−（ヒドロキシ−メトキシ−ホスホリル）−ブタ−２−エニル］−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニル−エチルエステル（６７ｍｇ、０．１０ｍｍｏｌ）およびＰｙＢＯＰ（２３４ｍｇ、０．４５０ｍｍｏｌ）のＤＭＦ（１．５ｍＬ）溶液を、（Ｓ）−（−）−乳酸エチル（５３ｍｇ、０．４５ｍｍｏｌ）およびＤＩＥＡ（１７４μＬ、１．００ｍｍｏｌ）と共に、周囲温度で、１時間攪拌し、そのとき、出発物質の完全な消費が認められた。塩化ナトリウム飽和水溶液および酢酸エチルを加えることにより、この反応物をワークアップした。その有機層を分離し、そして５％塩化リチウム水溶液で洗浄した。この有機層を真空中で乾燥し、その残留物をシリカゲルクロマトグラフィー（これは、ＭｅＯＨ−ＣＨ_２Ｃｌ_２（０〜２０％）を使用する）で精製して、透明オイルとして、５７ｍｇ（７４％）の所望生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.02 (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 および 3.77 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (見かけ上 t, 2H, J= 7 Hz), 4.20 (dq, 2H, J=3, 7 Hz), 4.29 (見かけ上 t, 2H, J= 9 Hz), 4.85- 4.99 (m, 1H), 5.12 (s, 2H),5.19 (br t, 1H, J= 6 Hz), 5.33- 5.61 (m, 2H) ppm; ³¹P (121.4MHz, CDCl₃) δ 28.9, 29.9 ppm; MS (m/z) 791.4 [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 μL, 1.00 mmol) at ambient temperature for 1 hour, when complete starting material was Consumption was allowed. The reaction was worked up by adding saturated aqueous sodium chloride and ethyl acetate. The organic layer was separated and washed with 5% aqueous lithium chloride. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography (using MeOH—CH ₂ Cl ₂ (0-20%)) to give 57 mg (74% The desired product was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.02 (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 (apparent t, 2H, J = 7 Hz), 4.20 (dq, 2H, J = 3, 7 Hz), 4.29 (apparent t, 2H, J = 9 Hz), 4.85 -4.99 (m, 1H), 5.12 (s, 2H), 5.19 (br t, 1H, J = 6 Hz), 5.33- 5.61 (m, 2H) ppm; ³¹ P (121.4MHz, CDCl ₃ ) δ 28.9, 29.9 ppm; MS (m / z) 791.4 [M + Na] ⁺ .

（２−｛４−［（１−エトキシカルボニル−エトキシ）−メトキシ−ホスホリル］−ブタ−２−エニル｝−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸）
２−｛４−［（１−エトキシカルボニル−エトキシ）−メトキシ−ホスホリル］−ブタ−２−エニル｝−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニル−エチルエステル（１４ｍｇ、０．０１８ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液を、ＴＢＡＦの１Ｍ ＴＨＦ（５５μＬ、０．０５５ｍｍｏｌ）溶液と共に、１時間攪拌した。その反応混合物を濃縮し、１Ｎ ＨＣｌで酸性化し、そしてＥｔＯＡｃで抽出した。その有機層をブラインて洗浄し、そして乾燥した。その生成物をシリカゲルカラムクロマトグラフィー（ＥｔＯＨ−ＥｔＯＡｃ（０〜１０％））で精製した。この生成物をＣＨ_２Ｃｌ_２に溶解し、その化合物を１３ｍｍ Ａｃｒｏｄｉｓｃ注射器フィルター（これは、０．４５μｍのナイロン膜を備えている）に通すことにより、さらに精製して、８ｍｇ（７７％）の生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.92 (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 および3.74 (d, 3H, J= 11 Hz), 3.76 (s, 3H), 4.07 (m, 2H), 4.96 (dq, 1H, J=7 Hz), 5.20 (s, 2H), 5.27 (br t, 1H, J= 7 Hz), 5.33- 5.55 (m, 2H), 7.51-7.56 (m, 1H), 7.68- 7.74 (m, 1H) ppm; ³¹P (121.4 MHz, CDCl₃)δ 29.0, 30.1 ppm; MS (m/z) 569.2 [M+H] ⁺, 591.3 [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). , TBAF in 1M THF (55 μL, 0.055 mmol) was stirred for 1 hour. The reaction mixture was concentrated, acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with brine and dried. The product was purified by silica gel column chromatography (EtOH-EtOAc (0-10%)). The product was further purified by dissolving in CH ₂ Cl ₂ and passing the compound through a 13 mm Acrodisc syringe filter (which is equipped with a 0.45 μm nylon membrane) to yield 8 mg (77%) The product was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.92 (t, 3H, J = 7 Hz), 1.30 (d, 3H, J = 8 Hz), 1.79 (s, 3H), 2.10-2.39 (m, 4H ), 2.15 (s, 3H), 2.53 (d, 1H, J = 8 Hz), 2.65 (d, 1H, J = 22 Hz), 2.68 (d, 1H, J = 22 Hz), 3.38 (d, 2H , J = 7 Hz), 3.70 and 3.74 (d, 3H, J = 11 Hz), 3.76 (s, 3H), 4.07 (m, 2H), 4.96 (dq, 1H, J = 7 Hz), 5.20 (s , 2H), 5.27 (br t, 1H, J = 7 Hz), 5.33- 5.55 (m, 2H), 7.51-7.56 (m, 1H), 7.68-7.74 (m, 1H) ppm; ³¹ P (121.4 MHz , CDCl ₃ ) δ 29.0, 30.1 ppm; MS (m / z) 569.2 [M + H] ⁺ , 591.3 [M + Na] ⁺ .

（２−｛４−［（１−カルボキシ−エトキシ）−ヒドロキシ−ホスホリル］−ブタ−２−エニル｝−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニル−エチルエステル）
２−｛４−［（１−エトキシカルボニル−エトキシ）−メトキシ−ホスホリル］−ブタ−２−エニル｝−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニルエチルエステル（１２ｍｇ、０．０１６ｍｍｏｌ）の第三級ブチルアミン（１ｍＬ、９．６ｍｍｏｌ）溶液を、６５℃で、１６時間加熱した。この溶液を室温まで冷却し、そして濃縮して、オイルとして、粗生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.03 (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 (見かけ上 t, 2H, J=9 Hz), 4.25- 4.33 (m, 2H), 4.75- 4.84 (m, 1H), 5.13 (s, 2H), 5.15- 5.23 (m,1H), 5.33- 5.55 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ28.9 ppm; MS (m/z) 725.3 [M-H]^-。

(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-trimethylsilanyl ethyl ester (12 mg, 0.016 mmol) in tertiary butylamine (1 mL, The solution (9.6 mmol) 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 ) δ0.03 (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 (apparently t, 2H, J = 9 Hz), 4.25- 4.33 (m, 2H), 4.75- 4.84 (m, 1H), 5.13 (s, 2H), 5.15- 5.23 ( m, 1H), 5.33-5.55 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 28.9 ppm; MS (m / z) 725.3 [MH] ⁻ .

（２−｛４−［（１−カルボキシ−エトキシ）−ヒドロキシ−ホスホリル］−ブタ−２−エニル｝−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸）
粗２−｛４−［（１−カルボキシ−エトキシ）−ヒドロキシ−ホスホリル］−ブタ−２−エニル｝−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニル−エチルエステル（ＡＣ−２１０１−５９）およびフッ化テトラブチルアンモニウムのＴＨＦ（１Ｍ、５４μＬ、０．０５４ｍｍｏｌ）溶液を、ＴＨＦ（１ｍＬ）と共に、周囲温度で、２時間攪拌し、そのとき、ＴＨＦ中のさらに多くのフッ化テトラブチルアンモニウム（５４μＬ、０．０５４ｍｍｏｌ）を加えた。その反応物をさらに１６時間攪拌し、その時点までに、この反応は完結した。この反応混合物を真空中で濃縮し、その生成物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−ＣＨ_３ＣＮ、０．１％ＴＦＡの溶離液と共に、Ｐｈｅｎｏｍｅｎｅｘ Ｓｙｎｅｒｇｉ ５μ Ｈｙｄｒｏ ＲＰ ８０Ａカラム（５０×２１．２ｍｍ）を使用する）で精製して、透明オイルとして、生成物（８．０ｍｇ）を得た。¹H NMR (300 MHz, CDCl₃) δ1.51 (d, 3H, J= 7 Hz), 1.79 (s, 3H), 2.05- 2.40 (m, 4H), 2.11 (s, 3H),2.49- 2.71 (m, 3H), 3.38 (d, 2H, J= 6 Hz), 3.76 (s, 3H), 4.85 (br s,1H), 5.20 (s, 2H), 5.21- 5.30 (m, 1H), 5.33- 5.63 (m, 2H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 27.7 ppm; MS (m/z) 525.2 [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 solution of THF (1M, 54 μL, 0.054 mmol) was stirred with THF (1 mL) at ambient temperature for 2 hours, when more tetrabutylammonium fluoride (54 μL, 0.054 mmol) in THF was then added. added. The reaction was stirred for an additional 16 hours, by which time the reaction was complete. The reaction mixture was concentrated in vacuo and the product was purified by RP HPLC (Phenomenex Synergi 5μ Hydro RP 80A with eluent of H ₂ O, 0.1% TFA-CH ₃ CN, 0.1% TFA. Purification on a column (using 50 × 21.2 mm) gave the product (8.0 mg) as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ1.51 (d, 3H, J = 7 Hz), 1.79 (s, 3H), 2.05- 2.40 (m, 4H), 2.11 (s, 3H), 2.49-2.71 (m, 3H), 3.38 (d, 2H, J = 6 Hz), 3.76 (s, 3H), 4.85 (br s, 1H), 5.20 (s, 2H), 5.21- 5.30 (m, 1H), 5.33 -5.63 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 27.7 ppm; MS (m / z) 525.2 [MH] ^- .

（２−｛４−［（１−エトキシカルボニル−エチルアミン）−メトキシ−ホスホリル］−ブタ−２−エニル｝−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニル−エチルエステル）
２−［４−（ヒドロキシ−メトキシ−ホスホリル）−ブタ−２−エニル］−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニル−エチルエステル（２０ｍｇ、０．０３０ｍｍｏｌ）、ＰｙＢＯＰ（６２．４ｍｇ、０．１２０ｍｍｏｌ）のＤＭＦ（１．０ｍＬ）溶液を、Ｌ−アラニンエチルエステル塩酸塩（１８ｍｇ、０．１２ｍｍｏｌ）およびＤＩＥＡ（２６μＬ、０．１５ｍｍｏｌ）と共に、周囲温度で、１時間攪拌し、そのとき、出発物質の完全な消費が認められた。その反応溶液が濁るまで水を加えることにより、この反応物をワークアップした。その混合物が再度透明になるまで、ＤＭＦを滴下した。この反応混合物をＡｃｒｏｄｉｓｃ（０．４５μｍのナイロン膜を備えた１３ｍｍの注射器フィルター）で濾過し、そしてＲＰ ＨＰＬＣ（これは、Ｐｈｅｎｏｍｅｎｅｘ Ｓｙｎｅｒｇｉ ５μ Ｈｙｄｒｏ ＲＰ ８０Ａカラム（５０×２１．２ｍｍ）を使用し、水およびアセトニトリルで溶出する）で精製した。その生成物を含有する画分を共にプールし、そして真空中で濃縮して、このアセトニトリルを除去した。残留している溶液を塩化ナトリウムで飽和し、そしてＥｔＯＡｃおよびアセトニトリルで抽出して、７．２ｍｇの生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.03 (s, 9H), 0.05 (s, 9H), 0.923 (見かけ上 t, 2H, J= 8 Hz), 1.18- 1.31 (m,5H), 1.41 (t, 3H, J= 7 Hz), 1.78 (s, 3H), 2.03- 2.36 (m, 4H), 2.18 (s,3H), 2.43- 2.63 (m, 3H), 3.10- 3.30 (m, 1H), 3.40 (d, 2H, J= 7 Hz), 3.62おおよび 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 (見かけ上 t, 2H, J= 8 Hz), 5.12 (s, 2H), 5.18-5.28 (m, 1H), 5.33- 5.67 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃)δ 30.4, 31.2 ppm; MS (m/z) 790.4 [M+Na]⁺。

(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 μL, 0.15 mmol) at ambient temperature for 1 hour when complete consumption of starting material Was recognized. The reaction was worked up 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 μm nylon membrane) and RP HPLC (which was a Phenomenex Synergi 5 μ Hydro RP 80A column (50 × 21.2 mm)) And eluted with acetonitrile). Fractions containing the product were pooled together and concentrated in vacuo to remove the 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 ) δ0.03 (s, 9H), 0.05 (s, 9H), 0.923 (apparently t, 2H, J = 8 Hz), 1.18- 1.31 (m, 5H), 1.41 (t, 3H, J = 7 Hz), 1.78 (s, 3H), 2.03- 2.36 (m, 4H), 2.18 (s, 3H), 2.43- 2.63 (m, 3H), 3.10- 3.30 (m, 1H ), 3.40 (d, 2H, J = 7 Hz), 3.62 and 3.65 (d, 3H, J = 11 Hz), 3.76 (s, 3H), 4.03-4.12 (m, 2H), 4.20 (dq, 2H , J = 2, 7 Hz), 4.29 (apparently t, 2H, J = 8 Hz), 5.12 (s, 2H), 5.18-5.28 (m, 1H), 5.33- 5.67 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 30.4, 31.2 ppm; MS (m / z) 790.4 [M + Na] ⁺ .

（２−｛４−［（１−エトキシカルボニル−エチルアミン）−メトキシ−ホスホリル］−ブタ−２−エニル｝−６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸）
２−｛４−［（１−エトキシカルボニル−エチルアミン）−メトキシ−ホスホリル］−ブタ−２−エニル｝−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニル−エチルエステル（７．２ｍｇ、９．３８ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液に、室温で、ＴＢＡＦ（４０μＬ、１Ｍ ＴＨＦ溶液）を加えた。その反応混合物を２０分間攪拌し、そのとき、ＬＣＭＳで判定すると、出発物質は、所望生成物に変換されていた。この反応混合物を真空中で乾燥し、そしてＤＭＦに再溶解した。その生成物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ−ＣＨ_３ＣＮの溶離液と共に、Ｐｈｅｎｏｍｅｎｅｘ Ｓｙｎｅｒｇｉ ５μ Ｈｙｄｒｏ ＲＰ ８０Ａカラム（５０×２１．２ｍｍ）を使用する）で精製した。所望生成物を含有する画分をプールし、そしてＤｏｗｅｘ ５０ＷＸ８−４００（これは、４．５ｃｍ×２ｃｍのカラムに充填した）でさらに精製して、Ｈ_２Ｏ−ＭｅＯＨ（１：１）のナトリウム塩を溶出し、３．２ｍｇの所望生成物を得た。¹H NMR (300 MHz, CD₃OD) δ1.26 (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= 7Hz), 3.60 および 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; ³¹P (121.4 MHz, CD₃OD) δ 33.8, 34.2 ppm; MS (m/z)568.2 [M+H]⁺, 590.3 [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 μL, 1M THF solution) at room temperature. The reaction mixture was stirred for 20 minutes when the starting material was converted to the desired product as judged by LCMS. The reaction mixture was dried in vacuo and redissolved in DMF. The product was purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80A column (50 × 21.2 mm) with eluent of H ₂ O—CH ₃ CN. Fractions containing the desired product were pooled and further purified with Dowex 50WX8-400 (which was packed in a 4.5 cm × 2 cm column) and sodium H ₂ O—MeOH (1: 1). The salt was eluted to give 3.2 mg of the desired product. ¹ H NMR (300 MHz, CD ₃ OD) δ1.26 (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 = 7Hz), 3.60 and 3.65 (d, 3H, J = 11 Hz), 3.74 (s, 3H), 3.83-3.96 (m, 1H), 4.18 (q, 2H, J = 8 Hz), 5.15 (s, 2H), 5.25- 5.42 (m, 2H), 5.55- 5.69 (m, 1H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 33.8, 34.2 ppm; MS (m / z) 568.2 [M + H] ⁺ , 590.3 [M + Na] ⁺ .

（６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−［４−（ヒドロキシ−メトキシ−ホスホリル）−ブタ−２−エニル］−４−メチル−ヘキサ−４−エン酸）
２−［４−（ヒドロキシ−メトキシ−ホスホリル）−ブタ−２−エニル］−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸２−トリメチルシラニルエチルエステル（１１ｍｇ、０．０１６ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液に、室温で、ＴＢＡＦ（５０μＬ、１Ｍ ＴＨＦ溶液）を加えた。この溶液を１６時間攪拌し、そして濃縮した。この溶液を減圧下にて乾燥し、そしてＤＭＦ（０．８ｍＬ）および水（０．２５ｍＬ）に再懸濁した。この溶液をＡｃｒｏｄｉｓｃ（０．４５μｍのナイロン膜を備えた１３ｍｍの注射器フィルター）で濾過し、そしてＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−ＣＨ_３ＣＮ、０．１％ＴＦＡの溶離液と共に、Ｐｈｅｎｏｍｅｎｅｘ Ｓｙｎｅｒｇｉ ５μ Ｈｙｄｒｏ ＲＰ ８０Ａカラム（５０×２１．２ｍｍ）を使用する）で精製した。このカラムから得た生成物をイオン交換クロマトグラフィー（ナトリウム塩形状のＤｏｗｅｘ ５０ＷＸ８−４００）（これは、２×４．５ｃｍカラムを使用し、Ｈ_２Ｏ−ＭｅＯＨ（１：１）で溶出する）にかけて、オイルとして、７．５ｍｇの所望生成物を得た。
¹H NMR (300 MHz, CDCl₃) δ 1.80(s, 3H), 2.01- 2.29 (m, 5H), 2.11 (s, 3H), 2.35 (d, 2H, J= 22 Hz), 3.38(d, 2H, J= 7 Hz), 3.53 (d, 3H, J= 11 Hz), 3.75 (s, 3H), 5.19 (s,2H), 5.26 (t, 1H, J= 6 Hz), 5.43- 5.54 (m, 2H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 23.5 ppm; MS (m/z) 469.2 [M+H]⁺,491.3 [M+Na]⁺。

(6- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2- [4- (hydroxy-methoxy-phosphoryl) -buta-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, TBAF (50 μL, 1M THF solution) was added. The solution was stirred for 16 hours and concentrated. The solution was dried under reduced pressure and resuspended in DMF (0.8 mL) and water (0.25 mL). The solution was filtered through Acrodisc (13 mm syringe filter with 0.45 μm nylon membrane) and RP HPLC (which was H ₂ O, 0.1% TFA-CH ₃ CN, 0.1% TFA. Purified on a Phenomenex Synergi 5μ Hydro RP 80A column (50 × 21.2 mm) with eluent). The product from this column was ion exchange chromatographed (sodium salt form Dowex 50WX8-400) (this uses a 2 × 4.5 cm column and elutes with H ₂ O—MeOH (1: 1)). To give 7.5 mg of the desired product as an oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ 1.80 (s, 3H), 2.01- 2.29 (m, 5H), 2.11 (s, 3H), 2.35 (d, 2H, J = 22 Hz), 3.38 (d, 2H, J = 7 Hz), 3.53 (d, 3H, J = 11 Hz), 3.75 (s, 3H), 5.19 (s, 2H), 5.26 (t, 1H, J = 6 Hz), 5.43- 5.54 ( m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 23.5 ppm; MS (m / z) 469.2 [M + H] ⁺ , 491.3 [M + Na] ⁺ .

（６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸メチルエステル）
６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エン酸メチルエステル（２２２ｍｇ、０．６６ｍｍｏｌ）、トリフェニルホスフィン（２６０ｍｇ、０．９９６ｍｍｏｌ）およびアゾジカルボン酸ジエチル（１７３ｍｇ、０．９９６ｍｍｏｌ）のＴＨＦ（３ｍＬ）溶液に、０℃で、２−トリメチルシリルエタノール（１４２μＬ、０．９９６ｍｍｏｌ）のＴＨＦ（３ｍＬ）溶液を加えた。得られた黄色溶液を室温まで温め、そして一晩攪拌した。その反応物を乾燥状態まで濃縮し、そしてエーテルおよびヘキサンを加えた。濾過によりトリフェニルホスフィンオキシドを除去し、その濾液を濃縮し、そしてシリカゲルクロマトグラフィーで精製して、無色オイルとして、２４８ｍｇの所望生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.03 (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- [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. 66 mmol), triphenylphosphine (260 mg, 0.996 mmol) and diethyl azodicarboxylate (173 mg, 0.996 mmol) in THF (3 mL) at 0 ° C. in 2-trimethylsilylethanol (142 μL, 0.996 mmol) in THF. (3 mL) 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 colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.03 (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−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−アセトアルデヒド）
６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸メチルエステル（６１８ｍｇ、１．４２ｍｍｏｌ）のＭｅＯＨ（１０ｍＬ）、ＣＨ_２Ｃｌ_２（１０ｍＬ）およびピリジン（５０μＬ、０．６１８ｍｍｏｌ）溶液を、Ｓｍｉｔｈ，Ｄ．Ｂ．ｅｔ ａｌ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９６，６１，６，２２３６の手順に従って、ドライアイス／アセトン浴を使用して、−７０℃まで冷却した。その反応物が青色に着色するまで（１５分間）、気体分散チューブを経由して、この反応物にオゾン流れを泡立たせた。このオゾンラインを窒素流れで置き換え、泡立ちをさらに１５分間継続し、その時点までに、この青色は消失した。この溶液に、−７０℃で、チオ尿素（７５．７ｍｇ、０．９９４ｍｍｏｌ）を一度に加え、この冷却浴を取り除いた。その反応物を室温まで温め、そして１５時間攪拌した。この反応物を濾過によりワークアップして、固形チオ尿素Ｓ−ジオキシドを除去し、次いで、ＣＨ_２Ｃｌ_２と水との間で分配した。その有機層を除去した。その水層をＣＨ_２Ｃｌ_２でもう１回洗浄し、そして有機抽出物を合わせた。この有機層を１Ｎ ＨＣｌ水溶液、飽和ＮａＨＣＯ_３およびブラインで洗浄した。これらの有機抽出物を真空中で乾燥し、その残留物をシリカゲルクロマトグラフィーで精製して、白色固形物として、３５７ｍｇ（７５％）の生成物を得た。¹H NMR (300 MHz, CDCl₃) δ-0.01 (s, 9H), 1.05- 1.15 (m, 2H), 2.15 (s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J=1 Hz), 4.27- 4.39 (m, 2H), 5.11 (s, 2H), 9.72 (d, 1H, J= 1 Hz) ppm.

([6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde)
6- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-ene A solution of acid methyl ester (618 mg, 1.42 mmol) in MeOH (10 mL), CH ₂ Cl ₂ (10 mL) and pyridine (50 μL, 0.618 mmol) was added to Smith, D. et al. B. et al. , J .; Org. Chem. , 1996, 61, 6, 2236, using a dry ice / acetone bath to cool to -70 ° C. An ozone stream was bubbled through the reaction via a gas dispersion tube until the reaction colored blue (15 minutes). The ozone line was replaced with a stream of nitrogen and bubbling continued for an additional 15 minutes by which time the blue color had disappeared. To this solution was added thiourea (75.7 mg, 0.994 mmol) in one portion at −70 ° C. and the cooling bath was removed. The reaction was warmed to room temperature and stirred for 15 hours. The reaction was worked up by filtration to remove solid thiourea S-dioxide and then partitioned between CH ₂ Cl ₂ and water. The organic layer was removed. The aqueous layer was washed once more with CH ₂ Cl ₂ and the organic extracts were combined. The organic layer was washed with 1N aqueous HCl, saturated NaHCO ₃ and brine. These organic extracts were dried in vacuo and the residue was purified by silica gel chromatography to give 357 mg (75%) of product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ-0.01 (s, 9H), 1.05- 1.15 (m, 2H), 2.15 (s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J = 1 Hz), 4.27- 4.39 (m, 2H), 5.11 (s, 2H), 9.72 (d, 1H, J = 1 Hz) ppm.

（４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エナール）
［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−アセトアルデヒド（７０ｍｇ、０．２１ｍｍｏｌ）を、トルエン（２ｍＬ）中にて、１００℃で、２−（トリフェニル−ホスファニリデン）−プロピオンアルデヒド（７２．９ｍｇ、０．２３ｍｍｏｌ）と共に、一晩加熱した。２−（トリフェニル−ホスファニリデン）−プロピオンアルデヒド（３３ｍｇ、０．１１ｍｍｏｌ）の第二部分を加え、その反応混合物を、さらに１日加熱した。濃縮した後、その残留物をシリカゲルクロマトグラフィーで精製して、淡黄色オイルとして、５４ｍｇ（８３％）の所望生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.00 (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.

(4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2-yl Enal)
[6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde (70 mg, 0.21 mmol) was added to toluene. (2 mL) was heated at 100 ° C. with 2- (triphenyl-phosphanylidene) -propionaldehyde (72.9 mg, 0.23 mmol) overnight. A second portion of 2- (triphenyl-phosphanylidene) -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 ) δ0.00 (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−ヒドロキシ−３−メチル−ブタ−２−エニル）−５−メトキシ−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン）
４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エナール（１０３ｍｇ、０．２７ｍｍｏｌ）のメタノール（５ｍＬ）溶液を０℃まで冷却した。ＣｅＣｌ_３の溶液（０．６８ｍＬ、ＭｅＯＨ：Ｈ_２Ｏ、９：１）を加え、続いて、ＬｉＢＨ_４（０．１４ｍＬ、２Ｍ ＴＨＦ溶液０．２８ｍｍｏｌ）を加えた。氷浴を取り除き、その反応混合物を室温まで温めた。この反応混合物をさらに４０分間攪拌すると、ＴＬＣにより、出発物質のアルデヒドが完全に消費されたことが明らかとなった。１Ｎ ＨＣｌ水溶液（０．５ｍＬ）を加えることにより、この反応物をワークアップし、その生成物をＣＨ_２Ｃｌ_２で抽出した。その有機層を炭酸水素ナトリウム飽和水溶液およびブラインで洗浄した。この有機層を減圧下にて濃縮し、その残留物をシリカゲルクロマトグラフィーで精製して、透明液体として、１００ｍｇ（９７％）の生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.00 (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, 8Hz), 5.08 (s, 2H), 5.17- 5.44 (m, 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. A solution of CeCl ₃ (0.68 mL, MeOH: H ₂ O, 9: 1) was added followed by LiBH ₄ (0.14 mL, 0.2M mmol in 2M THF). The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for an additional 40 minutes and TLC revealed complete consumption of the starting aldehyde. The reaction was worked up by adding 1N aqueous HCl (0.5 mL) and the product was extracted with CH ₂ Cl ₂ . The organic layer was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give 100 mg (97%) of product as a clear liquid. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.00 (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, 8Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H) ppm.

（６−（２−ヒドロキシ−エチル）−５−メトキシ−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン）
［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−アセトアルデヒド（９７ｍｇ、０．２９ｍｍｏｌ）のＴＨＦ（５ｍＬ）溶液に、ＴＨＦ中の２Ｍ ＬｉＢＨ_４のアリコート（１５０μＬ、０．３００ｍｍｏｌ）を加えた。その反応混合物を、室温で、１時間攪拌し、そのとき、ＴＬＣにより、出発物質の完全な消費が認められた。１Ｎ ＨＣｌ水溶液を加えることより、この反応混合物をワークアップし、そしてＥｔＯＡｃで抽出した。その有機層を真空中で乾燥し、その残留物をシリカゲルクロマトグラフィーで精製して、この生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.00 (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.

(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 μL, 0.300 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour when complete consumption of starting material was observed by TLC. The reaction mixture was worked up by adding 1N aqueous HCl and extracted with EtOAc. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography to give the product. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.00 (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−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−エトキシメチル｝−ホスホン酸ジイソプロピルエステル）
６−（２−ヒドロキシ−エチル）−５−メトキシ−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン（７９ｍｇ、０．２３ｍｍｏｌ）の混合物を、ブロモメチルホスホン酸ジイソプロピルエステル（１２０ｍｇ、０．４６ｍｍｏｌ）と共に、リチウムｔ−ブトキシド（２２ｍｇ、０．２７ｍｍｏｌ）の存在下にて、ＤＭＦ（２ｍＬ）中で、７０℃で、一晩加熱した。その反応混合物をＲＰ ＨＰＬＣ（アセトニトリルおよび０．１％ ＣＦ_３ＣＯＯＨ水溶液）で精製して、所望生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.00 (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]⁺.
（実施例２９６）
本発明の代表的な化合物は、以下で図示するように、調製できる。

({2- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -ethoxymethyl} -diisopropylphosphonate 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 bromo Heated at 70 ° C. overnight in DMF (2 mL) in the presence of lithium t-butoxide (22 mg, 0.27 mmol) with methyl phosphonic acid diisopropyl ester (120 mg, 0.46 mmol). The reaction mixture was purified by RP HPLC (acetonitrile and 0.1% aqueous CF ₃ COOH) to give the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.00 (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 296)
Representative compounds of the present invention can be prepared as illustrated below.

（［２−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−エトキシメチル］−ホスホン酸）
｛２−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−エトキシメチル｝−ホスホン酸ジイソプロピルエステル（７．５ｍｇ、０．０１４ｍｍｏｌ）のアセトニトリル（２ｍＬ）および２，６−ルチジン（２５μＬ、０．２１ｍｍｏｌ）溶液に、室温で、臭化トリメチルシリル（２７μＬ、０．２１ｍｍｏｌ）を加えた。この反応は、１８時間進行し、そのとき、ＬＣＭＳにより、この反応が完結したことが明らかとなった。その反応物は、ＭｅＯＨを加えることによりクエンチし、そして濃縮した。その残留物をＲＰ−ＨＰＬＣ（これは、Ｃ１８カラムを使用する）で精製した。集めた生成物を１０％ＴＦＡ／ＣＨ_２Ｃｌ_２溶液に溶解して、完全な脱保護を確認した。その反応混合物を凍結乾燥して、所望生成物を得た。¹H NMR (300 MHz, CD₃OD) δ2.12 (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]^-.

([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 μL, 0.21 mmol), trimethylsilyl bromide (27 μL, 0.21 mmol) was added at room temperature. The reaction proceeded for 18 hours, at which time LCMS revealed that the reaction was complete. The reaction was quenched by adding MeOH and concentrated. The residue was purified by RP-HPLC (which uses a C18 column). The collected product was dissolved in 10% TFA / CH ₂ Cl ₂ solution to confirm complete deprotection. The reaction mixture was lyophilized to give the desired product. ¹ H NMR (300 MHz, CD ₃ OD) δ2.12 (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 [MH] ^- .

（実施例２９７）
本発明の代表的な化合物は、以下で図示するように、調製できる。

(Example 297)
Representative compounds of the present invention can be prepared as illustrated below.

（６−（４−ブロモ−３−メチル−ブタ−２−エニル）−７−ヒドロキシ−５−メトキシ−４−メチル−３Ｈ−イソベンゾフラン−１−オン）
重合体で支持したトリフェニルホスフィン（３ｍｍｏｌ／ｇ、０．５ｇ）を、１時間にわたって、ジクロロメタン（１０ｍＬ）に浸漬し、７−ヒドロキシ−６−（４−ヒドロキシ−３−メチル−ブタ−２−エニル）−５−メトキシ−４−メチル−３Ｈ−イソベンゾフラン−１−オン（１００ｍｇ、０．３６ｍｍｏｌ）および四臭化炭素（１４３ｍｇ、０．４３ｍｍｏｌ）を順次加え、その混合物を、室温で、１時間振盪した。さらに多くの四臭化炭素（１４３ｍｇ、０．４３ｍｍｏｌ）を加え、この混合物を、さらに１時間振盪した。この混合物を濾過し、その濾液を濃縮した。その残留物をシリカゲルクロマトグラフィー（０％〜６０％酢酸エチル／ヘキサン）にかけて、オイル（５２ｍｇ、４２％）として、６−（４−ブロモ−３−メチル−ブタ−２−エニル）−７−ヒドロキシ−５−メトキシ−４−メチル−３Ｈ−イソベンゾフラン−１−オンを得た；¹H NMR (300 MHz, CDCl₃) δ1.95 (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.

(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 soaked in dichloromethane (10 mL) for 1 hour to give 7-hydroxy-6- (4-hydroxy-3-methyl-but-2-ene). Enyl) -5-methoxy-4-methyl-3H-isobenzofuran-1-one (100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) were added sequentially and the mixture was added at room temperature to 1 Shake for hours. More 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 / hexanes) to give 6- (4-bromo-3-methyl-but-2-enyl) -7-hydroxy as an oil (52 mg, 42%). -5-methoxy-4-methyl-3H-isobenzofuran-1-one was obtained; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.95 (s, 3H), 2.16 (s, 3H), 3.44 (d , J = 7.2, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2H), 5.68 (t, J = 7.2 Hz, 1H), 7.71 (brs, 1H) ppm.

（［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−ホスホン酸ジメチルエステル）
６−（４−ブロモ−３−メチル−ブタ−２−エニル）−７−ヒドロキシ−５−メトキシ−４−メチル−３Ｈ−イソベンゾフラン−１−オン（３３ｍｇ、０．０９７ｍｍｏｌ）の亜リン酸トリメチル（１．０ｍＬ、８．５ｍｍｏｌ）溶液を、１時間にわたって、１００℃まで加熱すると、ＬＣＭＳにより、反応が完結したことが明らかとなった。減圧下にて過剰の試薬を除去することにより、この反応物をワークアップし、その残留物をシリカゲルクロマトグラフィー（これは、ＥｔＯＡｃ−ヘキサン（２０〜１００％）を使用する）で精製して、２０ｍｇ（６０％）の所望生成物を得た。¹H NMR (300 MHz, CDCl₃) δ1.90 (s, 3H), 2.09 (s, 3H), 2.48 (d, 2H, J= 22 Hz), 3.38 (t, 2H, J=6 Hz), 3.64 (d, 6H, J= 11 Hz), 3.72 (s, 3H), 5.14 (s, 2H),5.33 (q, 1H, J=6 Hz), 7.65 (br s, 1H) ppm; MS (m/z) 371 [M+H]⁺.
（実施例２９８）
本発明の代表的な化合物は、以下で図示するように、調製できる。

([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 When the (1.0 mL, 8.5 mmol) solution was heated to 100 ° C. over 1 hour, LCMS revealed that the reaction was complete. The reaction was worked up by removing excess reagent under reduced pressure and the residue was purified by silica gel chromatography (using EtOAc-hexane (20-100%)) 20 mg (60%) of the desired product was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ1.90 (s, 3H), 2.09 (s, 3H), 2.48 (d, 2H, J = 22 Hz), 3.38 (t, 2H, J = 6 Hz), 3.64 (d, 6H, J = 11 Hz), 3.72 (s, 3H), 5.14 (s, 2H), 5.33 (q, 1H, J = 6 Hz), 7.65 (br s, 1H) ppm; MS (m / z) 371 [M + H] ⁺ .
(Example 298)
Representative compounds of the present invention can be prepared as illustrated below.

（［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−ホスホン酸）
［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−ホスホン酸ジメチルエステル（１８ｍｇ、０．０４９ｍｍｏｌ）のアセトニトリル（２ｍＬ）溶液に、０℃で、ＴＭＳＢｒ（６３μＬ、０．４９ｍｍｏｌ）および２，６−ルチジン（８５μＬ、０．７３ｍｍｏｌ）を加えた。その反応溶液を室温まで温め、そして２時間攪拌し、そのとき、ＬＣＭＳにより、この反応が完結したことが認められた。この反応物を０℃まで冷却し、そしてＭｅＯＨを加えることにより、クエンチした。この反応混合物を減圧下にて濃縮し、その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ−アセトニトリル（５〜０％）の勾配で、２０分間にわたって、Ｃ１８カラムを使用する）で精製して、１２．２ｍｇ（７３％）の生成物を得た。¹H NMR (300 MHz, CD₃OD) δ1.95 (s, 3H), 2.15 (s, 3H), 2.48 (d, 2H, J= 22 Hz), 3.44 (t, 2H, J=6 Hz), 3.79 (s, 3H), 5.24 (s, 2H),5.38 (q, 1H, J= 7 Hz), 6.87 (br s, 1H)ppm; MS (m/z) 341 [M-H]^-.
（実施例２９９）
本発明の代表的な化合物は、以下で図示するように、調製できる。

([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 μL, 0.49 mmol) and 2,6-lutidine (85 μL, 0.73 mmol) were added to a solution of 18 mg, 0.049 mmol) in acetonitrile (2 mL) at 0 ° C. The reaction solution was warmed to room temperature and stirred for 2 hours, when LCMS showed the reaction was complete. The reaction was cooled to 0 ° C. and quenched by adding MeOH. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O-acetonitrile (5-0%) over 20 min). 12.2 mg (73%) of product was obtained. ¹ H NMR (300 MHz, CD ₃ OD) δ1.95 (s, 3H), 2.15 (s, 3H), 2.48 (d, 2H, J = 22 Hz), 3.44 (t, 2H, J = 6 Hz) , 3.79 (s, 3H), 5.24 (s, 2H), 5.38 (q, 1H, J = 7 Hz), 6.87 (br s, 1H) ppm; MS (m / z) 341 [MH] ^- .
(Example 299)
Representative compounds of the present invention can be prepared as illustrated below.

（［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−ホスホン酸モノフェニルエステルおよび［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−ホスホン酸ジフェニルエステル）
［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−ホスホン酸（４９ｍｇ、０．１３ｍｍｏｌ）のＤＭＦ（０．４ｍＬ）およびフェノール（６２ｍｇ、０．６５ｍｍｏｌ）溶液に、０℃で、ＤＭＦ（０．６ｍＬ）中のジシクロヘキシルカルボジイミド（１０７ｍｇ、０．５２ｍｍｏｌ）およびＤＭＡＰ（８ｍｇ、０．０６５ｍｍｏｌ）をゆっくりと加えた。その反応物を室温まで温め、そして１０時間にわたって、１４０℃まで加熱した。室温まで冷却した後、その混合物を濾過し、そして１Ｎ ＮａＯＨ水溶液で抽出した。その水層を１Ｎ ＨＣｌ水溶液で酸性化し、そしてＥｔＯＡｃで抽出した。その有機層をＮａ_２ＳＯ_４で乾燥し、そして乾燥状態まで濃縮した。その残留物をＲＰ ＨＰＬＣで精製して、淡黄色固形物として、１８．５ｍｇの［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−ホスホン酸モノフェニルエステルおよびまた、淡黄色固形物として、４．１ｍｇの［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−ホスホン酸ジフェニルエステル（少ない方の生成物）を得た。主要生成物： ¹H NMR (300 MHz, CD₃OD) δ1.82 (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; ³¹P (121.4MHz, CD₃OD) δ 17.3 ppm; MS (m/z) 449.0 [M+H]⁺, 471.2[M+Na]⁺. 少ない方の生成物: ¹H NMR (300 MHz, CD₃OD) δ1.82 (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; ³¹P (121.4 MHz, CD₃OD) δ 16.3 ppm; MS (m/z)525.2 [M+H]⁺, 547.2 [M+Na]⁺.
（実施例３００）
本発明の代表的な化合物は、以下で図示するように、調製できる。

([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) at 0 ° C. in dicyclohexylcarbodiimide (107 mg, 0.52 mmol) and DMAP (8 mg) in DMF (0.6 mL). 0.065 mmol) was added slowly. The reaction was warmed to room temperature and heated to 140 ° C. for 10 hours. After cooling to room temperature, the mixture was filtered and extracted with 1N aqueous NaOH. The aqueous layer was acidified with 1N aqueous HCl and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by RP HPLC to give 18.5 mg of [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-] as a pale yellow solid. 5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid monophenyl ester and also as a pale yellow solid, 4.1 mg of [4- (4-hydroxy-6-methoxy-7- Methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-enyloxymethyl] -phosphonic acid diphenyl ester (the less product) was obtained. Main products: ¹ H NMR (300 MHz, CD ₃ OD) δ1.82 (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 (121.4MHz, CD ₃ OD) δ 17.3 ppm; MS (m / z) 449.0 [M + H] ⁺ , 471.2 [M + Na] ⁺ . Object: ¹ H NMR (300 MHz, CD ₃ OD) δ1.82 (s, 3H), 2.15 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.77 (s, 3H), 3.98- 4.06 (m, 4H), 5.25 (s, 2H), 5.50- 5.61 (m, 1H), 7.10- 7.25 (m, 6H), 7.30-7.41 (m, 4H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 16.3 ppm; MS (m / z) 525.2 [M + H] ⁺ , 547.2 [M + Na] ⁺ .
(Example 300)
Representative compounds of the present invention can be prepared as illustrated below.

（２−｛［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−フェノキシ−ホスフィノイルオキシ｝−プロピオン酸エチルエステル）
［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−ホスホン酸モノフェニルエステル（１８．５ｍｇ、０．０４０ｍｍｏｌ）および（Ｓ）−（−）−乳酸エチル（４７μＬ、０．４００ｍｍｏｌ）のピリジン（０．５ｍＬ）溶液に、ＰｙＢＯＰ（３２ｍｇ、０．０６０ｍｍｏｌ）を加えた。この溶液を、室温で、１時間攪拌し、そのとき、ＰｙＢＯＰの追加部分（２１ｍｇ、０．０４０ｍｍｏｌ）を加えた。この溶液をさらに１時間攪拌し、そして濃縮した。その残留物をＨＰＬＣで精製して、透明オイルとして、７．５ｍｇの所望生成物を得た。¹H NMR (300 MHz, CD₃OD) δ1.22 および 1.25 (t, 3H, J= 7 Hz), 1.42 および 1.50 (d, 3H, J= 7 Hz),1.82 および 1.83 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J= 7 Hz), 3.78 (s,3H), 3.89 (d, 1H, J= 8 Hz), 3.93- 4.02 (m, 3H), 4.10- 4.22 (m, 2H),4.94- 5.08 (m, 1H), 5.25 (s, 2H), 5.50-5.60 (m, 1H), 7.15- 7.27 (m, 3H), 7.33-7.41 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 18.9, 20.3 ppm(リンにおけるジアステレオマー); MS (m/z) 549.2 [M+H]⁺, 571.3 [M+Na]⁺.
（実施例３０１）
本発明の代表的な化合物は、以下で図示するように、調製できる。

(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 μL, 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 time an additional portion of 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) δ1.22 and 1.25 (t, 3H, J = 7 Hz), 1.42 and 1.50 (d, 3H, J = 7 Hz), 1.82 and 1.83 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.78 (s, 3H), 3.89 (d, 1H, J = 8 Hz), 3.93- 4.02 (m, 3H), 4.10- 4.22 (m, 2H), 4.94- 5.08 (m, 1H), 5.25 (s, 2H), 5.50-5.60 (m, 1H), 7.15- 7.27 (m, 3H), 7.33-7.41 (m, 2H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 18.9, 20.3 ppm (diastereomers in phosphorus); MS (m / z) 549.2 [M + H] ⁺ , 571.3 [M + Na] ⁺ .
(Example 301)
Representative compounds of the present invention can be prepared as illustrated below.

（２−｛［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−フェノキシ−ホスフィノイルアミノ｝−プロピオン酸エチルエステル）
［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−ホスホン酸モノフェニルエステル（２０ｍｇ、０．０４５ｍｍｏｌ）およびＬ−アラニンエチルエステル塩酸塩（６８．５ｍｇ、０．４５ｍｍｏｌ）のピリジン（１．０ｍＬ）溶液に、ＰｙＢＯＰ（７０ｍｇ、０．１４ｍｍｏｌ）を加えた。一晩攪拌した後、この混合物を濃縮し、その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、無色ゲルとして、３．６ｍｇの生成物を得た。¹H NMR (300 MHz, CD₃OD) δ1.17-1.3 (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; ³¹P (121.4 MHz, CD₃OD) δ 24.1, 25.0 ppm(リンにおけるジアステレオマー); MS (m/z) 546.2 [M-H]⁺.
（実施例３０２）
本発明の代表的な化合物は、以下で図示するように、調製できる。

(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 (this was a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA, using a C18 column). Purification gave 3.6 mg of product as a colorless gel. ¹ H NMR (300 MHz, CD ₃ OD) δ1.17-1.3 (m, 6H), 1.8-1.9 (m, 3H), 2.16 (s, 3H), 3.17 (m, 1H), 3.47 (d, 2H ), 3.72-3.8 (m, 5H), 3.92-4.2 (m, 4H), 5.25 (s, 2H), 5.54 (m, 1H), 7.18 (m, 3H), 7.33 (m, 2H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 24.1, 25.0 ppm (diastereomers in phosphorus); MS (m / z) 546.2 [MH] ⁺ .
(Example 302)
Representative compounds of the present invention can be prepared as illustrated below.

（［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−ホスホン酸モノメチルエステル）
［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−ホスホン酸ジフェニルエステル（５３ｍｇ、０．１ｍｍｏｌ）のメタノール（０．５ｍＬ）溶液に、１Ｎ ＮａＯＨ水溶液（３００μＬ）を加えた。一晩攪拌した後、この混合物を濃縮し、その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、ホスホン酸モノフェニルエステル（７ｍｇ）およびホスホン酸ジメチルエステル（１４．５ｍｇ）と共に、無色ゲルとして、５ｍｇの生成物を得た。¹H NMR (300 MHz, CD₃OD) δ1.84 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J= 7 Hz), 3.6 (d, 2H, J=12 Hz), 3.75 (d, 3H, J= 11 Hz), 3.79 (s, 3H), 3.94 (s, 2H), 5.26 (s,2H), 5.53 (t, 1H, J= 7 Hz) ppm; ³¹P (121.4 MHz, CD₃OD)δ 21.5 ppm; MS (m/z) 385.2 [M-H]⁺, 387.1 [M+H]⁺.
（実施例３０３）
本発明の代表的な化合物は、以下で図示するように、調製できる。

([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] -diphenyl phosphonate To a solution of ester (53 mg, 0.1 mmol) in methanol (0.5 mL) was added 1N aqueous NaOH (300 μL). After stirring overnight, the mixture was concentrated and the residue was purified by RP HPLC (this was a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA, using a C18 column). Purification gave 5 mg of product as a colorless gel with phosphonic acid monophenyl ester (7 mg) and phosphonic acid dimethyl ester (14.5 mg). ¹ H NMR (300 MHz, CD ₃ OD) δ1.84 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.6 (d, 2H, J = 12 Hz) , 3.75 (d, 3H, J = 11 Hz), 3.79 (s, 3H), 3.94 (s, 2H), 5.26 (s, 2H), 5.53 (t, 1H, J = 7 Hz) ppm; ³¹ P ( 121.4 MHz, CD ₃ OD) δ 21.5 ppm; MS (m / z) 385.2 [MH] ⁺ , 387.1 [M + H] ⁺ .
Example 303
Representative compounds of the present invention can be prepared as illustrated below.

（（２−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−エチル）−ホスホン酸ジエチルエステル）
４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エナール（８４ｍｇ、０．２２ｍｍｏｌ）、（２−アミノ−エチル）−ホスホン酸ジエチルエステルオキサレート（９１ｍｇ、０．３３ｍｍｏｌ）およびトリアセトキシホウ水素化ナトリウム（９３ｍｇ、０．４４ｍｍｏｌ）のＤＭＦ（１．５ｍＬ）溶液に、室温で、酢酸（６０μＬ、１．０ｍｍｏｌ）を加えた。この溶液を２日間攪拌し、そのとき、飽和炭酸水素ナトリウム水溶液およびＥｔＯＡｃを加えることにより、クエンチした。その有機層を分離し、そして減圧下にて濃縮した。その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、オイルとして、１１５ｍｇ（９６％）の生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.04 (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= 7Hz), 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; ³¹P(121.4 MHz, CDCl₃) δ 27.8 ppm; MS (m/z) 542.3 [M+H]⁺,564.2 [M+Na]⁺.

((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) To the solution was added acetic acid (60 μL, 1.0 mmol) at room temperature. The solution was stirred for 2 days when it was quenched by the addition of saturated aqueous sodium bicarbonate and EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) and 115 mg (96%) as an oil. Product was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.04 (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 = 7Hz), 3.54 (s, 2H), 3.78 (s, 3H), 4.14 (pent , 4H, J = 7 Hz), 4.30- 4.37 (m, 2H), 5.13 (s, 2H), 5.65 (t, 1H, J = 7 Hz), 6.23 (br s, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 27.8 ppm; MS (m / z) 542.3 [M + H] ⁺ , 564.2 [M + Na] ⁺ .

（｛２−［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルアミノ］−エチル｝−ホスホン酸）
（２−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−エチル）−ホスホン酸ジエチルエステル（３０ｍｇ、０．０５５ｍｍｏｌ）、ＴＭＳＢｒ（７２μＬ、０．５５ｍｍｏｌ）および２，６−ルチジン（６４μＬ、０．５５ｍｍｏｌ）の溶液を、ＣＨ_２Ｃｌ_２（１ｍＬ）およびＤＭＦ（０．５ｍＬ）中にて、室温で、１時間攪拌した。その反応混合物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、白色固形物として、７．８ｍｇの生成物を得た。¹H NMR (300 MHz, CD₃OD) δ1.96 (s, 3H), 1.95- 2.07 (m, 2H), 2.16 (s, 3H), 3.10-3.24 (m, 2H), 3.51 (d, 2H,J= 7 Hz), 3.57 (s, 2H), 3.81 (s, 3H), 5.25 (s, 2H), 5.73 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CD₃OD) δ 20.2 ppm; ¹⁹FNMR (282.6 MHz, CD₃OD) δ -74.0 ppm; MS (m/z) 386.3 [M+H]⁺.
（実施例３０４）
本発明の代表的な化合物は、以下で図示するように、調製できる。

({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-buta -2-enylamino} -ethyl) -phosphonic acid diethyl ester (30 mg, 0.055 mmol), TMSBr (72 μL, 0.55 mmol) and 2,6-lutidine (64 μL, 0.55 mmol) were added to CH ₂ Cl _2. (1 mL) and DMF (0.5 mL) were stirred at room temperature for 1 hour. The reaction mixture was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) to give 7.8 mg as a white solid. Product was obtained. ¹ H NMR (300 MHz, CD ₃ OD) δ1.96 (s, 3H), 1.95- 2.07 (m, 2H), 2.16 (s, 3H), 3.10-3.24 (m, 2H), 3.51 (d, 2H , J = 7 Hz), 3.57 (s, 2H), 3.81 (s, 3H), 5.25 (s, 2H), 5.73 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CD ₃ OD ) δ 20.2 ppm; ¹⁹ FNMR (282.6 MHz, CD ₃ OD) δ -74.0 ppm; MS (m / z) 386.3 [M + H] ⁺ .
(Example 304)
Representative compounds of the present invention can be prepared as illustrated below.

（［２−（メタンスルホニル−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−アミノ）−エチル］−ホスホン酸ジエチルエステル）
（２−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−エチル）−ホスホン酸ジエチルエステル（４５ｍｇ、０．０９２ｍｍｏｌ）のＣＨ_２Ｃｌ_２（０．５ｍＬ）溶液を、塩化メタンスルホニル（２１μＬ、０．２８ｍｍｏｌ）およびピリジン（４５μＬ、０．５５ｍｍｏｌ）と共に、室温で、一晩攪拌した。水を２滴加えることにより、この反応をクエンチした。その反応混合物を濃縮し、そしてＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、透明ゲルとして、３６ｍｇの生成物（６３％）を得た。¹H NMR (300 MHz, CDCl₃) δ0.05 (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= 7Hz), 4.30- 4.37 (m, 2H), 5.13 (s, 2H), 5.45 (t, 1H, J= 7 Hz) ppm; ³¹P(121.4 MHz, CD₃Cl) δ 27.5 ppm; MS (m/z) 642.2 [M+Na]⁺.

([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-buta 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 μL, 0.28 mmol) and pyridine (45 μL,. 55 mmol) at room temperature overnight. The reaction was quenched by adding 2 drops of water. The reaction mixture was concentrated and purified by RP HPLC (which was a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA, using a C18 column) as a clear gel, 36 mg of product (63%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.05 (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 = 7Hz), 4.30- 4.37 (m, 2H), 5.13 (s, 2H), 5.45 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz , CD ₃ Cl) δ 27.5 ppm; MS (m / z) 642.2 [M + Na] ⁺ .

（（２−｛［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−メタンスルホニル−アミノ｝−エチル）−ホスホン酸）
［２−（メタンスルホニル−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−アミノ）−エチル］−ホスホン酸ジエチルエステル（１８ｍｇ、０．０２９ｍｍｏｌ）のアセトニトリル（０．５ｍＬ）溶液を、ＴＭＳＢｒ（３８μＬ、０．２９ｍｍｏｌ）および２，６−ルチジン（３４μＬ、０．２９ｍｍｏｌ）と共に、室温で、２時間攪拌した。ＥｔＯＡｃおよび１Ｎ ＨＣｌ水溶液を加えることにより、この反応物をワークアップした。その有機層をブラインで洗浄し、真空中で溶媒を除去した。その残留物を１０％ＴＦＡ−ＣＨ_２Ｃｌ_２溶液に１０分間懸濁した後、乾燥して、白色固形物として、９．９ｍｇの所望生成物（７３％）を得た。¹H NMR (300 MHz, DMSO-d6) δ1.76 (s, 3H), 1.76- 1.88 (m, 2H), 2.10 (s, 3H), 2.87 (s, 3H), 3.24- 3.35 (m,2H), 3.39 (d, 2H, J= 7 Hz), 3.65 (s, 2H), 3.75 (s, 3H), 5.22 (s, 2H),5.41- 5.48 (m, 1H) ppm; ³¹P (121.4 MHz, DMSO-d6) δ 21.4 ppm;MS (m/z) 464.1 [M+H]⁺.
（実施例３０５）
本発明の代表的な化合物は、以下で図示するように、調製できる。

((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 μL, 0.29 mmol) and 2,6- Stir with lutidine (34 μL, 0.29 mmol) for 2 hours at room temperature. The reaction was worked up by adding EtOAc and 1N aqueous HCl. The organic layer was washed with brine and the solvent was removed in vacuo. The residue was suspended in 10% TFA-CH ₂ Cl ₂ solution for 10 minutes and dried to give 9.9 mg of the desired product (73%) as a white solid. ¹ H NMR (300 MHz, DMSO-d6) δ1.76 (s, 3H), 1.76- 1.88 (m, 2H), 2.10 (s, 3H), 2.87 (s, 3H), 3.24- 3.35 (m, 2H ), 3.39 (d, 2H, J = 7 Hz), 3.65 (s, 2H), 3.75 (s, 3H), 5.22 (s, 2H), 5.41-5.48 (m, 1H) ppm; ³¹ P (121.4 MHz , DMSO-d6) δ 21.4 ppm; MS (m / z) 464.1 [M + H] ⁺ .
(Example 305)
Representative compounds of the present invention can be prepared as illustrated below.

（［２−（アセチル−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−アミノ）−エチル］−ホスホン酸ジエチルエステル）
（２−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−エチル）−ホスホン酸ジエチルエステル（３２ｍｇ、０．０５９ｍｍｏｌ）の酢酸（０．５ｍＬ）溶液に、無水酢酸（０．５ｍＬ）を加えた。この溶液を、室温で、９０分間攪拌し、そのとき、水２滴を加えることにより、クエンチした。この溶液を真空中で乾燥し、その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、透明ゲルとして、２８ｍｇの生成物（８１％）を得た。次いで、この化合物のＮＭＲデータにより、７０：３０の比で、２種の回転異性体が明らかとなる。¹H NMR (300 MHz, CDCl₃) δ0.05 (s, 9H), 1.17- 1.27 (m, 2H), 1.30 および 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 および 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; ³¹P (121.4 MHz, CDCl₃) δ 27.5 および 28.9 ppm; MS (m/z)584.1 [M+H]⁺, 606.2 [M+Na]⁺.

([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-buta 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 time it was quenched by adding 2 drops of water. The solution was dried in vacuo and the residue was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA). 28 mg of product (81%) was obtained as a clear gel. The NMR data of this compound then reveals two rotamers at a 70:30 ratio. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.05 (s, 9H), 1.17- 1.27 (m, 2H), 1.30 and 1.31 (t, 6H, J = 7 Hz), 1.70-1.79 (m, 2H) , 1.76 (s, 3H), 2.00 (s, 3H), 2.18 (s, 3H), 3.40-3.52 (m, 2H), 3.46 (d, 2H, J = 7 Hz), 3.77 (s, 3H), 3.79 and 3.93 (s, 3H), 4.07 (pent, 4H, J = 7 Hz), 4.27-4.35 (m, 2H), 5.13 (s, 2H), 5.22- 5.30 (m, 1H) ppm; ³¹ P ( 121.4 MHz, CDCl ₃ ) δ 27.5 and 28.9 ppm; MS (m / z) 584.1 [M + H] ⁺ , 606.2 [M + Na] ⁺ .

（（２−｛アセチル−［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−アミノ｝−エチル）−ホスホン酸）
［２−（アセチル−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−アミノ）−エチル］−ホスホン酸ジエチルエステル（１４ｍｇ、０．０２４ｍｍｏｌ）のアセトニトリル（０．５ｍＬ）溶液に、ＴＭＳＢｒ（３１μＬ、０．２４ｍｍｏｌ）および２，６−ルチジン（２８μＬ、０．２４ｍｍｏｌ）を加えた。この溶液を、室温で、１時間攪拌した。メタノールおよび１Ｎ ＨＣｌ水溶液を加えることより、この反応をクエンチした。その生成物をＥｔＯＡｃで抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４で乾燥し、そして真空中で濃縮した。この生成物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、白色固形物として、５．４ｍｇの生成物（５３％）を得た。この化合物のＮＭＲデータにより、２種の回転異性体が明らかとなる。¹H NMR (300 MHz, CDCl₃) δ1.67 および 1.73 (s, 3H), 1.85- 2.12 (m, 5H), 2.13 (s, 3H), 3.30-3.61 (m, 4H),3.75 (s, 3H), 3.76 (br s, 2H), 5.17 (s, 2H), 5.31 (br s, 1H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 27.5 および 28.8 ppm; MS (m/z) 428.2 [M+H]⁺,450.2 [M+Na]⁺.
（実施例３０６）
本発明の代表的な化合物は、以下で図示するように、調製できる。

((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 μL, 0.24 mmol) and 2,6-lutidine. (28 μL, 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 aqueous HCl. The product was extracted with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The product was purified by RP HPLC (which used a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) to give 5.4 mg as a white solid. Of 53% was obtained. The NMR data of this compound reveals two rotamers. ¹ H NMR (300 MHz, CDCl ₃ ) δ1.67 and 1.73 (s, 3H), 1.85- 2.12 (m, 5H), 2.13 (s, 3H), 3.30-3.61 (m, 4H), 3.75 (s, 3H), 3.76 (br s, 2H), 5.17 (s, 2H), 5.31 (br s, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 27.5 and 28.8 ppm; MS (m / z) 428.2 [ M + H] ⁺ , 450.2 [M + Na] ⁺ .
(Example 306)
Representative compounds of the present invention can be prepared as illustrated below.

（［２−（ベンジル−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−アミノ）−エチル］−ホスホン酸ジエチルエステル）
（２−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−エチル）−ホスホン酸ジエチルエステル（３０ｍｇ、０．０５５ｍｍｏｌ）、ベンズアルデヒド（５．６μＬ、０．０５５ｍｍｏｌ）およびトリアセトキシホウ水素化ナトリウム（２３ｍｇ、０．１１ｍｍｏｌ）の溶液を、酢酸（１５．７μＬ、０．２８ｍｍｏｌ）と共に、ＤＭＦ（０．５ｍＬ）中にて、室温で、一晩攪拌した。この反応を１０％Ｎａ_２ＣＯ_３水溶液でクエンチし、その生成物をＥｔＯＡｃで抽出した。その有機層を乾燥し、そして減圧下にて濃縮した。この生成物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、透明ゲルとして、１５ｍｇの生成物（４３％）を得た。¹H NMR (300 MHz, CDCl₃) δ0.02 (s, 9H), 1.18- 1.25 (m, 2H), 1.24 (t, 6H, J= 7 Hz), 1.86 (s, 3H),1.88- 2.02 (m, 2H), 2.16 (s, 3H), 2.65- 2.74 (m, 2H), 3.93 (s, 2H), 3.46 (br d,4H, J= 7 Hz), 3.76 (s, 3H), 4.00 (pent, 4H, J= 7 Hz), 4.25- 4.34(m, 2H), 5.11 (s, 2H), 5.34- 5.43 (m, 1H), 7.18- 7.33 (m, 5H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 30.9 ppm; MS (m/z) 632.4 [M+H]⁺,654.3 [M+Na]⁺.

([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-buta 2-enylamino} -ethyl) -phosphonic acid diethyl ester (30 mg, 0.055 mmol), benzaldehyde (5.6 μL, 0.055 mmol) and sodium triacetoxyborohydride (23 mg, 0.11 mmol) (15.7 μL, 0.28 mmol) and stirred in DMF (0.5 mL) at room temperature overnight. The reaction was quenched with 10% aqueous Na ₂ CO ₃ and the product was extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure. The product was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) to give 15 mg of product as a clear gel. (43%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.02 (s, 9H), 1.18- 1.25 (m, 2H), 1.24 (t, 6H, J = 7 Hz), 1.86 (s, 3H), 1.88- 2.02 (m, 2H), 2.16 (s, 3H), 2.65- 2.74 (m, 2H), 3.93 (s, 2H), 3.46 (br d, 4H, J = 7 Hz), 3.76 (s, 3H), 4.00 (pent, 4H, J = 7 Hz), 4.25- 4.34 (m, 2H), 5.11 (s, 2H), 5.34- 5.43 (m, 1H), 7.18-7.33 (m, 5H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 30.9 ppm; MS (m / z) 632.4 [M + H] ⁺ , 654.3 [M + Na] ⁺ .

（（２−｛ベンジル−［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−アミノ｝−エチル）−ホスホン酸）
（２−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−エチル）−ホスホン酸ジエチルエステル（１５ｍｇ、０．０２４ｍｍｏｌ）のアセトニトリル（０．５ｍＬ）溶液を、ＴＭＳＢｒ（３１μＬ、０．２４ｍｍｏｌ）および２，６−ルチジン（２８μＬ、０．２４ｍｍｏｌ）で処理した。この溶液を、室温で、１時間攪拌し、そのとき、メタノールでクエンチした。減圧下にて溶媒を除去し、その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、白色固形物として、１１ｍｇの生成物（９３％）を得た。¹H NMR (300 MHz, CD₃OD) δ1.89 (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; ³¹P (121.4 MHz, CDCl₃) δ 20.1ppm; MS (m/z) 476.3 [M+H]⁺, 498.3 [M+Na]⁺.
（実施例３０７）
本発明の代表的な化合物は、以下で図示するように、調製できる。

((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-buta A solution of 2-enylamino} -ethyl) -phosphonic acid diethyl ester (15 mg, 0.024 mmol) in acetonitrile (0.5 mL) was added TMSBr (31 μL, 0.24 mmol) and 2,6-lutidine (28 μL, 0.24 mmol). ). The solution was stirred at room temperature for 1 hour when it was quenched with methanol. The solvent was removed under reduced pressure and the residue was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA). 11 mg of product (93%) was obtained as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ1.89 (s, 3H), 2.03- 2.15 (m, 2H), 2.14 (s, 3H), 3.30-3.47 (m, 2H), 3.50 (br s, 2H), 3.62 (br s, 2H), 3.79 (s, 3H), 4.28 (s, 2H), 5.23 (s, 2H), 5.76 (br s, 1H), 7.46 (br s, 5H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 20.1ppm; MS (m / z) 476.3 [M + H] ⁺ , 498.3 [M + Na] ⁺ .
(Example 307)
Representative compounds of the present invention can be prepared as illustrated below.

（［２−（ホルミル−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−アミノ）−エチル］−ホスホン酸ジエチルエステル）
（２−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−エチル）−ホスホン酸ジエチルエステル（７４ｍｇ、０．１４ｍｍｏｌ）のギ酸（１ｍＬ）溶液に、無水ギ酸（１ｍＬ）を加え、この溶液を、室温で、１時間攪拌した。この反応混合物を濃縮し、その粗生成物を次の工程に進めた。この化合物のＮＭＲデータにより、７０：３０の比で、２種の回転異性体が明らかとなる。¹H NMR (300 MHz, CDCl₃) δ0.05 (s, 9H), 1.18- 1.28 (m, 2H), 1.28 および 1.30 (t, 6H, J= 7 Hz), 1.74(s, 3H), 1.84- 2.08 (m, 2H), 2.19 (s, 3H), 3.34- 3.45 (m, 2H), 3.47 (d, 2H, J=7 Hz), 3.72 および 3.87 (s, 2H), 3.78 および 3.79 (s, 3H), 4.06 および 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 および 8.19 (s,1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 27.5 および 28.1 ppm; MS (m/z)570.1 [M+H]⁺, 592.2 [M+Na]⁺.

([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-buta To a solution of 2-enylamino} -ethyl) -phosphonic acid diethyl ester (74 mg, 0.14 mmol) in formic acid (1 mL) was added anhydrous formic acid (1 mL), and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the crude product was carried on to the next step. The NMR data of this compound reveals two rotamers at a 70:30 ratio. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.05 (s, 9H), 1.18- 1.28 (m, 2H), 1.28 and 1.30 (t, 6H, J = 7 Hz), 1.74 (s, 3H), 1.84 -2.08 (m, 2H), 2.19 (s, 3H), 3.34- 3.45 (m, 2H), 3.47 (d, 2H, J = 7 Hz), 3.72 and 3.87 (s, 2H), 3.78 and 3.79 (s , 3H), 4.06 and 4.07 (pent, 4H, J = 7 Hz), 4.26- 4.37 (m, 2H), 5.13 (s, 2H), 5.30-5.46 (m, 1H), 8.03 and 8.19 (s, 1H ) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 27.5 and 28.1 ppm; MS (m / z) 570.1 [M + H] ⁺ , 592.2 [M + Na] ⁺ .

（（２−｛ホルミル−［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−アミノ｝−エチル）−ホスホン酸）
粗［２−（ホルミル−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−アミノ）−エチル］−ホスホン酸ジエチルエステル（７８ｍｇ、０．１４ｍｍｏｌ）のアセトニトリル（１ｍＬ）溶液に、ＴＭＳＢｒ（１７７μＬ、１．４ｍｍｏｌ）および２，６−ルチジン（１６３μＬ、１．４ｍｍｏｌ）を加えた。この溶液を、室温で、１時間攪拌し、そのとき、メタノールおよび１Ｎ ＨＣｌ水溶液を加えることにより、クエンチした。その生成物をＥｔＯＡｃで抽出し、そしてＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、白色固形物として、２９ｍｇの生成物を得た。この化合物のＮＭＲデータにより、約７０：３０の比で、２種の回転異性体が明らかとなる。¹H NMR (300 MHz, CD₃OD) δ1.62 および 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 および 3.91 (s, 2H), 5.22 (s, 2H), 5.39- 5.52 (m, 1H), 8.03 および8.18 (s, 1H) ppm; MS (m/z) 414.2 [M+H]⁺, 436.2 [M+Na]⁺.
（実施例３０８）
本発明の代表的な化合物は、以下で図示するように、調製できる。

((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 μL, 1.4 mmol) and 2,6-lutidine ( 163 μL, 1.4 mmol) was added. The solution was stirred at room temperature for 1 hour, at which time it was quenched by the addition of methanol and 1N aqueous HCl. The product was extracted with EtOAc and purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) to give a white solid As a product, 29 mg of product was obtained. NMR data for this compound reveals two rotamers in a ratio of about 70:30. ¹ H NMR (300 MHz, CD ₃ OD) δ1.62 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 308)
Representative compounds of the present invention can be prepared as illustrated below.

（（｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−メチル）−ホスホン酸ジエチルエステル）
４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エナール（５００ｍｇ、１．３３ｍｍｏｌ）、（２−アミノメチル）ホスホン酸ジエチルエステルオキサレート（３７６ｍｇ、１．４６ｍｍｏｌ）、トリアセトキシホウ水素化ナトリウム（５６３ｍｇ、２．６６ｍｍｏｌ）のＤＭＦ（１０ｍＬ）溶液に、室温で、酢酸（３８０μＬ、６．６５ｍｍｏｌ）を加えた。この溶液を一晩攪拌し、そのとき、炭酸ナトリウム飽和水溶液およびＥｔＯＡｃを加えることにより、クエンチした。その有機層を分離し、そして減圧下にて濃縮した。その残留物をシリカゲルクロマトグラフィーで精製して、オイルとして、５００ｍｇ（７１％）の生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.00 (s, 9H), 1.13- 1.23 (m, 2H), 1.25 および 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 および 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; ³¹P(121.4 MHz, CDCl₃) δ 26.5 ppm; MS (m/z) 528.1 [M+H]⁺,550.2 [M+Na]⁺.

(({{4- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-buta 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 μL, 6.65 mmol) was added. The solution was stirred overnight, at which time it was quenched by the addition of saturated aqueous sodium carbonate and EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 500 mg (71%) of product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.00 (s, 9H), 1.13- 1.23 (m, 2H), 1.25 and 1.27 (t, 6H, J = 7 Hz), 1.65-1.75 (m, 2H) , 1.77 (s, 3H), 2.13 (s, 3H), 2.80 (s, 1H), 3.14 (s, 2H), 3.41 (d, 2H, J = 7 Hz), 3.73 (s, 3H), 4.08 and 4.09 (pent, 4H, J = 7 Hz), 4.20- 4.30 (m, 2H), 5.08 (s, 2H), 5.30 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 26.5 ppm; MS (m / z) 528.1 [M + H] ⁺ , 550.2 [M + Na] ⁺ .

（｛［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルアミノ］−メチル｝−ホスホン酸）
（｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−メチル）−ホスホン酸ジエチルエステル（２０ｍｇ、０．０３８ｍｍｏｌ）のＤＭＦ（０．５ｍＬ）溶液に、ＴＭＳＢｒ（４９μＬ、０．３８ｍｍｏｌ）および２，６−ルチジン（４４μＬ、０．３８ｍｍｏｌ）を加えた。この溶液を、室温で、１時間攪拌し、そのとき、メタノールを加えることにより、クエンチした。その生成物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、白色固形物として、５．６ｍｇの生成物を得た。¹H NMR (300 MHz, CD₃OD およびCDCl₃) δ 1.93 (s, 3H), 2.13 (s, 3H), 2.94 (br d, 2H, J= 11Hz), 3.42-3.53 (m, 2H), 3.60 (s, 2H), 3.78 (s, 3H), 5.22 (s, 2H), 5.71 (br s,1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 8.5 ppm; MS (m/z)372.2 [M+H]⁺, 743.2 [2M+H]⁺.
（実施例３０９）
本発明の代表的な化合物は、以下で図示するように、調製できる。

({[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 -Ethylamino} -methyl) -phosphonic acid diethyl ester (20 mg, 0.038 mmol) in DMF (0.5 mL) with TMSBr (49 μL, 0.38 mmol) and 2,6-lutidine (44 μL, 0.38 mmol). added. The solution was stirred at room temperature for 1 hour when it was quenched by adding methanol. The product was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) to give 5.6 mg as a white solid. Product was obtained. ¹ H NMR (300 MHz, CD ₃ OD and CDCl ₃ ) δ 1.93 (s, 3H), 2.13 (s, 3H), 2.94 (br d, 2H, J = 11Hz), 3.42-3.53 (m, 2H), 3.60 (s, 2H), 3.78 (s, 3H), 5.22 (s, 2H), 5.71 (br s, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 8.5 ppm; MS (m / z) 372.2 [M + H] ⁺ , 743.2 [2M + H] ⁺ .
(Example 309)
Representative compounds of the present invention can be prepared as illustrated below.

（２−（｛２−［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルアミノ］−エチル｝−フェノキシ−ホスフィノイルオキシ）−プロピオン酸エチルエステル）
４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エナール（１８８ｍｇ、０．５ｍｍｏｌ）の溶液を、ＣＨ_２Ｃｌ_２（３ｍＬ）中の２−［（２−アミノエチル）フェノキシ−ホスフィノイルオキシ］−プロピオン酸エチルエステル酢酸塩（３１５．８ｍｇ、０．７５ｍｍｏｌ）と共に、室温で、２時間攪拌した。この溶液にトリアセトキシホウ水素化ナトリウム（１５９ｍｇ、０．７５ｍｍｏｌ）を加え、その反応を１時間進行させた。ＮａＨＣＯ_３飽和水溶液を加えることにより、この反応をクエンチし、その生成物をＥｔＯＡｃで抽出した。その有機層を減圧下にて除去し、その残留物を、１時間にわたって、１０％ＴＦＡ／ＣＨ_２Ｃｌ_２に再懸濁した。この反応混合物を濃縮し、その生成物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、白色固形物として、１９８ｍｇの生成物を得た。この化合物のＮＭＲデータにより、約４５：５５の比で、リンにおける２種のジアステレオマーが明らかである。¹H NMR (300 MHz, CD₃OD) δ1.23 および 1.24 (t, 3H, J= 7 Hz), 1.38 および 1.52 (d, 3H, J= 7 Hz),1.97 および 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; ³¹P (121.4 MHz, CD₃OD) δ22.6, 24.3 ppm; MS (m/z) 561.9 [M+H]⁺.
（実施例３１０）
本発明の代表的な化合物は、以下で図示するように、調製できる。

(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 A solution of (188 mg, 0.5 mmol) was added 2-[(2-aminoethyl) phenoxy-phosphinoyloxy] -propionic acid ethyl ester acetate (315.8 mg, 0.3 mL) in CH ₂ Cl ₂ (3 mL). The mixture was stirred at room temperature for 2 hours. To this solution was added sodium triacetoxyborohydride (159 mg, 0.75 mmol) 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 layer was removed under reduced pressure and the residue was resuspended in 10% TFA / CH ₂ Cl ₂ for 1 hour. The reaction mixture is concentrated and the product is purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) 198 mg of product was obtained as a solid. The NMR data of this compound reveals two diastereomers in phosphorus at a ratio of about 45:55. ¹ H NMR (300 MHz, CD ₃ OD) δ1.23 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) δ22.6, 24.3 ppm; MS (m / z) 561.9 [M + H] ⁺ .
(Example 310)
Representative compounds of the present invention can be prepared as illustrated below.

（２−［ヒドロキシ−（２−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−エチル）−ホスフィノイルオキシ］−プロピオン酸エチルエステル）
４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エナール（３８ｍｇ、０．１ｍｍｏｌ）の溶液を、ＣＨ_２Ｃｌ_２（１ｍＬ）中の２−［（２−アミノエチル）−フェノキシ−ホスフィノイルオキシ］−プロピオン酸エチルエステル酢酸（６３ｍｇ、０．１５ｍｍｏｌ）と共に、室温で、２時間攪拌した。この溶液にトリアセトキシホウ水素化ナトリウム（３２ｍｇ、０．１５ｍｍｏｌ）を加え、その反応を１時間進行させた。ＮａＨＣＯ_３飽和水溶液を加えることにより、この反応をクエンチし、その生成物をＥｔＯＡｃで抽出した。その有機層を減圧下にて除去し、その残留物を、１時間にわたって、１０％ＴＦＡ／ＣＨ_２Ｃｌ_２に再懸濁した。この反応混合物を濃縮し、その生成物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、１５ｍｇの生成物（１５４−２）を得た。¹H NMR (300 MHz, CDCl₃) δ0.04 (s, 9H), 1.15- 1.24 (m, 2H), 1.26 (t, 3H, J= 7 Hz), 1.48 (d, 3H, J=7 Hz), 1.93 (s, 3H), 2.10- 2.25 (m, 2H), 2.18 (s, 3H), 3.10- 3.31 (m, 2H), 3.48(d, 2H, J= 7 Hz), 3.48- 3.61 (m, 2H), 3.77 (s, 3H), 4.04- 4.21 (m, 2H),4.29- 4.40 (m, 2H), 4.81- 4.92 (m, 1H), 5.13 (s, 2H), 5.64 (t, 1H, J= 7 Hz),8.70- 9.11 (m, 3H) ppm; 31P (121.4 MHz, CDCl3) δ 21.9 ppm; MS (m/z) 586.3[M+H]+, 1171.4 [2M+H]+.

(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 A solution of (38 mg, 0.1 mmol) was added 2-[(2-aminoethyl) -phenoxy-phosphinoyloxy] -propionic acid ethyl ester acetic acid (63 mg, 0.15 mmol) in CH ₂ Cl ₂ (1 mL). The mixture was stirred at room temperature for 2 hours. To this solution was added sodium triacetoxyborohydride (32 mg, 0.15 mmol) 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 layer was removed under reduced pressure and the residue was resuspended in 10% TFA / CH ₂ Cl ₂ for 1 hour. The reaction mixture was concentrated and the product was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) to give 15 mg Product (154-2) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.04 (s, 9H), 1.15- 1.24 (m, 2H), 1.26 (t, 3H, J = 7 Hz), 1.48 (d, 3H, J = 7 Hz ), 1.93 (s, 3H), 2.10- 2.25 (m, 2H), 2.18 (s, 3H), 3.10- 3.31 (m, 2H), 3.48 (d, 2H, J = 7 Hz), 3.48- 3.61 ( m, 2H), 3.77 (s, 3H), 4.04- 4.21 (m, 2H), 4.29- 4.40 (m, 2H), 4.81- 4.92 (m, 1H), 5.13 (s, 2H), 5.64 (t, 1H, J = 7 Hz), 8.70- 9.11 (m, 3H) ppm; 31P (121.4 MHz, CDCl3) δ 21.9 ppm; MS (m / z) 586.3 [M + H] +, 1171.4 [2M + H] + .

（２−（ヒドロキシ−｛２−［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルアミノ］−エチル｝−ホスフィノイルオキシ）−プロピオン酸）
２−［ヒドロキシ−（２−｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−エチル）−ホスフィノイルオキシ］−プロピオン酸エチルエステル（１５ｍｇ、０．０２６ｍｍｏｌ）の１０％ＴＦＡ−ＣＨ_２Ｃｌ_２（１ｍＬ）溶液を、室温で、１０分間攪拌した。溶媒を除去することにより、この反応物をワークアップした。その残留物をＴＨＦ（０．５ｍＬ）および水（０．４ｍＬ）に溶解し、そして１Ｎ ＮａＯＨ水溶液（０．１ｍＬ）を加えた。この溶液を、室温で、２０分間攪拌し、そのとき、１Ｎ ＨＣｌ水溶液で酸性化した。得られた溶液をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、白色固形物として、６．８ｍｇの生成物を得た。¹H NMR (300 MHz, CDCl₃) δ1.38 (d, 3H, J= 7 Hz), 1.91 (s, 3H), 2.13 (s, 3H), 2.12- 2.28 (m, 2H),3.12- 3.33 (m, 2H), 3.41 (d, 2H, J= 6 Hz), 3.56 (br s, 2H), 3.75 (s,3H), 4.71- 4.88 (m, 1H), 5.16 (s, 2H), 5.58- 5.71 (m, 1H), 7.88 (br s, 3H),8.60 (br s, 1H), 8.78 (br s, 1H) ppm; ³¹P (121.4 MHz, CDCl₃)δ 22.0 ppm; MS (m/z) 458.3 [M+H]⁺, 480.3 [M+Na]⁺.

(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) at room temperature for 10 Stir for minutes. The reaction was worked up 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 time it was acidified with 1N aqueous HCl. The resulting solution was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) as a white solid. 8 mg of product was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ1.38 (d, 3H, J = 7 Hz), 1.91 (s, 3H), 2.13 (s, 3H), 2.12- 2.28 (m, 2H), 3.12- 3.33 (m, 2H), 3.41 (d, 2H, J = 6 Hz), 3.56 (br s, 2H), 3.75 (s, 3H), 4.71- 4.88 (m, 1H), 5.16 (s, 2H), 5.58 -5.71 (m, 1H), 7.88 (br s, 3H), 8.60 (br s, 1H), 8.78 (br s, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 22.0 ppm; MS (m / z) 458.3 [M + H] ⁺ , 480.3 [M + Na] ⁺ .

（実施例３１１）
本発明の代表的な化合物は、以下で図示するように、調製できる。

(Example 311)
Representative compounds of the present invention can be prepared as illustrated below.

（｛１−シアノ−５−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−３−メチル−ペンタ−３−エニル｝−ホスホン酸ジエチルエステル）
ホスホン酸ジエチルシアノメチル（２４１ｍｇ、１．３８ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液に、ナトリウムビス（トリメチルシリル）アミド（１．０Ｍ、１．１３ｍＬ、１．１５ｍｍｏｌ）のＴＨＦ溶液を加えた。３０分間攪拌した後、この溶液を、６−（４−ブロモ−３−メチル−ブタ−２−エニル）−７−ヒドロキシ−５−メトキシ−４−メチル−３Ｈ−イソベンゾフラン−１−オン（１００ｍｇ、０．２３ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液に滴下した。得られた混合物を、室温で、１時間攪拌した後、塩化アンモニウム飽和水溶液を加えた。この反応混合物を酢酸エチルで抽出した。その有機層を硫酸ナトリウムで乾燥し、そして乾燥状態まで濃縮した。その残留物をシリカゲルクロマトグラフィーで精製して、１１０ｍｇ（９０％）の所望生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.04 (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; ³¹P (121.4 MHz, CDCl₃) δ 18.18 ppm; MS (m/z)560 [M+Na] ⁺.

({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 THF (1 mL) solution of diethyl cyanomethyl phosphonate (241 mg, 1.38 mmol) was added a THF solution of sodium bis (trimethylsilyl) amide (1.0 M, 1.13 mL, 1.15 mmol). After stirring for 30 minutes, the solution was dissolved in 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, and then a saturated aqueous ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel chromatography to give 110 mg (90%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.04 (s, 9H), 1.24 (dd, J = 7, 8 Hz, 2H), 1.36 (t, 6H), 1.86 (s, 3H), 2.17 (s , 3H), 2.43-2.57 (m, 2H), 3.04-3.17 (m, 1H), 3.47 (d, J = 7.2 Hz, 2H), 3.79 (s, 3H), 4.12-4.37 (m, 6H), 5.13 (s, 2H), 5.44 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 18.18 ppm; MS (m / z) 560 [M + Na] ⁺ .

（［１−シアノ−５−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−３−メチル−ペンタ−３−エニル］−ホスホン酸ジエチルエステル）
｛１−シアノ−５−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−３−メチル−ペンタ−３−エニル｝−ホスホン酸ジエチルエステル（２５ｍｇ、０．０４７ｍｍｏｌ）を１０％ＴＦＡ／ＣＨ_２Ｃｌ_２（５ｍＬ）の溶液に溶解し、そして室温で、２時間攪拌した。この反応混合物を減圧下にて乾燥し、その生成物をＲＰ−ＨＰＬＣで精製して、白色固形物として、１６ｍｇ（８０％）の所望生成物を得た。¹H NMR (300 MHz, CDCl₃) δ1.38 (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; 31P (121.4 MHz, CDCl3) δ 18.09 ppm; MS(m/z) 436 [M-H]-, 438 [M+H] +.
（実施例３１２）
本発明の代表的な化合物は、以下で図示するように、調製できる。

([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- Penta-3-enyl} -phosphonic acid diethyl ester (25 mg, 0.047 mmol) was dissolved in a solution of 10% TFA / CH ₂ Cl ₂ (5 mL) and stirred at room temperature for 2 hours. The reaction mixture was dried under reduced pressure and the product was purified by RP-HPLC to give 16 mg (80%) of the desired product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ1.38 (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; 31P (121.4 MHz, CDCl3) δ 18.09 ppm; MS (m / z) 436 [MH]-, 438 [M + H] +.
(Example 312)
Representative compounds of the present invention can be prepared as illustrated below.

（［１−シアノ−５−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−３−メチル−ペンタ−３−エニル］−ホスホン酸）
｛１−シアノ−５−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−３−メチル−ペンタ−３−エニル｝−ホスホン酸ジエチルエステル（３５ｍｇ、０．０６５ｍｍｏｌ）のアセトニトリル（２ｍＬ）溶液に、ＴＭＳＢｒ（１８０μＬ、１．３８ｍｍｏｌ）および２，６−ルチジン（１６０μＬ、１．３８ｍｍｏｌ）を加えた。この反応溶液を、室温で、１時間攪拌した後、ＭｅＯＨでクエンチした。この反応混合物を減圧下にて乾燥し、その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、白色固形物として、１５ｍｇ（６０％）の所望生成物を得た。¹H NMR (300 MHz, CD₃OD) δ1.86 (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;³¹P (121.4 MHz, CD₃OD) δ 15.28 ppm; MS (m/z) 380[M-H]^-, 382 [M+H] ⁺.
（実施例３１３）
本発明の代表的な化合物は、以下で図示するように、調製できる。

([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 penta-3-enyl} -phosphonic acid diethyl ester (35 mg, 0.065 mmol) in acetonitrile (2 mL) was added TMSBr (180 μL, 1.38 mmol) and 2,6-lutidine (160 μL, 1.38 mmol). . The reaction solution was stirred at room temperature for 1 hour and then quenched with MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC (which uses 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 as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ1.86 (s, 3H), 2.15 (s, 3H), 2.38-2.57 (m, 2H), 3.17-3.28 (m, 1H), 3.44 (d, J = 7.2 Hz, 2H), 3.80 (s, 3H), 5.25 (s, 2H), 5.47 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 15.28 ppm; MS ( m / z) 380 [MH] ^- , 382 [M + H] ⁺ .
(Example 313)
Representative compounds of the present invention can be prepared as illustrated below.

（｛１−シアノ−５−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−１，３−ジメチル−ペンタ−３−エニル｝−ホスホン酸ジエチルエステル）
｛１−シアノ−５−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−３−メチル−ペンタ−３−エニル｝−ホスホン酸ジエチルエステル（４５ｍｇ、０．０８４ｍｍｏｌ）のＴＨＦ（０．５ｍＬ）溶液に、ナトリウムビス（トリメチルシリル）アミド（１．０Ｍ、１．１３ｍＬ、１．１５ｍｍｏｌ）を加えた。２０分間攪拌した後、ヨードメタン（５２μＬ、０．８４ｍｍｏｌ）を滴下し、得られた混合物を、室温で、２時間攪拌した。この反応混合物を塩化アンモニウム飽和水溶液でクエンチし、そして酢酸エチルで抽出した。その有機層を硫酸ナトリウムで乾燥し、そして乾燥状態まで濃縮した。その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、６．６ｍｇ（２３％）の所望生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.00 (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; ³¹P(121.4 MHz, CDCl₃) δ 22.26 ppm; MS (m/z) 574 [M+Na] ⁺.

({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 penta-3-enyl} -phosphonic acid diethyl ester (45 mg, 0.084 mmol) in THF (0.5 mL). . After stirring for 20 minutes, iodomethane (52 μL, 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 layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) to yield 6.6 mg (23%) The desired product was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.00 (s, 9H), 1.16 (dd, J = 7, 8 Hz, 2H), 1.31 (t, 6H), 1.38 (d, 3H), 1.92 (s , 3H), 2.17 (s, 3H), 2.23 (m, 1H), 2.65 (m, 1H), 3.30-3.42 (m, 2H), 3.73 (s, 3H), 4.14-4.27 (m, 6H), 5.08 (s, 2H), 5.28 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 22.26 ppm; MS (m / z) 574 [M + Na] ⁺ .

（［１−シアノ−５−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−１，３−ジメチル−ペンタ−３−エニル］−ホスホン酸）
｛１−シアノ−５−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−１，３−ジメチル−ペンタ−３−エニル｝−ホスホン酸ジエチルエステル（１８ｍｇ、０．０４ｍｍｏｌ）のＤＭＦ（０．５ｍＬ）およびＤＣＭ（０．５ｍＬ）溶液に、ＴＭＳＢｒ（５１μＬ、０．４ｍｍｏｌ）および２，６−ルチジン（４６μＬ、０．４ｍｍｏｌ）を加えた。その反応混合物を、室温で、一晩攪拌した後、ＭｅＯＨでクエンチした。この反応混合物を減圧下にて乾燥し、その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、４．５ｍｇ（３３％）の所望生成物を得た。¹H NMR (300 MHz, CD₃OD) δ1.37 (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; ³¹P (121.4 MHz,CD₃OD) δ 21.47 ppm; MS (m/z) 422 [M-H]^-, 424 [M+H]⁺.

([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 μL, 0.4 mmol) and 2,6- Lutidine (46 μL, 0.4 mmol) was added. The reaction mixture was stirred at room temperature overnight and then quenched with MeOH. The reaction mixture is dried under reduced pressure and the residue is purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA). 4.5 mg (33%) of the desired product was obtained. ¹ H NMR (300 MHz, CD ₃ OD) δ1.37 (d, 3H), 1.87 (s, 3H), 2.13 (s, 3H), 2.26 (m, 1H), 2.64 (m, 1H), 3.39 ( m, 2H), 3.75 (s, 3H), 5.18 (s, 2H), 5.34 (m, 1H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 21.47 ppm; MS (m / z) 422 (MH ] ^- , 424 [M + H] ⁺ .

（実施例３１４）
本発明の代表的な化合物は、以下で図示するように、調製できる。

(Example 314)
Representative compounds of the present invention can be prepared as illustrated below.

（２−エチル−４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−ブタ−２−エナール）
［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−アセトアルデヒド（１．５ｇ、４．４６ｍｍｏｌ）のトルエン（１４ｍＬ）溶液を、１００℃で、２−（トリフェニル−ホスファニリデン）−ブチルアルデヒド（１．６８ｇ、５．３５ｍｍｏｌ）と共に、一晩加熱した。２−（トリフェニル−ホスファニリデン）−ブチルアルデヒドの第二部分（４９５ｍｇ、１．４９ｍｍｏｌ）を加え、その反応混合物をさらに１日加熱した。濃縮した後、その残留物をシリカゲルクロマトグラフィーで精製して、オイルとして、１．３ｇ（８３％）の所望生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.01 (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.

(2-Ethyl-4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -but-2-yl 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) A toluene (14 mL) solution was heated at 100 ° C. with 2- (triphenyl-phosphanylidene) -butyraldehyde (1.68 g, 5.35 mmol) 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 chromatography to give 1.3 g (83%) of the desired product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.01 (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−ヒドロキシメチル−ペンタ−２−エニル）−５−メトキシ−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン）
２−エチル−４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−ブタ−２−エナール（１．３ｇ、３．３０ｍｍｏｌ）のメタノール（１０ｍＬ）およびＴＨＦ（１０ｍＬ）溶液を、０℃まで冷却した。ＣｅＣｌ_３の溶液（８．２５ｍＬ、０．４Ｍ、ＭｅＯＨ：Ｈ_２Ｏ、９：１）を加え、続いて、ＬｉＢＨ_４（１．６６ｍＬ、２Ｍ ＴＨＦ溶液３．３０ｍｍｏｌ）を加えた。氷浴を取り除き、その反応混合物を室温まで温めた。この反応混合物をさらに４０分間攪拌すると、ＴＬＣにより、出発物質であるアルデヒドが完全に消費されたことが明らかとなった。１Ｎ ＨＣｌ水溶液を加えることにより、この反応をワークアップし、その生成物をＥｔＯＡｃで抽出した。その有機層を炭酸ナトリウム飽和水溶液およびブラインで洗浄した。その有機層を減圧下にて濃縮し、その残留物をシリカゲルクロマトグラフィーで精製して、無色オイルとして、９４８ｍｇ（７３％）の生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.00 (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-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. A solution of CeCl ₃ (8.25 mL, 0.4 M, MeOH: H ₂ O, 9: 1) was added followed by LiBH ₄ (1.66 mL, 2.30 mmol in 2M THF solution). The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for an additional 40 minutes and TLC revealed complete consumption of the starting aldehyde. The reaction was worked up by adding 1N aqueous HCl and the product was extracted with EtOAc. The organic layer was washed with saturated aqueous sodium carbonate and brine. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give 948 mg (73%) of product as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.00 (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−ブロモメチル−ペンタ−２−エニル）−５−メトキシ−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン）
重合体で支持したトリフェニルホスフィン（３ｍｍｏｌ／ｇ、０．６６ｇ）を、１時間にわたって、ジクロロメタン（６ｍＬ）に浸漬し、６−（３−ヒドロキシメチル−ペンタ−２−エニル）−５−メトキシ−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン（２６０ｍｇ、０．６６ｍｍｏｌ）および四臭化炭素（６５７ｍｇ、１．９８ｍｍｏｌ）を順次加え、その混合物を、室温で、１時間振盪した。この混合物を濾過し、その濾液を濃縮した。その残留物をシリカゲルクロマトグラフィーで精製して、白色固形物として、２３３ｍｇ（７７％）の生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.00 (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.

(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 soaked in dichloromethane (6 mL) for 1 hour to give 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 added. And shaken at room temperature for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography to give 233 mg (77%) of product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.00 (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−エチル−４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−ブタ−２−エニル］−ホスホン酸）
６−（３−ブロモメチル−ペンタ−２−エニル）−５−メトキシ−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン（２３０ｍｇ、０．５ｍｍｏｌ）の亜リン酸トリメチル（１．５ｍＬ、１２．７５ｍｍｏｌ）溶液を、１００℃で、４時間加熱した。減圧下にて、過剰の亜リン酸トリメチルを除去することにより、この反応物をワークアップした。その残留物をアセトニトリル（１ｍＬ）に溶解し、そして０℃で、ＴＭＳＢｒ（６４６μＬ、５．０ｍｍｏｌ）および２，６−ルチジン（５８０μＬ、５．０ｍｍｏｌ）を加えた。この反応溶液を室温まで温め、そして４時間攪拌した。この反応物を０℃まで冷却し、そしてＭｅＯＨを加えることにより、クエンチした。この反応混合物を減圧下にて乾燥し、その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、７７ｍｇ（５８％）の生成物を得た。¹H NMR (300 MHz, CD₃OD) δ1.08 (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= 7Hz) ppm.; ³¹P (121.4 MHz, CD₃OD) δ 25.65 ppm.; MS (m/z)355 [M-H]^-, 357 [M+H] ⁺.
（実施例３１５）
本発明の代表的な化合物は、以下で図示するように、調製できる。

([2-Ethyl-4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -but-2-enyl] -phosphonic acid)
Of 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 phosphite (1.5 mL, 12.75 mmol) was heated at 100 ° C. for 4 hours. The reaction was worked up by removing excess trimethyl phosphite under reduced pressure. The residue was dissolved in acetonitrile (1 mL) and at 0 ° C. TMSBr (646 μL, 5.0 mmol) and 2,6-lutidine (580 μL, 5.0 mmol) were added. The reaction solution was warmed to room temperature and stirred for 4 hours. The reaction was cooled to 0 ° C. and quenched by adding MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA). 77 mg (58%) of product was obtained. ¹ H NMR (300 MHz, CD ₃ OD) δ1.08 (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 = 7Hz) ppm .; ³¹ P (121.4 MHz, CD ₃ OD) δ 25.65 ppm .; MS (m / z) 355 [MH] ^- , 357 [M + H] ⁺ .
(Example 315)
Representative compounds of the present invention can be prepared as illustrated below.

（｛１−シアノ−３−エチル−５−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−ペンタ−３−エニル｝−ホスホン酸ジエチルエステル）
ホスホン酸ジエチルシアノメチル（２３３ｍｇ、１．３２ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液に、ナトリウムビス（トリメチルシリル）アミド（１．０Ｍ、１．２１ｍＬ、１．２１ｍｍｏｌ）のＴＨＦ溶液を加えた。３０分間攪拌した後、この溶液を、６−（３−ブロモメチル−ペンタ−２−エニル）−５−メトキシ−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン（１００ｍｇ、０．２２ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液に滴下した。得られた混合物を、室温で、一晩攪拌した後、塩化アンモニウム飽和水溶液を加えた。この反応混合物を酢酸エチルで抽出した。その有機層を硫酸ナトリウムで乾燥し、そして乾燥状態まで濃縮した。その残留物を分取逆相ＨＰＬＣで精製して、５１ｍｇ（４２％）の所望生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.04 (s, 9H), 1.07 (t,3H), 1.24 (dd, 2H, J= 7, 8 Hz), 1.36 (t, 6H), 2.12 (m,1H), 2.18 (s, 3H), 2.35-2.47 (m, 2H), 2.67 (m,1H), 3.00-3.14 (m, 1H), 3.44 (d, J= 7.2, 2H), 3.79 (s, 3H), 4.12-4.37 (m, 6H), 5.13 (s, 2H), 5.38 (t, J =7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 18.26 ppm; MS (m/z)574 [M+Na] ⁺.

({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 cyanomethyl phosphonate (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 -Added dropwise to a solution of ON (100 mg, 0.22 mmol) in THF (1 mL). The resulting mixture was stirred overnight at room temperature and then a saturated aqueous ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by preparative reverse phase HPLC to give 51 mg (42%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.04 (s, 9H), 1.07 (t, 3H), 1.24 (dd, 2H, J = 7, 8 Hz), 1.36 (t, 6H), 2.12 (m , 1H), 2.18 (s, 3H), 2.35-2.47 (m, 2H), 2.67 (m, 1H), 3.00-3.14 (m, 1H), 3.44 (d, J = 7.2, 2H), 3.79 (s , 3H), 4.12-4.37 (m, 6H), 5.13 (s, 2H), 5.38 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 18.26 ppm; MS (m / z) 574 [M + Na] ⁺ .

（［１−シアノ−３−エチル−５−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−ペンタ−３−エニル］−ホスホン酸）
｛１−シアノ−３−エチル−５−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−ペンタ−３−エニル｝−ホスホン酸ジエチルエステル（１９．５ｍｇ、０．０３５ｍｍｏｌ）を１０％ＴＦＡ／ＣＨ_２Ｃｌ_２の溶液（２ｍＬ）に溶解し、そして室温で、１０分間攪拌した。その反応混合物を減圧下にて乾燥し、そしてＲＰ−ＨＰＬＣで精製して、９．５ｍｇ（６１％）の所望生成物を得た。この物質をＤＭＦ（０．５ｍＬ）およびＤＣＭ（０．５ｍＬ）に溶解し、そしてＴＭＳＢｒ（２７μＬ、０．２ｍｍｏｌ）および２，６−ルチジン（２３μＬ、０．２ｍｍｏｌ）を加えた。その反応溶液を、室温で、一晩攪拌した後、ＭｅＯＨでクエンチした。この反応混合物を減圧下にて乾燥し、そしてその残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、白色固形物として５．１ｍｇ（６５％）の所望生成物を得た。¹H NMR (300 MHz, CD₃OD) δ1.10 (t,3H), 2.16 (s, 3H), 2.23-2.52 (m, 3H), 2.67 (m,1H), 3.05-3.20 (m, 1H),3.48 (d, J = 7.2, 2H), 3.81 (s, 3H), 5.26 (s, 2H), 5.43 (t, J =7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 14.18 ppm; MS (m/z)394 [M-H]^-, 396 [M+H]⁺.
（実施例３１６）
本発明の代表的な化合物は、以下で図示するように、調製できる。

([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]- Penta-3-enyl} -phosphonic acid diethyl ester (19.5 mg, 0.035 mmol) was dissolved in a solution of 10% TFA / CH ₂ Cl ₂ (2 mL) and stirred at room temperature for 10 minutes. The reaction mixture was dried under reduced pressure and purified by RP-HPLC to give 9.5 mg (61%) of the desired product. This material was dissolved in DMF (0.5 mL) and DCM (0.5 mL) and TMSBr (27 μL, 0.2 mmol) and 2,6-lutidine (23 μL, 0.2 mmol) were added. The reaction solution was stirred at room temperature overnight and then quenched with MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA). Purification gave 5.1 mg (65%) of the desired product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ1.10 (t, 3H), 2.16 (s, 3H), 2.23-2.52 (m, 3H), 2.67 (m, 1H), 3.05-3.20 (m, 1H ), 3.48 (d, J = 7.2, 2H), 3.81 (s, 3H), 5.26 (s, 2H), 5.43 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 14.18 ppm; MS (m / z) 394 [MH] ^- , 396 [M + H] ⁺ .
(Example 316)
Representative compounds of the present invention can be prepared as illustrated below.

（｛２−エチル−４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−ブタ−２−エニルオキシメチル｝−ホスホン酸ジイソプロピルエステル）
ブロモメチルホスホン酸ジイソプロピルエステル（６８０ｍｇ、２．６２ｍｍｏｌ）および６−（３−ヒドロキシメチル−ペンタ−２−エニル）−５−メトキシ−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン（６８８ｍｇ、１．７５ｍｍｏｌ）のＤＭＦ（３ｍＬ）溶液に、リチウムｔ−ブトキシド（ＴＨＦ中で１．０Ｍ；２．６ｍＬ）を加えた。その反応物を、７０℃で、２時間加熱した。室温まで冷却した後、さらに多くのブロモメチルホスホン酸ジイソプロピルエステル（６８０ｍｇ、２．６２ｍｍｏｌ）およびリチウムｔ−ブトキシド（ＴＨＦ中で１．０Ｍ；２．６ｍＬ）を加えた。その反応混合物を、７０℃で、さらに１時間加熱し、冷却し、塩化リチウムの溶液（５％水溶液）に注ぎ、そして酢酸エチルで抽出した。有機抽出物を乾燥し、その生成物をシリカゲルクロマトグラフィー（これは、ヘキサン−酢酸エチルで溶出する）で精製して、無色オイルとして、３４７ｍｇ（３５％）の生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.04 (s, 9H), 1.09 (t, 3H, J= 7.5 Hz), 1.20- 1.26 (m, 2H), 1.31 (t, 12H,J= 6 Hz), 2.18 (s, 3H), 2.29 (q, 2H, J= 7.5 Hz), 3.5 (m, 2H),3.59 (d, 2H, J= 8.7 Hz), 3.78 (s, 3H), 3.98 (s, 2H), 4.28- 4.35 (m, 2H),4.6-4.8 (m, 2H), 5.13 (s, 2H), 5.4 (t, 1H, J= 7 Hz) ppm; ³¹P(121.4 MHz, CDCl₃) δ 20.26 ppm; MS (m/z) 593.3[M+Na]⁺.

({2-Ethyl-4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -buta-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 in THF; 2.6 mL). The reaction was heated at 70 ° C. for 2 hours. After cooling to room temperature, more bromomethylphosphonic acid diisopropyl ester (680 mg, 2.62 mmol) and lithium t-butoxide (1.0 M in THF; 2.6 mL) were added. The reaction mixture was heated at 70 ° C. for an additional hour, cooled, poured into a solution of lithium chloride (5% aqueous solution) and extracted with ethyl acetate. The organic extract was dried and the product was purified by silica gel chromatography (eluting with hexane-ethyl acetate) to give 347 mg (35%) of the product as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.04 (s, 9H), 1.09 (t, 3H, J = 7.5 Hz), 1.20- 1.26 (m, 2H), 1.31 (t, 12H, J = 6 Hz ), 2.18 (s, 3H), 2.29 (q, 2H, J = 7.5 Hz), 3.5 (m, 2H), 3.59 (d, 2H, J = 8.7 Hz), 3.78 (s, 3H), 3.98 (s , 2H), 4.28- 4.35 (m, 2H), 4.6-4.8 (m, 2H), 5.13 (s, 2H), 5.4 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 20.26 ppm; MS (m / z) 593.3 [M + Na] ⁺ .

（［２−エチル−４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−ブタ−２−エニルオキシメチル］−ホスホン酸）
｛２−エチル−４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−ブタ−２−エニルオキシメチル｝−ホスホン酸ジイソプロピルエステル（３４７ｍｇ、０．６１ｍｍｏｌ）のアセトニトリル（５ｍＬ）溶液に、２，６−ルチジン（０．７１ｍＬ、６．１ｍｍｏｌ）およびブロモトリメチルシラン（０．７８６ｍＬ、６．１ｍｍｏｌ）を加えた。この混合物を、室温で、３時間攪拌し、メタノール（５ｍＬ）でクエンチし、濃縮し、そして酢酸エチルと１Ｎ ＨＣｌ（水溶液）との間で分配した。その有機層を濃縮して、無色オイル（２０５ｍｇ、７０％）として、遊離ホスホン酸を得た。この物質（２０ｍｇ）をトリフルオロ酢酸（０．３ｍＬ）およびジクロロメタン（２．７ｍＬ）の溶液に溶解し、そして室温で、３０分間攪拌した。濃縮した後、その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、凍結乾燥後、白色固形物（１０ｍｇ）として、この生成物を得る。¹H NMR (300 MHz, CDCl₃) δ1.007 (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; ³¹P(121.4 MHz, CDCl₃) δ 22.8 ppm; MS (m/z) 385.2 [M-H]⁺,387.1 [M+H]⁺.
（実施例３１７）
本発明の代表的な化合物は、以下で図示するように、調製できる。

([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 to 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 layer 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 room temperature for 30 minutes. After concentration, the residue was purified by RP HPLC (which was a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA, using a C18 column) and after lyophilization, The product is obtained as a white solid (10 mg). ¹ H NMR (300 MHz, CDCl ₃ ) δ1.007 (t, 3H, J = 7.5 Hz), 2.13 (s, 3H), 2.32 (q, 2H, J = 7.5 Hz), 3.41 (d, 2H, J = 6.3 Hz), 3.56 (d, 2H, J = 9 Hz), 3.75 (s, 3H), 3.95 (s, 2H), 5.16 (s, 2H), 5.43 (t, 1H, J = 6.3 Hz) ppm ³¹ P (121.4 MHz, CDCl ₃ ) δ 22.8 ppm; MS (m / z) 385.2 [MH] ⁺ , 387.1 [M + H] ⁺ .
(Example 317)
Representative compounds of the present invention can be prepared as illustrated below.

（６−アリルオキシ−３−メチル−４−トリフルオロメタンスルホニルオキシ−フタル酸ジメチルエステル）
６−アリルオキシ−４−ヒドロキシ−３−メチル−フタル酸ジメチルエステル（８．０６ｇ、２８．８ｍｍｏｌ）［これは、以下に従って、合成した：Ｊ．Ｗ．Ｐａｔｔｅｒｓｏｎ，Ｔｅｔｒａｈｅｄｒｏｎ，１９９３，４９，４７８９−４７９８］およびピリジン（１１．４ｇ、１４４．０ｍｍｏｌ）のジクロロメタン（ＤＣＭ）（２０ｍＬ）溶液に、０℃で、無水トリフリック酸（１２．１９ｇ、４３．２ｍｍｏｌ）を加えた。その反応物を、０℃で、２時間攪拌し、その後、無水トリフリック酸（３ｍＬ）を追加した。０℃での攪拌をさらに１時間継続した。その反応混合物をＤＣＭおよびＨＣｌ（１Ｎ）の混合物に注いだ。層分離し、その水層をＤＣＭで抽出した。合わせた有機層を硫酸ナトリウムで乾燥した。濾過し、そして真空中で溶媒を蒸発させると、粗生成物が生じ、これを、シリカゲルクロマトグラフィーで精製して、オイルとして、８．３９ｇの生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝２．３２（ｓ， ３Ｈ），３．８９（ｓ，６Ｈ），４．６０（ｍ，２Ｈ），５．３３（ｄ，Ｊ＝９．３Ｈｚ，１Ｈ），５．４１（ｄ，Ｊ＝１８．６Ｈｚ，１Ｈ），５．９５（ｍ，１Ｈ），６．９５（ｓ，１Ｈ）ｐｐｍ；^１９Ｆ ＮＭＲ（２８２ＭＨｚ，ＣＤＣｌ_３）：δ＝−７４ ｐｐｍ。

(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) [This was synthesized according to the following: W. Patterson, Tetrahedron, 1993, 49, 4789-4798] and pyridine (11.4 g, 144.0 mmol) in dichloromethane (DCM) (20 mL) at 0 ° C. at 0 ° C. with triflic anhydride (12.19 g, 43.2 mmol). Was added. The reaction was stirred at 0 ° C. for 2 h, after which time triflic anhydride (3 mL) was added. Stirring at 0 ° C. was continued for an additional hour. The reaction mixture was poured into a mixture of DCM and HCl (1N). The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried with sodium sulfate. Filtration and evaporation of the solvent in vacuo yielded 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 ): δ = 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 ): δ = -74 ppm.

（６−ヒドロキシ−３−メチル−４−トリフルオロメタンスルホニルオキシ−フタル酸ジメチルエステル）
６−アリルオキシ−３−メチル−４−トリフルオロメタンスルホニルオキシ−フタル酸ジメチルエステル（８．３９ｇ、２０．３ｍｍｏｌ）のトルエン（２０ｍＬ）溶液に、窒素雰囲気下にて、室温で、テトラキストリフェニルホスフィンパラジウム（０．４７ｇ、０．４０ｍｍｏｌ）およびジエチルアミン（２．９７ｇ、４０．８６ｍｍｏｌ）を加えた。全ての出発物質が消費されるまで、室温での攪拌を継続した。その粗反応混合物をジエチルエーテルとＨＣｌ（０．１Ｎ）との間で分配した。その有機層をブラインで洗浄し、そして硫酸ナトリウムで乾燥した。濾過し、そして真空中で溶媒を蒸発させると、粗製物質が生じ、これを、シリカゲルクロマトグラフィーで精製して、灰白色固形物として、４．１６ｇ（５５％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝２．２０（ｓ，３Ｈ），３．９３（ｓ，３Ｈ），３．９５（ｓ，３Ｈ），７．０１（ｓ，１Ｈ）ｐｐｍ；^１９Ｆ ＮＭＲ（２８２ＭＨｚ，ＣＤＣｌ_３）：δ＝−７４ｐｐｍ。

(6-hydroxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethyl ester)
Tetrakistriphenylphosphine palladium in a solution of 6-allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethyl ester (8.39 g, 20.3 mmol) in toluene (20 mL) at room temperature under a nitrogen atmosphere. (0.47 g, 0.40 mmol) and diethylamine (2.97 g, 40.86 mmol) were added. Stirring at room temperature was continued until all starting material was consumed. The crude reaction mixture was partitioned between diethyl ether and HCl (0.1N). The organic layer was washed with brine and dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo yielded 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 ): δ = 2.20 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 7.01 (s, 1H) ppm; ¹⁹ F NMR (282 MHz, CDCl ₃ ): δ = −74 ppm.

（６−ヒドロキシ−３−メチル−４−ビニル−フタル酸ジメチルエステル）
６−ヒドロキシ−３−メチル−４−トリフルオロメタンスルホニルオキシ−フタル酸ジメチルエステル（２．１７ｇ、５．８５ｍｍｏｌ）のＮ−メチルピロリジン（１５ｍＬ）溶液に、塩化リチウム（７４３ｍｇ、１７．５ｍｍｏｌ）およびトリフェニルアルシン（１７９ｍｇ、０．５８５ｍｍｏｌ）を加えた。トリブチルビニルスズ（２．０４ｇ、６．４３ｍｍｏｌ）を加え、続いて、トリス（トリベンジリデンアセトン）ジパラジウム（０）−クロロホルム付加物（９０ｍｇ、０．０８７ｍｍｏｌ）を加えた。その反応物を窒素雰囲気下に置き、そして６０℃で、１８時間加熱した。この反応物を室温まで冷却し、そして氷（２０ｇ）、ＥｔＯＡｃ（４０ｍＬ）およびフッ化カリウム（１ｇ）の混合物に注いだ。攪拌を１時間継続した。その水層をＥｔＯＡｃで抽出し、有機抽出物をセライトで濾過した。合わせた有機層を水で洗浄し、そして硫酸ナトリウムで乾燥した。濾過し、そして真空中で溶媒を蒸発させると、粗製物質が生じ、これを、シリカゲルクロマトグラフィーで精製して、灰白色固形物として、１．２７ｇ（８７％）の生成物が得られた。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝２．１６（ｓ， ３Ｈ），３．９１（ｓ，３Ｈ），３．９２（ｓ，３Ｈ），５．４６（ｄｄ，Ｊ＝１１．１，１．２Ｈｚ，１Ｈ），５．７２（ｄｄ，Ｊ＝１７．１，０．９Ｈｚ，１Ｈ），６．８６（ｄｄ，Ｊ＝１７．１，１１．１Ｈｚ，１Ｈ），７．１４（ｓ，１Ｈ），１０．７９（ｓ，１Ｈ）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-methylpyrrolidine (15 mL) was added lithium chloride (743 mg, 17.5 mmol) and triethyl. 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 was continued for 1 hour. The aqueous layer was extracted with EtOAc and the organic extract was filtered through celite. The combined organic layers were washed with water and dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo yielded 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 ): δ = 2.16 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 5.46 (dd, J = 11.1 , 1.2 Hz, 1H), 5.72 (dd, J = 17.1, 0.9 Hz, 1H), 6.86 (dd, J = 17.1, 11.1 Hz, 1H), 7.14 ( s, 1H), 10.79 (s, 1H) ppm.

（４−エチル−６−ヒドロキシ−３−メチル−フタル酸ジメチルエステル）
６−ヒドロキシ−３−メチル−４−ビニル−フタル酸ジメチルエステル（１．２７ｇ、５．１１ｍｍｏｌ）をベンゼン（１０ｍＬ）およびＥｔＯＡｃ（１０ｍＬ）に溶解した。トリストリフェニルホスフィンロジウムクロライド（１５０ｍｇ）を加え、その反応物を水素雰囲気下に置いた。室温での攪拌を継続した。１４時間後、真空中で溶媒を除去し、その粗製物質をシリカゲルクロマトグラフィーで精製して、灰白色固形物として、１．１４ｇ（８８％）の所望生成物が得られた。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝１．１９（ｔ，Ｊ＝７．８Ｈｚ，３Ｈ），２．１０（ｓ，３Ｈ），２．６０（ｑ，Ｊ＝７．８Ｈｚ，２Ｈ），３．８９（ｓ，６Ｈ），６．８７（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 at room temperature was continued. 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 ): δ = 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.

（１ ６−アリルオキシ−４−エチル−３−メチル−フタル酸ジメチルエステル）
４−エチル−６−ヒドロキシ−３−メチル−フタル酸ジメチルエステル（１．０１ｇ、４．０２ｍｍｏｌ）をＤＭＦ（５ｍＬ）に溶解した。炭酸カリウム（３．３３ｇ、２４．１４ｍｍｏｌ）を加え、続いて、臭化アリル（２．９２ｇ、２４．１４ｍｍｏｌ）を加えた。その懸濁液を６０℃で加熱した。１４時間後、その反応物を室温まで冷却し、そして濾過した。真空中で溶媒を除去し、その粗製物質をシリカゲルクロマトグラフィーで精製して、無色オイルとして、０．９７６ｇ（８３％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝１．１６（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），２．２０（ｓ，３Ｈ），２．６２（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），３．８３（ｓ，３Ｈ），３．８４（ｓ，３Ｈ），４．５７（ｍ，２Ｈ），５．２６（ｄｄ，Ｊ＝９．３，１．５Ｈｚ，１Ｈ），５．４１（ｄｄ，Ｊ＝１３．５，１．５Ｈｚ，１Ｈ），５．９８（ｍ，１Ｈ），６．８２（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 at 60 ° C. After 14 hours, the reaction was cooled to room temperature and filtered. The solvent was removed in vacuo and the crude material was purified by silica gel chromatography to give 0.976 g (83%) of the desired product as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ = 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−アリル−５−エチル−３−ヒドロキシ−６−メチル−フタル酸ジメチルエステル）
６−アリルオキシ−４−エチル−３−メチル−フタル酸ジメチルエステル（１．２５ｇ、４．２８ｍｍｏｌ）を、２１０℃で、窒素雰囲気下にて、加熱した。１４時間後、その反応物を室温まで冷却した。その粗製物質をシリカゲルクロマトグラフィーで精製して、無色オイルとして、０．９７１ｇ（７７％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝１．１４（ｔ，Ｊ＝７．８Ｈｚ，３Ｈ），２．１７（ｓ，３Ｈ），２．６８（ｑ，Ｊ＝７．８Ｈｚ，２Ｈ），３．４９（ｍ，２Ｈ），３．８６（ｓ，３Ｈ），３．８９（ｓ，３Ｈ），４．８９−５．０１（ｍ，２Ｈ），５．９３（ｍ，１Ｈ），１１．２２（ｓ，１Ｈ） ｐｐｍ．

(4-allyl-5-ethyl-3-hydroxy-6-methyl-phthalic acid dimethyl ester)
6-allyloxy-4-ethyl-3-methyl-phthalic acid dimethyl ester (1.25 g, 4.28 mmol) was heated at 210 ° C. under a nitrogen atmosphere. After 14 hours, the reaction was cooled to room temperature. The crude material was purified by silica gel chromatography to give 0.971 g (77%) of the desired product as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.14 (t, J = 7.8 Hz, 3H), 2.17 (s, 3H), 2.68 (q, J = 7.8 Hz, 2H) , 3.49 (m, 2H), 3.86 (s, 3H), 3.89 (s, 3H), 4.89-5. 01 (m, 2H), 5.93 (m, 1H), 11.22 (s, 1H) ppm.

（５ ６−アリル−５−エチル−７−ヒドロキシ−４−メチル−３Ｈ−イソベンゾフラン−１−オン）
４−アリル−５−エチル−３−ヒドロキシ−６−メチル−フタル酸ジメチルエステル（０．９７１ｇ、３．３２ｍｍｏｌ）を、室温で、ＭｅＯＨ（８ｍＬ）に溶解した。水酸化ナトリウム（０．７９８ｇ、１９．９５ｍｍｏｌ）の水（１０ｍＬ）溶液を加え、その懸濁液を、５５℃で、加熱した。１６時間後、その反応物を室温まで冷却し、そしてジエチルエーテルで洗浄した。その有機層を酸性化し（１Ｎ ＨＣｌ）、この懸濁液をＥｔＯＡｃで抽出した。合わせた有機層を硫酸ナトリウムで乾燥した。濾過し、そして真空中で溶媒を蒸発させると、白色固形物（０．８４６ｇ、９８％、Ｍ^＋＝２６３）として、所望のビス酸が生じた。このビス酸を酢酸（６ｍＬ）およびＨＣｌ（濃塩酸、１．５ｍＬ）に溶解した。その反応物を８０℃で加熱した。Ｚｎダスト（それぞれ０．６３５ｇ、９．７２ｍｍｏｌ）を、７時間にわたって、毎時間、少しずつ加えた。８０℃での攪拌をさらに１０時間継続した。その反応物を室温まで冷却し、そして水を加えた。得られた懸濁液をＥｔＯＡｃで抽出した。合わせた有機抽出物を炭酸水素ナトリウム溶液で洗浄し、そして硫酸ナトリウムで乾燥した。濾過し、そして真空中で溶媒を蒸発させると、粗生成物が生じ、これを、シリカゲルクロマトグラフィーで精製して、白色固形物として、０．３７５ｇ（５０％）の生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝１．１４（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），２．１８（ｓ，３Ｈ），２．７１（ｑ，Ｊ＝７．５Ｈｚ，２Ｈ），３．４９（ｍ，２Ｈ），４．９５（ｄ，Ｊ＝１７．１Ｈｚ，１Ｈ），５．０２（ｄ，Ｊ＝１０．２Ｈｚ，１Ｈ），５．２３（ｓ，２Ｈ），５．９８（ｍ，１Ｈ），７．６６（ｓ，１Ｈ）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. A solution of sodium hydroxide (0.798 g, 19.95 mmol) in water (10 mL) was added and the suspension was heated at 55 ° C. After 16 hours, the reaction was cooled to room temperature and washed with diethyl ether. The organic layer was acidified (1N HCl) and the suspension was extracted with EtOAc. The combined organic layers were dried with sodium sulfate. Filtration and evaporation of the solvent in vacuo yielded the desired bis acid as a white solid (0.846 g, 98%, M ⁺ = 263). This bisacid was dissolved in acetic acid (6 mL) and HCl (concentrated hydrochloric acid, 1.5 mL). The reaction was heated at 80 ° C. Zn dust (0.635 g, 9.72 mmol, respectively) was added in portions over the course of 7 hours. Stirring at 80 ° C. was continued 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. Filtration and evaporation of the solvent in vacuo yielded 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 ): δ = 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−アリル−５−エチル−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン）
６−アリル−５−エチル−７−ヒドロキシ−４−メチル−３Ｈ−イソベンゾフラン−１−オン（１９９ｍｇ、０．８５７ｍｍｏｌ）、ＰＰｈ_３（３３７ｍｇ、１．２８６ｍｍｏｌ）および２−トリメチルシリルエタノールのＴＨＦ（３ｍＬ）溶液に、０℃で、アゾジカルボン酸ジイソプロピル（２５９ｍｇ、１．２８６ｍｍｏｌ）を加えた。得られた黄色溶液を室温まで温め、そして１時間攪拌した。真空中で溶媒を除去し、その粗製物質をジエチルエーテル（３ｍＬ）に溶解した。ヘキサン（１．５ｍＬ）を加えた。濾過によりトリフェニルホスフィンオキシドを除去し、その濾液を濃縮し、そしてシリカゲルクロマトグラフィーで精製して、透明オイルとして、所望生成物（２６１ｍｇ、９２％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝０．０４（ｓ，９Ｈ），１．１５（ｔ，Ｊ＝７．８Ｈｚ，３Ｈ），１．２５（ｍ，２Ｈ），２．２０（ｓ，３Ｈ），２．７３（ｑ，Ｊ＝７．８Ｈｚ，２Ｈ），３．５４（ｍ，２Ｈ），４．２８（ｍ，２Ｈ），４．９５（ｄ，Ｊ＝１７．１Ｈｚ，１Ｈ），５．０２（ｄ，Ｊ＝１０．２Ｈｚ，１Ｈ），５．１５（ｓ，２Ｈ），５．９５（ｍ，１Ｈ）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 in THF (3 mL ) To the solution was added diisopropyl azodicarboxylate (259 mg, 1.286 mmol) at 0 ° C. The resulting yellow solution was warmed to room temperature and stirred for 1 hour. The solvent was removed in vacuo and the crude material was dissolved in diethyl ether (3 mL). Hexane (1.5 mL) was added. Triphenylphosphine oxide was 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 ): δ = 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−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−アセトアルデヒド）
６−アリル−５−エチル−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン（２６１ｍｇ、０．７８８ｍｍｏｌ）のＭｅＯＨ（５ｍＬ）、ＣＨ_２Ｃｌ_２（５ｍＬ）およびピリジン（５０μＬ）溶液を、Ｓｍｉｔｈ，Ｄ．Ｂ．ｅｔ ａｌ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９６，６１，６，２２３６の手順に従って、ドライアイス／アセトン浴を使用して、−７８℃まで冷却した。その反応物が青色に着色するまで（１５分間）、気体分散チューブを経由して、この反応物にオゾン流れを泡立たせた。このオゾンラインを窒素流れで置き換え、泡立ちをさらに１５分間継続し、その時点までに、この青色は消失した。この溶液に、−７８℃で、チオ尿素（５９．９ｍｇ、０．７８８ｍｍｏｌ）を一度に加え、この冷却浴を取り除いた。その反応物を室温まで温め、そして１５時間攪拌した。この反応混合物を濾過し、次いで、ＣＨ_２Ｃｌ_２と水との間で分配した。その水層をＣＨ_２Ｃｌ_２でもう１回溶出し、そして有機抽出物を合わせ、１Ｎ ＨＣｌ水溶液、飽和ＮａＨＣＯ_３およびブラインで洗浄し硫酸ナトリウムで乾燥した。濾過し、そして真空中で溶媒を蒸発させると、粗生成物が生じ、これを、シリカゲルクロマトグラフィーで精製して、白色固形物として、１８１ｍｇ（６９％）の生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝０．０４（ｓ，９Ｈ），１．１１（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．１９（ｍ，２Ｈ），２．２１（ｓ，３Ｈ），２．６６（ｑ，Ｊ＝７．５Ｈｚ，２Ｈ），３．９０（ｓ，２Ｈ），４．３６（ｍ，２Ｈ），５．１８（ｓ，２Ｈ），９．７１（ｓ，１Ｈ）ｐｐｍ．

([6-Ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde)
6-allyl-5-ethyl-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (261 mg, 0.788 mmol) in MeOH (5 mL), CH ₂ Cl ₂ ( 5 mL) and pyridine (50 μL) solution were added to Smith, D. et al. B. et al. , J .; Org. Chem. , 1996, 61, 6, 2236, and cooled to −78 ° C. using a dry ice / acetone bath. An ozone stream was bubbled through the reaction via a gas dispersion tube until the reaction colored blue (15 minutes). The ozone line was replaced with a stream of nitrogen and bubbling continued for an additional 15 minutes by which time the blue color had disappeared. To this solution was added thiourea (59.9 mg, 0.788 mmol) in one portion at −78 ° C. 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 layer was eluted 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. Filtration and evaporation of the solvent in vacuo yielded 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 ): δ = 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−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エナール）
［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−アセトアルデヒド（９０ｍｇ、０．２６９ｍｍｏｌ）および２−（トリフェニル−ホスホリデン）−プロピオンアルデヒド（７２．９ｍｇ、０．２３ｍｍｏｌ）を、トルエン（３ｍＬ）中にて、１００℃で、加熱した。１５時間後、第二部分の２−（トリフェニル−ホスファニリデン）−プロピオンアルデヒド（３３ｍｇ、０．１１ｍｍｏｌ）を加え、その反応混合物をさらに９時間加熱した。真空中でトルエンを除去し、その残留物をシリカゲルクロマトグラフィーで精製して、淡黄色オイルとして、７７．６ｍｇ（７７％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝０．０３（ｓ，９Ｈ），１．１５（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．２１（ｍ，２Ｈ），１．９３（ｓ，３Ｈ），２．２１（ｓ，３Ｈ），２．７１（ｑ，Ｊ＝７．５Ｈｚ，２Ｈ），３．８２（ｄ，Ｊ＝６．９Ｈｚ，２Ｈ），４．３４（ｍ，２Ｈ），５．１８（ｓ，２Ｈ），６．３８（ｍ，１Ｈ），９．３５（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- (Triphenyl-phosphoridene) -propionaldehyde (72.9 mg, 0.23 mmol) was heated at 100 ° C. in toluene (3 mL). After 15 hours, a second portion of 2- (triphenyl-phosphanylidene) -propionaldehyde (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 ): δ = 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−エチル−６−（４−ヒドロキシ−３−メチル−ブタ−２−エニル）−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン）
４−［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エナール（７７．６ｍｇ、０．２０７ｍｍｏｌ）をＭｅＯＨ（４ｍＬ）に溶解した。ＣｅＣｌ_３（５１．１ｍｇ、０．２０７ｍｍｏｌ）のＭｅＯＨ／水（９／１、０．６６ｍＬ）溶液を加え、この溶液を０℃まで冷却した。ホウ水素化リチウムのＴＨＦ溶液（２Ｍ、０．１０５ｍＬ）を滴下した。１５分後、その反応を１Ｎ ＨＣｌ（０．５ｍＬ）でクエンチした。真空中でＭｅＯＨを除去し、その粗製物質をＤＣＭと水との間で分配した。その水層をＤＣＭで抽出し、合わせた有機層を炭酸水素ナトリウム水溶液で洗浄し、そして硫酸ナトリウムで乾燥した。濾過し、そして溶媒を蒸発させると、粗製オイルが生じ、これを、シリカゲルクロマトグラフィーで精製して、５７．２ｍｇ（７３％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝０．０４（ｓ，９Ｈ），１．１５（ｔ，Ｊ＝７．８Ｈｚ，３Ｈ），１．２６（ｍ，２Ｈ），１．８６（ｓ，３Ｈ），２．１９（ｓ，３Ｈ），２．７２（ｑ，Ｊ＝７．８Ｈｚ，２Ｈ），３．５２（ｄ，Ｊ＝６．３Ｈｚ，２Ｈ），３．９９（ｓ，２Ｈ），４．３４（ｍ，２Ｈ），５．１４（ｓ，２Ｈ），５．３２（ｍ，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 in vacuo and the crude material was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organic layers were washed with aqueous sodium bicarbonate and dried over sodium sulfate. Filtration and evaporation of the solvent yielded a crude oil that was purified by silica gel chromatography to give 57.2 mg (73%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ): δ = 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−ブロモ−３−メチル−ブタ−２−エニル）−５−エチル−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン）
５−エチル−６−（４−ヒドロキシ−３−メチル−ブタ−２−エニル）−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン（５７．２ｍｇ、０．１５２ｍｍｏｌ）をＤＣＭ（３．５ｍＬ）に溶解した。重合体が結合したトリフェニルホスフィン（３ｍｍｏｌ／ｇ、１５２．１ｍｇ）を加え、その混合物を、室温で、機械的に攪拌した。四臭化炭素（１５１．３ｍｇ、０．４５６ｍｍｏｌ）を加え、その溶液を室温で攪拌した。２時間後、その反応物を濾過し、そして真空中で溶媒を除去した。この粗製物質をシリカゲルクロマトグラフィーで精製して、５８．０ｍｇ（８７％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝０．０４（ｓ，９Ｈ），１．１５（ｔ，Ｊ＝７．８Ｈｚ，３Ｈ），１．２５（ｍ，２Ｈ），１．９５（ｓ，３Ｈ），２．２０（ｓ，３Ｈ），２．７０（ｑ，Ｊ＝７．８Ｈｚ，２Ｈ），３．５２（ｄ，Ｊ＝６．３Ｈｚ，２Ｈ），３．９４（ｓ，２Ｈ），４．２８（ｍ，２Ｈ），５．１４（ｓ，２Ｈ），５．５０（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 ): δ = 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−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−ホスホン酸）
臭化４−［６’−エチル−７’−メチル−３’−オキソ−４’−（２”−トリメチルシラニル−エトキシ）−１’，３’−ジヒドロ−イソベンゾフラン−５’−イル］−２−メチル−ブタ−２−エニル（５８ｍｇ、０．１３２ｍｍｏｌ）の亜リン酸トリメチル（０．８ｍＬ）溶液を、１１０℃で、加熱した。２時間後、その反応は完結した。この反応物を室温まで冷却し、そして真空中で過剰の亜リン酸トリメチルを除去した。その粗製物質を、さらに精製することなく、次の工程で使用した。

({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 bromide] A solution of 2-methyl-but-2-enyl (58 mg, 0.132 mmol) in trimethyl phosphite (0.8 mL) was heated at 110 ° C. After 2 hours, the reaction was complete. Was cooled to room temperature and the excess trimethyl phosphite was removed in vacuo and the crude material was used in the next step without further purification.

The crude product of this 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 at room temperature was continued. After 2 hours, additional trimethylsilyl bromide (202.2 mg, 1.321 mmol) was added and stirring at room temperature was continued. After 4 hours, the reaction was quenched with MeOH (2 mL). The solvent was removed in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN). Fractions containing product were combined and lyophilized to give 2.3 mg (5.1%) of free phosphonic acid. ¹ H NMR (300 MHz, DMSO-d6): δ = 1.07 (t, J = 7.5 Hz, 3H), 1.84 (s, 3H), 2.14 (s, 3H), 2.64 ( q, J = 7.5 Hz, 2H), 3.34 (m, 4H), 5.06 (m, 1H), 5.25 (s, 2H) ppm; ³¹ P NMR (121 MHz, DMSO-d6): δ = 22.19 ppm; MS = 341 [M ⁺ +1].

(Example 318)
Representative compounds of the present invention can be prepared as illustrated below.

（［２−エチル−４−［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−ブタ−２−エナール）
［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−アセトアルデヒド（９０ｍｇ、０．２６９ｍｍｏｌ）および２−（トリフェニル−ホスホリデン）−ブチルアルデヒド（９８．４ｍｇ、０．２９６ｍｍｏｌ）を、トルエン（３ｍＬ）中にて、１００℃で、加熱した。１５時間後、第二部分の２−（トリフェニル−ホスファニリデン）−ブチルアルデヒド（９８．４ｍｇ、０．２９６ｍｍｏｌ）を加え、その反応混合物を、さらに３３時間加熱した。濃縮した後、その残留物をシリカゲルクロマトグラフィーで精製して、淡黄色オイルとして、５０．３ｍｇ（４８％）の所望生成物を得た。

([2-Ethyl-4- [6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -buta-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- (Triphenyl-phosphoridene) -butyraldehyde (98.4 mg, 0.296 mmol) was heated at 100 ° C. in toluene (3 mL). 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−エチル−６−（３−ヒドロキシメチル−ペンタ−２−エニル）−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン）
２−エチル−４−［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−ブタ−２−エナール（５０．３ｍｇ、０．１２９ｍｍｏｌ）をＭｅＯＨ（３ｍＬ）に溶解した。ＣｅＣｌ_３（３１．９ｍｇ、０．１２９ｍｍｏｌ）のＭｅＯＨ／水（９／１、０．６６ｍＬ）溶液を加え、この溶液を０℃まで冷却した。ホウ水素化リチウムのＴＨＦ溶液（２Ｍ、０．０６５ｍＬ）を滴下した。１０分後、その反応を１Ｎ ＨＣｌ（０．５ｍＬ）でクエンチした。真空中でメタノールを除去し、その粗製物質をＤＣＭと水との間で分配した。その水層をＤＣＭで抽出し、合わせた有機層を炭酸水素ナトリウム水溶液で洗浄し、そして硫酸ナトリウムで乾燥した。濾過し、そして真空中で溶媒を蒸発させると、粗製オイルが生じ、これを、シリカゲルクロマトグラフィーで精製して、３５．４ｍｇ（７０％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝０．０４（ｓ，９Ｈ），１．１０−１．１９（ｍ，６Ｈ），１．２６（ｍ，２Ｈ），２．１９（ｓ，３Ｈ），２．３２（ｑ，Ｊ＝７．５Ｈｚ，２Ｈ），２．７２（ｑ，Ｊ＝７．５Ｈｚ，２Ｈ），３．５４（ｄ，Ｊ＝６．６Ｈｚ，２Ｈ），４．０５（ｓ，２Ｈ），４．２６（ｍ，２Ｈ），５．１４（ｓ，２Ｈ），５．２７（ｍ，１Ｈ）ｐｐｍ。

(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 in vacuo and the crude material was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organic layers were washed with aqueous sodium bicarbonate and dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo yielded 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 ): δ = 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−ブロモメチル−ペンタ−２−エニル）−５−エチル−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン）
５−エチル−６−（３−ヒドロキシメチル−ペンタ−２−エニル）−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン（３５．４ｍｇ、０．０９０ｍｍｏｌ）をＤＣＭ（３．０ｍＬ）に溶解した。重合体が結合したトリフェニルホスフィン（３ｍｍｏｌ／ｇ、９０．７ｍｇ）を加え、その混合物を、室温で、機械的に攪拌した。四臭化炭素（９０．２ｍｇ、０．２７２ｍｍｏｌ）を加え、その溶液を室温で攪拌した。２時間後、その反応物を濾過し、そして真空中で溶媒を除去した。この粗製物質をシリカゲルクロマトグラフィーで精製して、３２．０ｍｇ（７８％）の所望生成物を得た。この物質を、さらに性質決定することなく、次の工程で使用した。

(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, 0. 090 mmol) was dissolved in DCM (3.0 mL). Polymer-bound triphenylphosphine (3 mmol / g, 90.7 mg) was added and the mixture was mechanically stirred at room temperature. Carbon tetrabromide (90.2 mg, 0.272 mmol) was added and the solution was stirred at room temperature. After 2 hours, the reaction was filtered and the solvent removed in vacuo. The crude material was purified by silica gel chromatography to give 32.0 mg (78%) of the desired product. This material was used in the next step without further characterization.

（［２−エチル−４−（６−エチル−４−ヒドロキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−ブタ−２−エニル］−ホスホン酸）
６−（３−ブロモメチル−ペンタ−２−エニル）−５−エチル−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン（３２ｍｇ、０．０７０ｍｍｏｌ）の亜リン酸トリメチル（０．８ｍＬ）溶液を、１１０℃で、加熱した。２時間後、その反応は完結した。この反応物を室温まで冷却し、そして真空中で過剰の亜リン酸トリメチルを除去した。その粗製物質を、さらに精製することなく、次の工程で使用した。

([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 at 110 ° C. After 2 hours, the reaction was complete. The reaction was cooled to room temperature and excess trimethyl phosphite was removed in vacuo. The crude material was used in the next step without further purification.

The crude product of this 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 removed in vacuo 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): δ = 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): δ = 22.26 ppm; MS = 355 [M ⁺ +1].

(Example 319)
Representative compounds of the present invention can be prepared as illustrated below.

（（２−｛４−［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−エチル）−ホスホン酸ジエチルエステル）
４−［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エナール（１９．７ｍｇ、０．０５２ｍｍｏｌ）およびアミノエチルホスホン酸ジエチルエステルシュウ酸塩（１５．６ｍｇ、０．０５７ｍｍｏｌ）をＤＭＦ（０．５ｍＬ）に溶解した。酢酸（１５．７ｍｇ、０．２６３ｍｍｏｌ）を加え、続いて、トリアセトキシホウ水素化ナトリウム（２２．３ｍｇ、０．１０５ｍｍｏｌ）を加えた。４時間後、その粗反応混合物をＲＰ−ＨＰＬＣ（溶離液：水／ＭｅＣＮ）で精製して、凍結乾燥後、２７．７ｍｇ（９７％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝０．０４（ｓ，９Ｈ），１．１４（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．２６（ｍ，２Ｈ），１．３０（ｔ，Ｊ＝７．２Ｈｚ，６Ｈ），１．９５（ｓ，３Ｈ），２．１９（ｓ，３Ｈ），２．２３（ｍ，２Ｈ），２．６８（ｑ，Ｊ＝７．５Ｈｚ，２Ｈ），３．１８（ｍ，２Ｈ），３．５３（ｓ，２Ｈ），４．１３（ｍ，４Ｈ），４．２８（ｍ，２Ｈ），５．１５（ｓ，２Ｈ），５．５１（ｍ，１Ｈ）ｐｐｍ；^３１Ｐ ＮＭＲ（１２１ＭＨｚ，ＣＤＣｌ_３）：δ＝２７．３９ｐｐｍ；ＭＳ＝５４０［Ｍ^＋＋１］。

((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 ): δ = 0.04 (s, 9H), 1.14 (t, J = 7.5 Hz, 3H), 1.26 (m, 2H), 1.30 (t , J = 7.2 Hz, 6H), 1.95 (s, 3H), 2.19 (s, 3H), 2.23 (m, 2H), 2.68 (q, J = 7.5 Hz, 2H) ), 3.18 (m, 2H), 3.53 (s, 2H), 4.13 (m, 4H), 4.28 (m, 2H), 5.15 (s, 2H), 5.51 (M, 1H) ppm; ³¹ P NMR (121 MHz, CDCl ₃ ): δ = 27.39 ppm; MS = 540 [M ⁺ +1].

（｛２−［４−（６−エチル−４−ヒドロキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルアミノ］−エチル｝−ホスホン酸）
（２−｛４−［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニルアミノ｝−エチル）−ホスホン酸ジエチルエステル（２７．７ｍｇ、０．０５１ｍｍｏｌ）をＤＭＦ（０．５ｍＬ）およびＤＣＭ（０．５ｍＬ）に溶解した。臭化トリメチルシリル（７８．３ｍｇ、０．５１２ｍｍｏｌ）を加え、その反応物を室温で攪拌した。２０時間後、この反応をＭｅＯＨ（０．３ｍＬ）でクエンチした。真空中で溶媒を蒸発させ、その粗製物質をＲＰ−ＨＰＬＣ（溶離液：水／ＭｅＣＮ）で精製した。生成物を含有する画分を合わせ、そして凍結乾燥して、１４．２ｍｇ（５７％）の遊離ホスホン酸［ＭＳ：４８４ Ｍ^＋＋１］を得た。

({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-buta -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 in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN). Fractions containing product were combined and lyophilized to give 14.2 mg (57%) of free phosphonic acid [MS: 484 M ⁺ +1].

This material was dissolved in DCM (0.5 mL). TFA (0.05 mL) was added and stirring at room temperature was continued. After 20 minutes, the solvent was removed in vacuo 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 the TFA salt. ¹ H NMR (300 MHz, DMSO-d6): δ = 1.07 (t, J = 7.5 Hz, 3H), 1.84 (s, 3H), 1.90 (m, 2H), 2.11 ( s, 3H), 2.63 (q, J = 7.5 Hz, 2H), 2.99 (m, 2H), 3.43 (d, J = 6.3 Hz, 2H), 3.51 (s, 2H), 5.26 (s, 2H), 5.45 (m, 1H) ppm; ³¹ P NMR (121 MHz, DMSO-d6): δ = 20.02 ppm; MS = 384 [M ⁺ +1].

（（２−｛２−エチル−４−［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−ブタ−２−エニルアミノ｝−エチル）−ホスホン酸ジエチルエステル）
２−エチル−４−［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−ブタ−２−エナール（２６．６ｍｇ、０．０６８ｍｍｏｌ）およびアミノエチルホスホン酸ジエチルエステルシュウ酸塩（２０．４ｍｇ、０．０７５ｍｍｏｌ）をＤＭＦ（０．８ｍＬ）に溶解した。酢酸（２０．５ｍｇ、０．３４２ｍｍｏｌ）を加え、続いて、トリアセトキシホウ水素化ナトリウム（２７．６ｍｇ、０．１３７ｍｍｏｌ）を加えた。８時間後、その粗反応混合物をＲＰ−ＨＰＬＣ（溶離液：水／ＭｅＣＮ）で精製して、凍結乾燥後、２４．９ｍｇ（６５％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝０．０５（ｓ，９Ｈ），１．１０−１．２４（ｍ，８Ｈ），１．３５（ｔ，Ｊ＝７．５Ｈｚ，６Ｈ），２．１９（ｓ，３Ｈ），２．２３（ｍ，２Ｈ），２．３５（ｑ，Ｊ＝７．８Ｈｚ，２Ｈ），２．７０（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），３．２５（ｍ，２Ｈ），３．５６（ｍ，４Ｈ），４．１５（ｍ，４Ｈ），４．２９（ｍ，２Ｈ），５．１５（ｓ，２Ｈ），５．４７（ｍ，１Ｈ）ｐｐｍ；^３１Ｐ ＮＭＲ（１２１ＭＨｚ，ＣＤＣｌ_３）：δ＝２７．７１ｐｐｍ；ＭＳ＝５５４［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 mixture 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 ): δ = 0.05 (s, 9H), 1.10-1.24 (m, 8H), 1.35 (t, J = 7.5 Hz, 6H), 2 .19 (s, 3H), 2.23 (m, 2H), 2.35 (q, J = 7.8 Hz, 2H), 2.70 (q, J = 7.2 Hz, 2H), 3.25 (M, 2H), 3.56 (m, 4H), 4.15 (m, 4H), 4.29 (m, 2H), 5.15 (s, 2H), 5.47 (m, 1H) ³¹ P NMR (121 MHz, CDCl ₃ ): δ = 27.71 ppm; MS = 554 [M ⁺ +1].

（｛２−［２−エチル−４−（６−エチル−４−ヒドロキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−ブタ−２−エニルアミノ］−エチル｝−ホスホン酸）
（２−｛２−エチル−４−［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−ブタ−２−エニルアミノ｝−エチル）−ホスホン酸ジエチルエステル（２４．９ｍｇ、０．０４５ｍｍｏｌ）をＤＭＦ（０．５ｍＬ）およびＤＣＭ（０．５ｍＬ）に溶解した。臭化トリメチルシリル（６８．７ｍｇ、０．４４９ｍｍｏｌ）を加え、その反応物を室温で攪拌した。２０時間後、この反応をＭｅＯＨ（０．１５ｍＬ）でクエンチした。真空中で溶媒を蒸発させ、その粗製物質をＲＰ−ＨＰＬＣ（溶離液：水／ＭｅＣＮ）で精製した。生成物を含有する画分を合わせ、そして凍結乾燥して、８．０ｍｇの遊離ホスホン酸［ＭＳ：４９８ Ｍ^＋＋１］を得た。

({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] -buta -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 in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN). Fractions containing product were combined and lyophilized to yield 8.0 mg of free phosphonic acid [MS: 498 M ⁺ +1].

This material was dissolved in DCM (0.5 mL). TFA (0.05 mL) was added and stirring at room temperature was continued. After 20 minutes, the solvent was removed in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN ^* 0.1% TFA). Fractions containing the product were combined and lyophilized to give 4.4 mg (54%) of product as the TFA salt. ¹ H NMR (300 MHz, DMSO-d6): δ = 1.05 (m, 6H), 1.60 (m, 2H), 2.10 (s, 3H), 2.67 (q, J = 7. 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 (121 MHz, DMSO-d6): δ = 16.93 ppm; MS = 398 [M ⁺ +1].

(Example 320)
Representative compounds of the present invention can be prepared as illustrated below.

（２−（｛４−［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−フェノキシ−ホスフィノイルアミノ）−プロピオン酸エチルエステル）
４−［６’−エチル−７’−メチル−３’−オキソ−４’−（２”−トリメチルシラニル−エトキシ）−１’，３’−ジヒドロ−イソベンゾフラン−５’−イル］−２−メチル−ブタ−２−エン−ホスホン酸（４４．８ｍｇ、０．１０１ｍｍｏｌ）、ジシクロヘキシルカルボジイミド（５２．６ｍｇ、０．２５４ｍｍｏｌ）およびフェノール（９５．８ｍｇ、１．０１８ｍｍｏｌ）をピリジン（０．３ｍＬ）に溶解し、そして７０℃で、４時間加熱した。その反応混合物を室温まで冷却し、そして真空中でピリジンを除去した。その粗製物質をＤＣＭとＨＣｌ（０．１Ｎ）との間で分配した。その水層をＤＣＭで抽出し、そして合わせた有機層を硫酸ナトリウムで乾燥した。濾過し、そして真空中で溶媒を蒸発させると、粗製物質が生じ、これを、さらに精製することなく、次の工程で使用した。

(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) in pyridine (0.3 mL) And heated for 4 hours at 70 ° C. The reaction mixture was cooled to room temperature and the pyridine was removed in vacuo The crude material was partitioned between DCM and HCl (0.1 N). The aqueous layer was extracted with DCM and the combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to yield a crude material that was further filtered. Used in the next step without further purification.

  This 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 solvent was removed in vacuo and the crude material was partitioned between chloroform and aqueous HCl (1N). The aqueous layer was extracted with chloroform. The combined organic layers were dried with sodium sulfate. Filtration and evaporation of the solvent yielded the crude product as a mixture of monophenyl ester and its 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 at room temperature was continued. After 20 minutes, complete conversion of the anhydride was observed. After 2 hours, PyBOP (101 mg, 0.202 mmol) was added and stirring at room temperature was continued. 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 ): δ = 0.03 (s, 9H), 1.13-1.28 (m, 8H), 2.03 (s, 3H), 2.19 (s, 3H) ), 2.62-2.74 (m, 4H), 3.38 (m, 1H), 3.53 (t, J = 6.3 Hz, 2H), 4.03 (m, 3H), 4. 30 (m, 2H), 5.14 (s, 2H), 5.31 (m, 1H), 7.11-7.17 (m, 3H), 7.25-7.30 (m, 2H) ³¹ P NMR (121 MHz, CDCl ₃ ): δ = 27.04, 27.73 ppm; MS = 615 [M ⁺ +1].

（２−｛［４−（６−エチル−４−ヒドロキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−フェノキシ−ホスフィノイルアミノ｝−プロピオン酸エチルエステル）
２−（｛４−［６−エチル−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−フェノキシ−ホスフィノイルアミノ）−プロピオン酸エチルエステル（７．５ｍｇ、０．０１２ｍｍｏｌ）を、−２０℃で、ＴＦＡ／ＤＣＭ（１０％、０．３ｍＬ）に溶解した。その反応混合物を０℃まで温め、この温度で、４５分間攪拌した。ピリジン（０．０９ｍＬ）を加え、そして真空中で溶媒を除去した。その粗製物質をＲＰ−ＨＰＬＣ（溶離液：水／ＭｅＣＮ）で精製した。生成物を含有する画分を合わせ、そして凍結乾燥すると、白色粉末（５．５ｍｇ、８７％）が生じた。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝１．１２−１．２９（ｍ，６Ｈ），２．０３（ｓ，３Ｈ），２．１７（ｓ，３Ｈ），２．６５−２．７４（ｍ，４Ｈ），３．３８（ｍ，１Ｈ），３．５３（ｔ，Ｊ＝６．３Ｈｚ，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；^３１Ｐ ＮＭＲ（１２１ＭＨｚ，ＣＤＣｌ_３）：δ＝２７．１１，２７．５７ｐｐｍ；ＭＳ＝５１５［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-buta 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 in vacuo. The crude material was purified by RP-HPLC (eluent: water / MeCN). Fractions containing product were combined and lyophilized to yield a white powder (5.5 mg, 87%). ¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.12-1.29 (m, 6H), 2.03 (s, 3H), 2.17 (s, 3H), 2.65-2.74 (M, 4H), 3.38 (m, 1H), 3.53 (t, J = 6.3 Hz, 2H), 4.03 (m, 3H), 5.22 (s, 2H), 5. 36 (m, 1H), 7.11-7.16 (m, 3H), 7.24-7.30 (m, 2H), 7.72 (m, 1H) ppm; ³¹ P NMR (121 MHz, CDCl ₃ ): δ = 27.11, 27.57 ppm; MS = 515 [M ⁺ +1].

(Example 321)
Representative compounds of the present invention can be prepared as illustrated below.

（６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸）
メタノール（２０ｍＬ）および水（７ｍＬ）の混合物中の６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸メチルエステル（１．５ｇ、３．４５ｍｍｏｌ）および水酸化ナトリウム（５５２ｍｇ）の混合物を、室温で、１時間攪拌した。その溶液を１Ｎ ＨＣｌで酸性化した。その沈殿物を吸引濾過により集め、そして水で洗浄して、所望生成物（１．２ｇ、８３％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）d０．０２（ｓ，９Ｈ），１．１５−１．２２（ｍ，２Ｈ），１．７６（ｓ，３Ｈ），２．１３（ｓ，３Ｈ），２．１２−２．２８（ｍ，２Ｈ），２．３５−２．４１（ｍ，２Ｈ），３．３７（ｄ，２Ｈ，Ｊ＝７Ｈｚ），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-hex-4- Enoic acid)
6- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5 in a mixture of methanol (20 mL) and water (7 mL). A mixture of -yl] -4-methyl-hex-4-enoic 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−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エノイルアミノ｝−メチル）−ホスホン酸ジエチルエステル）
６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸（５０ｍｇ、０．１２ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液に、０℃で、クロロギ酸イソブチル（１７μＬ、０．１３ｍｍｏｌ）およびトリエチルアミン（５０μＬ、０．３６ｍｍｏｌ）を加えた。０℃で２時間攪拌した後、ジエチル（アミノメチル）ホスホネートオキサレート（６２ｍｇ、０．２６ｍｍｏｌ）を加え、そして室温での攪拌を２０分間継続した。溶媒を除去した後、その残留物を分取逆相ＨＰＬＣで精製して、５４．８ｍｇ（８１％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）d０．０３（ｓ，９Ｈ），１．１５−１．２２（ｍ，２Ｈ），１．３１（ｔ，６Ｈ），１．８１（ｓ，３Ｈ），２．１８（ｓ，３Ｈ），２．３０（ｍ，４Ｈ），３．４１（ｄ，２Ｈ，Ｊ＝７Ｈｚ），３．６５（ｄｄ，２Ｈ，Ｊ＝６，１２Ｈｚ），３．７７（ｓ，３Ｈ），３．７７−４．１６（ｍ，４Ｈ），４．２６−４．３２（ｍ，２Ｈ），５．１２（ｓ，２Ｈ），５．１７−５．１９（ｍ，１Ｈ），５．８６（ｂｓ，１Ｈ）ｐｐｍ；^３１Ｐ （１２１．４ＭＨｚ，ＣＤＣｌ_３）d２３．０１ｐｐｍ；ＭＳ（ｍ／ｚ）５６８［Ｍ−Ｈ］⁻，５９２［Ｍ＋Ｎａ］^＋。

(({6- [6-Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hexa- 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 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol). After stirring at 0 ° C. for 2 hours, diethyl (aminomethyl) phosphonate oxalate (62 mg, 0.26 mmol) was added and stirring at room temperature was continued for 20 minutes. After removal of the solvent, the residue was purified by preparative reverse phase HPLC to give 54.8 mg (81%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) 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−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エノイルアミノ］−メチル｝−ホスホン酸）
（｛６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エノイルアミノ｝−メチル）−ホスホン酸ジエチルエステル（４０ｍｇ、０．０７ｍｍｏｌ）のアセトニトリル（１ｍＬ）溶液に、ＴＭＳＢｒ（９１μＬ、０．７ｍｍｏｌ）を加え、続いて、２，６−ルチジン（８１．５μＬ、０．７ｍｍｏｌ）を加えた。その反応を一晩進行させ、そのとき、ＬＣＭＳで判定したとき、この反応が完結していた。その反応混合物をＭｅＯＨでクエンチし、そして乾燥状態まで濃縮した。その残留物を分取逆相ＨＰＬＣで精製して、白色固形物として、２．６ｍｇ（９％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δ１．６７（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；^３１Ｐ （１２１．４ＭＨｚ，ＣＤ_３ＯＤ）d１０．２７ｐｐｍ；ＭＳ（ｍ／ｚ）４１２［Ｍ−Ｈ］⁻，４１４［Ｍ＋Ｈ］^＋．
（実施例３２２）
本発明の代表的な化合物は、以下で図示するように、調製できる。

({[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-hexa-4 -Enoylamino} -methyl) -phosphonic acid diethyl ester (40 mg, 0.07 mmol) in acetonitrile (1 mL) was added TMSBr (91 μL, 0.7 mmol) followed by 2,6-lutidine (81.5 μL, 0.7 mmol) was added. The reaction was allowed to proceed overnight, at which time the reaction was complete as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by preparative reverse phase HPLC to give 2.6 mg (9%) of the desired product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.67 (s, 3H), 2.17 (m, 5H), 2.30-2.46 (m, 2H), 2.80-2.86 (m , 2H), 3.55 (m, 2H), 3.82 (s, 3H), 5.26 (s, 3H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) d 10.27 ppm; MS (m / Z) 412 [M−H] ⁻ , 414 [M + H] ⁺ .
(Example 322)
Representative compounds of the present invention can be prepared as illustrated below.

（（２−｛６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エノイルアミノ｝−エチル）−ホスホン酸ジエチルエステル）
６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸（５０ｍｇ、０．１２ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液に、０℃で、クロロギ酸イソブチル（１７μＬ、０．１３ｍｍｏｌ）およびトリエチルアミン（５０μＬ、０．３６ｍｍｏｌ）を加えた。０℃で２時間攪拌した後、ジエチル（アミノエチル）ホスホネートオキサレート（６２ｍｇ、０．２６ｍｍｏｌ）を加え、そして室温での攪拌を１時間継続した。溶媒を除去した後、その残留物を分取逆相ＨＰＬＣで精製して、白色固形物として、３７ｍｇ（５４％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）d０．０３（ｓ，９Ｈ），１．１５−１．２２（ｍ，２Ｈ），１．３１（ｔ，６Ｈ），１．８１（ｓ，３Ｈ），１．８５−１．９３（ｍ，２Ｈ），２．１８（ｓ，３Ｈ），２．３０（ｍ，４Ｈ），３．４１（ｄ，２Ｈ，Ｊ＝７Ｈｚ），３．４８−３．５４（ｍ，２Ｈ），３．７７（ｓ，３Ｈ），３．７７−４．１６（ｍ，４Ｈ），４．２６−４．３２（ｍ，２Ｈ），５．１２（ｓ，２Ｈ），５．１７−５．１９（ｍ，１Ｈ），６．３０（ｂｓ，１Ｈ）ｐｐｍ；^３１Ｐ （１２１．４ＭＨｚ，ＣＤＣｌ_３）d２９．９１ｐｐｍ；ＭＳ（ｍ／ｚ）５８４［Ｍ＋Ｈ］^＋。

((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 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol). After stirring at 0 ° C. for 2 hours, diethyl (aminoethyl) phosphonate oxalate (62 mg, 0.26 mmol) was added and stirring at room temperature was continued for 1 hour. After removal of the solvent, the residue was purified by preparative 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−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−ヘキサ−４−エノイルアミノ］−エチル｝−ホスホン酸）
（２−｛６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エノイルアミノ｝−エチル）−ホスホン酸ジエチルエステル（３６．６ｍｇ、０．０６３ｍｍｏｌ）のアセトニトリル（１ｍＬ）溶液に、ＴＭＳＢｒ（８１μＬ、０．６３ｍｍｏｌ）を加え、続いて、２，６−ルチジン（７３μＬ、０．６３ｍｍｏｌ）を加えた。その反応を一晩進行させ、そのとき、ＬＣＭＳで判定したとき、この反応が完結していた。この反応混合物をＭｅＯＨでクエンチし、そして乾燥状態まで濃縮した。その残留物を分取逆相ＨＰＬＣで精製して、白色固形物として、５．８ｍｇ（２９％）の所望生成物を得た。^１Ｈ ＮＭＲ （３００ＭＨｚ，ＣＤ_３ＯＤ）d１．８０（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；^３１Ｐ （１２１．４ＭＨｚ，ＣＤ_３ＯＤ）d２６．０３ｐｐｍ；ＭＳ（ｍ／ｚ）４２６［Ｍ−Ｈ］⁻，４２８［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-hexa 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 μL, 0.63 mmol) followed by 2,6-lutidine ( 73 μL, 0.63 mmol) was added. The reaction was allowed to proceed overnight, at which time the reaction was complete as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by preparative reverse phase HPLC to give 5.8 mg (29%) of the desired product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) 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) d26.03 ppm; MS (m / z) 426 [M−H] ⁻ , 428 [M + H] ⁺ .

(Example 323)
Representative compounds of the present invention can be prepared as illustrated below.

（｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−ホスホン酸ジフェニルエステル）
［｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−ホスホン酸（２６０ｍｇ、０．５９ｍｍｏｌ）のＤＭＦ（６ｍＬ）およびフェノール（５５５ｍｇ、５．９ｍｍｏｌ）溶液に、ジシクロヘキシルカルボジイミド（１．２１ｇ、５．９ｍｍｏｌ）およびＤＭＡＰ（３６ｍｇ、０．２９５ｍｍｏｌ）を加えた。その反応混合物を、３０分間にわたって、１４０℃まで加熱した。室温まで冷却した後、この混合物をＥｔＯＡｃ／ヘキサン（１：１）と５％ＬｉＣｌ水溶液との間で分配した。その有機層を５％ＬｉＣｌ水溶液で繰り返し洗浄し、次いで、Ｎａ_２ＳＯ_４で乾燥した。溶媒を除去した後、その残留物をシリカゲルクロマトグラフィーで精製して、７５ｍｇ（２１％）の所望生成物を得た。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 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 to 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 layer was washed repeatedly with 5% aqueous LiCl and then dried over Na ₂ SO ₄ . After removing the solvent, the residue was purified by silica gel chromatography to give 75 mg (21%) of the desired product. MS (m / z) 617 [M + Na] ^< +>.

（｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−ホスホン酸モノフェニルエステル）
｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−ホスホン酸ジフェニルエステル（７５ｍｇ、０．１２６ｍｍｏｌ）のＴＨＦ（５ｍＬ）溶液に、１Ｎ ＮａＯＨ（０．１ｍＬ）溶液を加えた。その混合物を、室温で、１６時間攪拌した。ＥｔＯＡｃを加え、得られた混合物を１Ｈ ＨＣｌで洗浄した。その有機層を乾燥状態まで濃縮し、その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、２４．８ｍｇ（３８％）の所望生成物を得た。ＭＳ（ｍ／ｚ）５１７［Ｍ−Ｈ］⁻、５４１［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- A solution of 1N NaOH (0.1 mL) was added to a THF (5 mL) solution of enyl} -phosphonic acid diphenyl ester (75 mg, 0.126 mmol). The mixture was stirred at room temperature for 16 hours. EtOAc was added and the resulting mixture was washed with 1H HCl. The organic layer is concentrated to dryness and the residue is purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA). 24.8 mg (38%) of the desired product. MS (m / z) 517 [MH] ^- , 541 [M + Na] ^< +>.

（２−（｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−フェノキシ−ホスフィノイルオキシ）−プロピオン酸エチルエステル）
｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−ホスホン酸モノフェニルエステル（２５ｍｇ、０．０４８ｍｍｏｌ）および（Ｓ）−（−）−乳酸エチル（３４ｍｇ、０．２８８ｍｍｏｌ）のピリジン（１ｍＬ）溶液に、ＰｙＢＯＰ（１２５ｍｇ、０．２４ｍｍｏｌ）を加えた。この溶液を、室温で、１６時間攪拌し、そして濃縮した。その残留物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、２４ｍｇ（８３％）の所望生成物を得た。ＭＳ（ｍ／ｚ）６４１［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 (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) to yield 24 mg (83%) of the desired product. I got a thing. MS (m / z) 641 [M + Na] ^< +>.

（２−｛［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−フェノキシ−ホスフィノイルオキシ｝−プロピオン酸エチルエステル）
２−（｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−フェノキシ−ホスフィノイルオキシ）−プロピオン酸エチルエステル（２４ｍｇ、０．０３９ｍｍｏｌ）のＤＣＭ（１ｍＬ）溶液に、ＴＦＡ（０．５ｍＬ）を加え、その混合物を、室温で、１０分間攪拌した。この反応混合物を減圧下にて乾燥し、その残留物をＲＰ−ＨＰＬＣで精製して、透明オイルとして、１８ｍｇ（９０％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，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＝７．２Ｈｚ，１Ｈ），７．０５−７．１８（ｍ，５Ｈ）ｐｐｍ；^３１Ｐ （１２１．４ＭＨｚ，ＣＤＣｌ_３）d２４．５９，２６．１３ｐｐｍ；ＭＳ（ｍ／ｚ）５１７［Ｍ−Ｈ］⁻，５１９［Ｍ＋Ｈ］^＋。

(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-buta 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 added at room temperature for 10 Stir for minutes. The reaction mixture was dried under reduced pressure and the residue was purified by RP-HPLC to give 18 mg (90%) of the desired product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) 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 324)
Representative compounds of the present invention can be prepared as illustrated below.

（２−｛［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−フェノキシ−ホスフィノイルオキシ｝−プロピオン酸）
２−｛［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−フェノキシ−ホスフィノイルオキシ｝−プロピオン酸エチルエステル（１０ｍｇ、０．０１９ｍｍｏｌ）のＴＨＦ（３ｍＬ）溶液に、１Ｎ ＮａＯＨ（２３２μＬ）を加え、その混合物を、室温で、１時間攪拌した。この反応混合物を減圧下にて乾燥し、その残留物をＲＰ−ＨＰＬＣで精製して、透明オイルとして、６ｍｇ（７７％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）d１．４１（ｄ，Ｊ＝７Ｈｚ，３Ｈ），１．９７（ｓ，３Ｈ），２．１６（ｓ，３Ｈ），２．５９（ｄ，Ｊ＝２２Ｈｚ，２Ｈ），３．４５（ｍ，２Ｈ），３．７９（ｓ，３Ｈ），４．８３（ｍ，１Ｈ），５．２６（ｓ，２Ｈ），５．４３（ｔ，Ｊ＝７．２Ｈｚ，１Ｈ）ｐｐｍ；^３１Ｐ （１２１．４ＭＨｚ，ＣＤ_３ＯＤ）d２７．０２ｐｐｍ；ＭＳ（ｍ／ｚ）４１３［Ｍ−Ｈ］⁻，４１５［Ｍ＋Ｈ］^＋。

(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 μL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was dried under reduced pressure and the residue was purified by RP-HPLC to give 6 mg (77%) of the desired product as a clear oil. ¹ H NMR (300 MHz, CD ₃ OD) 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 325)
Representative compounds of the present invention can be prepared as illustrated below.

（２−｛［４−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニル］−フェノキシ−ホスフィノイルアミノ｝−プロピオン酸エチルエステル）
｛４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エニル｝−ホスホン酸モノフェニルエステル（１ｇ、約１．９ｍｍｏｌ）をｐｙＢＯＰ（２ｇ、４ｍｍｏｌ）およびＤＭＡＰ（１２０ｍｇ、０．９６ｍｍｏｌ）と混ぜ合わせた。このモノ酸混合物にＬ−アラニンエチルエステル塩酸塩（２．９ｇ、１９ｍｍｏｌ）およびジイソプロピルエチルアミン（６．７ｍＬ、３８ｍｍｏｌ）のピリジン（５ｍＬ）溶液を加え、その反応物を、室温で、１２時間攪拌した。次いで、この反応混合物を濃縮し、そしてカラムクロマトグラフィー（１％ＭｅＯＨ／ＣＨ_２Ｃｌ_２ ３％ＭｅＯＨ／ＣＨ_２Ｃｌ_２）で２回精製した。得られたオイルを、−４０℃で、１０％ＴＦＡ／ＣＨ_２Ｃｌ_２（３０ｍＬ）の激しく攪拌した溶液に溶解した。約３時間後、この反応は完結した。ピリジン（４．５ｍＬ）を加え、この反応混合物を濃縮した。その生成物を分取ＴＬＣ（５％ＭｅＯＨ／ＣＨ_２Ｃｌ_２）で精製し、そして濃縮して、淡黄色オイルとして、２１０ｍｇ（２１％）の所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．８３−７．７０（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；^３１Ｐ ＮＭＲ（１２１ＭＨｚ，ＣＤＣｌ_３）δ２８．０，２７．５ｐｐｍ；ＭＳ（ｍ／ｚ）５１６［Ｍ−Ｈ］⁻。

(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). To this monoacid mixture was added L-alanine ethyl ester hydrochloride (2.9 g, 19 mmol) and diisopropylethylamine (6.7 mL, 38 mmol) in pyridine (5 mL) 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 a vigorously stirred solution of 10% TFA / CH ₂ Cl ₂ (30 mL) at −40 ° C. After about 3 hours, the reaction was complete. Pyridine (4.5 mL) was added and the reaction mixture was concentrated. The product was purified by preparative TLC (5% MeOH / CH ₂ Cl ₂ ) and concentrated to 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 326)
Representative compounds of the present invention can be prepared as illustrated below.

（２−（ジメトキシ−ホスホリル）−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸メチルエステル）
トリメチルホスホノアセテート（６３μＬ、０．３９ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液に、室温で、ＮａＮ（ＴＭＳ）_２（０．３９ｍｍｏｌ、０．３９ｍＬ）を加えた。３０分後、６−（４−ブロモ−３−メチル−ブタ−２−エニル）−５−メトキシ−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン（６９ｍｇ、０．１５６ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液を加えた。その反応混合物を２時間攪拌し、そのとき、沈殿物が認められた。この反応混合物を、塩化アンモニウムの飽和水溶液を加えて生成物をＥｔＯＡｃで抽出することにより、ワークアップした。その有機抽出物を乾燥し、この生成物を、シリカゲルクロマトグラフィー（これは、０〜１００％のＥｔＯＡｃ−ヘキサンを使う）を使用して精製して、無色オイルとして、４０ｍｇの所望生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）d０．０５（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＝４，１２，２３Ｈｚ），３．３９（ｄ，２Ｈ，Ｊ＝７Ｈｚ），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＝７Ｈｚ）ｐｐｍ；^３１Ｐ （１２１．４ＭＨｚ，ＣＤＣｌ_３）d２５．１ｐｐｍ；ＭＳ（ｍ／ｚ）５６５．２［Ｍ＋Ｎａ］^＋。

(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 μL, 0.39 mmol) in THF (1 mL) at room temperature was added NaN (TMS) ₂ (0.39 mmol, 0.39 mL). 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 when a precipitate was observed. The reaction mixture was worked up by adding a saturated aqueous solution of ammonium chloride and extracting the product with EtOAc. The organic extract is dried and the product is purified using silica gel chromatography (which uses 0-100% EtOAc-hexanes) to give 40 mg of the desired product as a colorless oil. It was. 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−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−４−メチル−２−ホスホノ−ヘキサ−４−エン酸メチルエステル）
２−（ジメトキシ−ホスホリル）−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸メチルエステル（３０ｍｇ、０．０５５ｍｍｏｌ）のアセトニトリル（２ｍＬ）溶液に、臭化トリメチルシリル（０．１８ｍＬ）を加えた。１０分後、その反応物に、室温で、２，６−ルチジン（０．１６ｍＬ）を加えた。この反応を、１６時間進行し、その後乾燥状態まで濃縮した。その残留物を、ＤＭＦ：Ｈ_２Ｏ（８：２、１ｍＬ）の溶液に懸濁し、そしてＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、白色粉末として、１８ｍｇの生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）d１．８１（ｓ，３Ｈ），２．１６（ｓ，３Ｈ），２．４０−２．４９（ｍ，１Ｈ），２．６３（ｄｔ，１Ｈ，Ｊ＝６，１７Ｈｚ），３．０７（ｄｄｄ，１Ｈ，Ｊ＝４，１２，２３Ｈｚ），３．３８（３，２Ｈ，Ｊ＝７Ｈｚ），３．５２（ｓ，３Ｈ），３．７７（ｓ，３Ｈ），５．２５（ｓ，２Ｈ），５．２８（ｔ，１Ｈ，Ｊ＝７Ｈｚ）ｐｐｍ；^３１Ｐ （１２１．４ＭＨｚ，ＣＤＣｌ_３）d１９．５ｐｐｍ；ＭＳ（ｍ／ｚ）４１５．２［Ｍ＋Ｈ］^＋，４３７．２［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 -To a solution of methyl-hex-4-enoic acid methyl ester (30 mg, 0.055 mmol) in acetonitrile (2 mL) was added trimethylsilyl bromide (0.18 mL). After 10 minutes, 2,6-lutidine (0.16 mL) was added to the reaction at room temperature. The reaction proceeded for 16 hours and then concentrated to dryness. The residue was suspended in a solution of DMF: H ₂ O (8: _{2, 1} mL) and RP HPLC (which was a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA). , Using a C18 column) 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 327)
Representative compounds of the present invention can be prepared as illustrated below.

（２−（ビス−（２，２，２−トリフルオロエトキシ）ホスホリル）−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸メチルエステル）
［ビス−（２，２，２−トリフルオロ−エトキシ）−ホスホリル］−酢酸メチルエステル（１８６μＬ、０．８８ｍｍｏｌ）の無水ＴＨＦ（２ｍＬ）溶液に、１Ｎ ＮａＮ（ＴＭＳ）_２のＴＨＦ（０．８８ｍＬ、０．８８ｍｍｏｌ）溶液を加えた。この溶液を、室温で、３０分間攪拌し、それから、６−（４−ブロモ−３−メチル−ブタ−２−エニル）−５−メトキシ−４−メチル−７−（２−トリメチルシラニル−エトキシ）−３Ｈ−イソベンゾフラン−１−オン（９８ｍｇ、０．２２ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液を加えた。その反応混合物を一晩攪拌すると、そのとき、沈殿物が認められた。この反応混合物を、塩化アンモニウムの飽和水溶液を加えて生成物をＥｔＯＡｃで抽出することにより、ワークアップした。その有機抽出物を乾燥し、この生成物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、無色オイルとして、７２ｍｇ（４８％）の生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）d０．０５（ｓ，９Ｈ），１．２２（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．８１（ｓ，３Ｈ），２．１８（ｓ，３Ｈ），２．５−２．７（ｍ，２Ｈ），３．３（ｄｄｄ，１Ｈ，Ｊ＝４，１２，２３Ｈｚ），３．４０（ｄ，２Ｈ，Ｊ＝７Ｈｚ），３．６５（ｓ，３Ｈ），３．７６（ｓ，３Ｈ），４．２９−５．１３（ｍ，６Ｈ），５．１３（ｓ，２Ｈ），５．２８（ｔ，１Ｈ，Ｊ＝７Ｈｚ）ｐｐｍ；ＭＳ（ｍ／ｚ）７０１．２［Ｍ＋Ｎａ］^＋。

(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 μL, 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 is stirred for 30 minutes at room temperature and then 6- (4-bromo-3-methyl-but-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy). ) -3H-isobenzofuran-1-one (98 mg, 0.22 mmol) in THF (1 mL) was added. The reaction mixture was stirred overnight when a precipitate was observed. The reaction mixture was worked up by adding a saturated aqueous solution of ammonium chloride and extracting the product with EtOAc. The organic extract was dried and the product was purified by RP HPLC (which uses a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA) 72 mg (48%) of product was obtained as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) d 0.05 (s, 9H), 1.22 (t, 3H, J = 7 Hz), 1.81 (s, 3H), 2.18 (s, 3H), 2 5-2.7 (m, 2H), 3.3 (ddd, 1H, J = 4, 12, 23 Hz), 3.40 (d, 2H, J = 7 Hz), 3.65 (s, 3H) , 3.76 (s, 3H), 4.29-5.13 (m, 6H), 5.13 (s, 2H), 5.28 (t, 1H, J = 7 Hz) ppm; MS (m / m z) 701.2 [M + Na] ⁺ .

（２−（ビス−（２，２，２−トリフルオロエトキシ）ホスホリル）−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−ヒドロキシオキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸メチルエステル）
（［２−（ビス−（２，２，２−トリフルオロエトキシ）ホスホリル）−６−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−４−メチル−ヘキサ−４−エン酸メチルエステル（７０ｍｇ）を、１０％トリフルオロ酢酸のジクロロメタン（５ｍＬ）溶液に溶解した。１０分後、この混合物を濃縮し、その生成物をＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、無色オイルとして、４５ｍｇ（７５％）の生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，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＝７Ｈｚ），３．６５（ｓ，３Ｈ），３．７７（ｓ，３Ｈ），４．３３−４．４３（ｍ，４Ｈ），５．２１（ｓ，２Ｈ），５．３３（ｔ，１Ｈ，Ｊ＝７Ｈｚ）ｐｐｍ；^３１Ｐ （１２１．４ＭＨｚ，ＣＤＣｌ_３）d２５．８ｐｐｍ；ＭＳ（ｍ／ｚ）６０１．２［Ｍ＋Ｎａ］^＋。

(2- (Bis- (2,2,2-trifluoroethoxy) phosphoryl) -6- [6-methoxy-7-methyl-3-oxo-4- (2-hydroxyoxy) -1,3-dihydro- Isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid methyl ester)
([2- (Bis- (2,2,2-trifluoroethoxy) phosphoryl) -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1, 3-Dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid methyl ester (70 mg) was dissolved in 10% trifluoroacetic acid in dichloromethane (5 mL). And purified the product by RP HPLC (which is a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA, using a C18 column) as a colorless oil. 45 mg (75%) of product was obtained ¹ H NMR (300 MHz, CDCl ₃ ) d 1.81 (s, 3H), 2.16 (s, 3H), 2.5-2.7 (m, 2H) ), 3.3 (d d, 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 328)
Representative compounds of the present invention can be prepared as illustrated below.

（６−（４−ヒドロキシ−６−メトキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−［ヒドロキシ−（２，２，２−トリフルオロ−エトキシ）−ホスホリル］−４−メチル−ヘキサ−４−エン酸）
［ビス−（２，２，２−トリフルオロ−エトキシ）−ホスホリル］−酢酸メチルエステル（１８６μＬ、０．８８ｍｍｏｌ）の無水ＴＨＦ（０．５ｍＬ）溶液に、１Ｎ ＮａＯＨ（水溶液；０．０６ｍＬ）およびＮ−メチルピロリジノン（０．２ｍＬ）溶液を加えた。６．５時間後、１Ｎ ＮａＯＨの他のアリコート（０．０６ｍＬ）を加え、その混合物を一晩攪拌した。濃縮した後、その残留物をＤＭＦ（＜１ｍＬ）に懸濁し、数滴のＴＦＡで中和し、そしてＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ、０．１％ＴＦＡ−アセトニトリル、０．１％ＴＦＡの勾配で、Ｃ１８カラムを使用する）で精製して、凍結乾燥後、白色粉末として、５．６ｍｇ（７２％）の生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）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＝７Ｈｚ）ｐｐｍ；ＭＳ（ｍ／ｚ）５０５．２［Ｍ＋Ｎａ］^＋。

(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 μL, 0.88 mmol) in anhydrous THF (0.5 mL), 1N NaOH (aq; 0.06 mL) and N-methylpyrrolidinone (0.2 mL) solution was 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 (<1 mL), neutralized with a few drops of TFA, and RP HPLC (which was H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA). 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] ⁺ .

（実施例３２９）
本発明の代表的な化合物は、以下で図示するように、調製できる。

(Example 329)
Representative compounds of the present 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-phosphite] -2- Methyl-but-2-enyl} ester)
6- (4-Hydroxy-3-methyl-but-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (75 mg, 0 .20 mmol) and DIEA (49 μL, 0.28 mmol) in dioxane (2 mL) were added to Shadid, B. et al. et al. , Tetrahedron, 1989, 45, 12, 3889, 2-chloro-4H-1,3,2-benzodioxaphospholin-4-one (56.7 mg, 0.28 mmol) was added. After 10 minutes, another portion of 2-chloro-4H-1,3,2-benzodioxaphospholin-4-one (40 mg, 0.20 mmol) and DIEA (35 μL, 0.20 mmol) were added. The reaction proceeded for an additional hour at room temperature, after which the reaction was quenched by adding H ₂ O. The solution was stirred for an additional 10 minutes and concentrated in vacuo to a small volume. The product was triturated with diethyl ether and co-evaporated 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 (brs, 3H), 2.17 (s, 3H), 3 .46 (brs, 2H), 3.76 (s, 3H), 4.21-4.39 (m, 4H), 5.12 (s, 2H), 5.43-5.60 (m, 1H) ), 7.83 (brs, 1 H); ³¹ P (121.4 MHz, CDCl ₃ ) d 7.22; MS (m / z) 441 [M−H] ⁻ .

（実施例３３０）
本発明の代表的な化合物は、以下で図示するように、調製できる。

(Example 330)
Representative compounds of the present 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 -Buta-2-enyl} ester (27 mg, 0.06 mmol) in dioxane (1 mL) together with DIEA (21 μL, 0.12 mmol) and N, O-bis (trimethylsilyl) acetamide (29 μL, 0.12 mmol) Stir at room temperature for 3 hours. 2,2′-dipyridyl disulfide (16 mg, 0.072 mmol) was added to the reaction solution and the mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was diluted by adding H ₂ O and the solution was stirred for an additional 2 hours when it was concentrated. The residue was dissolved in a solution of 10% TFA / CH ₂ Cl ₂ and stirred at room temperature for 9 hours. The reaction mixture was dried under reduced pressure and the product was purified by reverse phase HPLC to give the desired product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) 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 331)
Some compounds of the invention are presented below.

（実施例３３２）
本発明のさらに他の代表的な化合物およびそれらの中間体は、以下で提示した方法に従って、調製できる。

(Example 332)
Still other representative compounds of the invention and their intermediates can be prepared according to the methods presented below.

（Ｒ_１、Ｒ_２が異なるフェンアセトアルデヒド（ｐｈｅｎａｃｅｔａｌｄｅｈｙｄｅ）の合成）
その親化合物（Ｒ_１＝ＯＭｅ；Ｒ_２＝Ｍｅ）は、以下のようにして、ミコフェノール酸からの半合成により、アクセス可能である：

(Synthesis of phenacetaldehyde having different R ₁ and R ₂ )
Its parent compound (R ₁ = OMe; R ₂ = Me) is accessible by semi-synthesis from mycophenolic acid as follows:

ミコフェノール酸（５００ｇ、１．５６ｍｏｌ）のＭｅＯＨ（４Ｌ）溶液に、窒素雰囲気下にて、硫酸（１０ｍＬ）を滴下し、その懸濁液を、室温で、攪拌した。２時間後、その反応物は、均一になり、その後すぐに、沈殿物が形成された。この反応物を、室温で、１０時間攪拌し、その時点で、ＴＬＣにより、反応が完結したことが明らかとなった。この反応物を、氷浴中にて、１０℃まで冷却し、次いで、ブフナー漏斗を使用し、濾過した。その濾過ケークを氷冷メタノール（７５０ｍＬ）で洗浄し、続いて、ヘキサン（７５０ｍＬ）で洗浄し、次いで、乾燥して、固形物として、４９７ｇ（９５％）の所望生成物を得た：^１Ｈ ＮＭＲ（３００ＭＨｚ，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＝７Ｈｚ），３．６２（ｓ，３Ｈ），３．７７（ｓ，３Ｈ），５．１３（ｓ，２Ｈ），５．２２（ｍ，１Ｈ），７．１７（ｓ，１Ｈ）。

To a solution of mycophenolic acid (500 g, 1.56 mol) in MeOH (4 L), sulfuric acid (10 mL) was added dropwise under a nitrogen atmosphere, and the suspension was stirred at room temperature. After 2 hours, the reaction became homogeneous and soon after that a precipitate formed. The reaction was stirred at room temperature for 10 hours, at which point TLC revealed that the reaction was complete. The reaction was cooled to 10 ° C. in an ice bath and then filtered using a Buchner funnel. The filter cake was washed with ice cold methanol (750 mL) followed by hexane (750 mL) and then 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).

ＴＨＦ（６０ｍＬ）中の溶液（３．９９ｇ、１１．９ｍｍｏｌ）、ＰＰｈ_３（４．６８ｇ、１７．９ｍｍｏｌ）およびアゾジカルボン酸ジイソプロピル（３．４６ｍＬ、１７．９ｍｍｏｌ）に、０℃で、２−トリメチルシリルエタノール（２．０５ｍＬ、１４．３ｍｍｏｌ）のＴＨＦ（２０ｍＬ）溶液を加えた。得られた黄色溶液を室温まで温め、そして４時間攪拌した。この溶液を乾燥状態まで濃縮してエーテルおよびヘキサンを加えることにより、この反応物をワークアップした。濾過によりトリフェニルホスフィンオキシドを除去し、その濾液を濃縮し、そしてシリカゲルクロマトグラフィーで精製して、４．８ｇ（１００％）の透明オイルを得た：^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）d０．０３（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＝７Ｈｚ），３．６２（ｓ，３Ｈ），３．７７（ｓ，３Ｈ），４．２５−４．３５（ｍ，２Ｈ），５．１３（ｓ，２Ｈ），５．１２−５．２２（ｍ，１Ｈ）。

To a solution in THF (60 mL) (3.99 g, 11.9 mmol), PPh ₃ (4.68 g, 17.9 mmol) and diisopropyl azodicarboxylate (3.46 mL, 17.9 mmol) at 0 ° C., 2- A solution of trimethylsilylethanol (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 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 4.8 g (100%) of a clear oil: ¹ H NMR (300 MHz, CDCl ₃ ) d0. 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).

ＭｅＯＨ（９０ｍＬ）、ＣＨ_２Ｃｌ_２（９０ｍＬ）およびピリジン（０．７ｍＬ）中の溶液（９．６ｇ、２２ｍｍｏｌ）を、ドライアイス／アセトン浴を使用して、−７０℃まで冷却した。その反応物が青色に着色するまで（１.５時間）、気体分散チューブを経由して、この反応物にオゾン流れを泡立たせた。このオゾンラインを窒素流れで置き換え、泡立ちをさらに３０分間継続し、その時点までに、この青色は消失した。この溶液に、−７０℃で、チオ尿素（１．２ｇ、１５．４ｍｍｏｌ）を一度に加え、この冷却浴を取り除いた。その反応物を室温まで温め、そして１５時間攪拌した。この反応物を濾過によりワークアップして、固形チオ尿素Ｓ−ジオキシドを除去し、次いで、ＣＨ_２Ｃｌ_２と水との間で分配した。その有機層を除去した。その水層をＣＨ_２Ｃｌ_２で洗浄し、そして有機抽出物を合わせ、１Ｎ ＨＣｌ水溶液、飽和ＮａＨＣＯ_３およびブラインで洗浄し、そして真空中で乾燥した。その残留物をシリカゲルクロマトグラフィーで精製して、白色固形物として、７．３ｇ（９９％）の生成物を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，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＝１Ｈｚ），４．２７−４．３９（ｍ，２Ｈ），５．１１（ｓ，２Ｈ），９．７２（ｄ，１Ｈ，Ｊ＝１Ｈｚ）。

A solution (9.6 g, 22 mmol) in MeOH (90 mL), CH ₂ Cl ₂ (90 mL) and pyridine (0.7 mL) was cooled to −70 ° C. using a dry ice / acetone bath. An ozone stream was bubbled through the reaction via a gas dispersion tube until the reaction colored blue (1.5 hours). The ozone line was replaced with a nitrogen stream and bubbling continued for another 30 minutes by which time the blue color had disappeared. To this solution was added thiourea (1.2 g, 15.4 mmol) in one portion at −70 ° C. and the cooling bath was removed. The reaction was warmed to room temperature and stirred for 15 hours. The reaction was worked up by filtration to remove solid thiourea S-dioxide and then partitioned between CH ₂ Cl ₂ and water. The organic layer was removed. The aqueous layer was washed with CH ₂ Cl ₂ and the organic extracts were combined, washed with 1N aqueous 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).

(Variants of _{R 1)}

この出発物質（これは、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９６，３９，４１８１−４１９６に従って、合成した）は、上記方法と類似の方法を使用して、所望のアルデヒドに変換される。

This starting material, which was synthesized according to J. Med.

この出発物質（これは、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９６，３９，４１８１−４１９６に従って、合成した）は、上記方法と類似の方法を使用して、所望のアルデヒドに変換される。

This starting material, which was synthesized according to J. Med.

この出発物質（これは、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９６，３９，４１８１−４１９６に従って、合成した）は、上記方法と類似の方法を使用して、所望のアルデヒドに変換される。

This starting material, which was synthesized according to J. Med.

このアルデヒドは、有機溶媒（例えば、メタノール）に溶解され、そしてホウ水素化ナトリウムが加えられる。その反応の終わりに、ＨＣｌ水溶液が加えられ、そして真空中で溶媒が除去される。さらなる精製は、クロマトグラフィーにより達成される。

The aldehyde is dissolved in an organic solvent (eg methanol) and sodium borohydride is added. At the end of the reaction, aqueous HCl is added and the solvent is removed in vacuo. Further purification is achieved by chromatography.

  The resulting alcohol is dissolved in an organic solvent (eg, dichloromethane (DCM)). Pyridine and acetic anhydride are added and stirring at room temperature is continued. At the end of the reaction, DCM is added and the solution is washed with aqueous HCl, aqueous sodium bicarbonate and dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo gives the crude product. Further purification is achieved by chromatography.

  This acetate is described in J. Org. Med. Chem. , 1996, 39, 4181-4196, dissolved in DCM and bromine is added. At the end of the reaction, DCM is added and the solution is washed with aqueous sodium thiosulfate and brine. The organic layer is dried with sodium sulfate. Filtration and evaporation of the solvent gives the crude material. Further purification is achieved by chromatography.

  The products of the previous step, lithium chloride, triphenylarsine, tributylvinyltin and tris (dibenzylideneacetone) dipalladium (0) -chloroform adduct are described in J. Am. Med. Chem. , 1996, 39, 4181-4196, in an organic solvent (eg, N-methylpyrrolidinone) at a high temperature of about 55 ° C. At the end of the reaction, the mixture is cooled to room temperature and poured into a mixture of ice, potassium fluoride, water and ethyl acetate. Stirring is continued for 1 hour. The suspension is filtered through celite and extracted with ethyl acetate. The combined organic extracts are dried with sodium sulfate. The solvent is removed in vacuo and the crude material is further purified by chromatography.

  The product of the previous step is dissolved in an organic solvent (eg, DCM or THF). 1,1,1-tris (acyloxy) -1,1-dihydro-1,2-benzoindoxol-3- (1H) -one (Dess-Martin reagent) is added and the solution is described in J. Am. Org. Chem. , 1984, 48, 4155-4156 at room temperature. At the end of the reaction, diethyl ether is added, followed by aqueous sodium hydroxide. The layers are separated and the organic layer is washed with aqueous sodium hydroxide, water, and dried over sodium sulfate. Filtration and evaporation of the solvent yields the crude product. Further purification is achieved by chromatography.

この出発物質は、有機溶媒（例えば、トルエン）に溶解される。Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２００３，６８，４５２−４５９の手順に従って、Ｐ（イソブチルＮＣＨ_２ＣＨ_２）_３Ｎ、酢酸パラジウム（ＩＩ）、ナトリウム第三級ブトキシドおよびベンジルアミンが加えられ、その混合物は、８０℃で、加熱される。この反応の終わりに、この混合物は、室温まで冷却され、そして真空中で溶媒が除去される。この粗製物質は、クロマトグラフィーにより、精製される。いずれかの残留しているアセテートは、含メタノールナトリウムメトキシドで短時間処理することにより、除去される。

This starting material is dissolved in an organic solvent (eg, toluene). J. et al. Org. Chem. , 2003, 68, 452-459, P (isobutyl NCH ₂ CH ₂ ) ₃ N, palladium (II) acetate, sodium tertiary butoxide and benzylamine are added and the mixture is heated at 80 ° C. Is done. At the end of the reaction, the mixture is cooled to room temperature and the solvent is removed in vacuo. This crude material is purified by chromatography. Any remaining acetate is removed by brief treatment with methanolic sodium methoxide.

  The benzyl protected aniline is dissolved in an organic solvent (eg, DMF). Palladium on carbon is added and the reaction mixture is placed under a hydrogen atmosphere. At the end of the reaction, the mixture is filtered through celite. The solvent is removed in vacuo. Further purification is achieved by chromatography.

  The resulting primary aniline is described in J. Org. Org. As described in Chem, 1996, 61, 3849-3862, it is dissolved in an organic solvent (eg, THF, acetonitrile or DMF) and treated with formaldehyde and sodium triacetoxyborohydride. The reaction is quenched with aqueous sodium bicarbonate and the product is extracted with an organic solvent (eg, ethyl acetate). The crude material is treated with di-t-butyl dicarbonate in an organic solvent (eg, dimethylformamide and aqueous sodium hydroxide). The carbamate obtained is purified by chromatography.

  This primary alcohol product is dissolved in an organic solvent (eg, DCM or THF). 1,1,1-tris (acyloxy) -1,1-dihydro-1,2-benzoindoxol-3- (1H) -one (Dess-Martin reagent) is added and the solution is described in J. Am. Org. Chem. , 1984, 48, 4155-4156 at room temperature. At the end of the reaction, diethyl ether is added, followed by aqueous sodium hydroxide. The layers are separated and the organic layer is washed with aqueous sodium hydroxide, water, and dried over sodium sulfate. Filtration and evaporation of the solvent yields the crude product. Further purification is achieved by chromatography.

この出発物質は、Ｒｅｃｌ．Ｔｒａｖ．Ｃｈｅｍ．Ｐａｙ−Ｂａｓ，１９８２，１０１，４６０の手順に従って、有機溶媒（例えば、ＤＣＭまたはＴＨＦ）に溶解され、そしてギ酸およびピバリン酸の混合無水物で処理される。この反応の終わりに、真空中で溶媒および全ての揮発性物質が除去され、その粗生成物は、クロマトグラフィーでさらに精製される。

This starting material is described in Recl. Trav. Chem. According to the procedure of Pay-Bas, 1982, 101, 460, it is dissolved in an organic solvent (eg DCM or THF) and treated with a mixed anhydride of formic acid and pivalic acid. At the end of the reaction, the solvent and all volatiles are removed in vacuo and the crude product is further purified by chromatography.

  This product is dissolved in an organic solvent (eg, DCM or THF). 1,1,1-tris (acyloxy) -1,1-dihydro-1,2-benzoindoxol-3- (1H) -one (Dess-Martin reagent) is added and the solution is described in J. Am. Org. Chem. , 1984, 48, 4155-4156 and stirred at room temperature. At the end of the reaction, diethyl ether is added, followed by aqueous sodium hydroxide. The layers are separated and the organic layer is washed with aqueous sodium hydroxide, water, and dried over sodium sulfate. Filtration and evaporation of the solvent yields the crude product. Further purification is achieved by chromatography.

(Variant of R ₂ )

この出発物質は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９６，３９，４１８１−４１９６の手順に従って、有機溶媒（例えば、ＤＭＦ）に溶解され、そしてＮ−クロロスクシンイミドと反応される。この出発物質が消費された後、その反応混合物は、水に注がれ、その生成物は、ジエチルエーテルで抽出される。合わせた有機層は、硫酸ナトリウムで乾燥される。濾過し溶媒を蒸発させると、粗反応生成物が得られる。

This starting material is described in J. Am. Med. Chem. , 1996, 39, 4181-4196, is dissolved in an organic solvent (eg, DMF) and reacted with N-chlorosuccinimide. After the starting material is consumed, the reaction mixture is poured into water and the product is extracted with diethyl ether. The combined organic layers are dried with sodium sulfate. Filtration and evaporation of the solvent gives the crude reaction product.

  The product of Step 1 is dissolved in a mixture of organic solvents (eg, methanol, DCM and pyridine). The solution is cooled to −78 ° C. and ozone is bubbled through the solution until the blue color persists. Excess ozone is removed from the nitrogen stream. The reaction mixture is warmed to room temperature and thiourea is added. Stirring at room temperature is continued. The reaction mixture is filtered and partitioned between DCM and water. The aqueous layer is extracted with DCM and the combined organic layers are washed with HCl (1N), saturated aqueous sodium bicarbonate, and brine. The solution is dried with sodium sulfate. Filtration and removal of the solvent gives the crude aldehyde. Further purification is achieved by chromatography.

この出発物質は、有機溶媒（例えば、メタノール、ＤＣＭおよびピリジン）の混合物に溶解される。その溶液は、−７８℃まで冷却され、そして青色が持続するまで、この溶液にオゾンが泡立たされる。過剰のオゾンは、窒素流れから除去される。その反応混合物は、室温まで温められ、そしてチオ尿素が加えられる。室温での攪拌が継続される。この反応混合物は、濾過され、そしてＤＣＭと水との間で分配される。その水層は、ＤＣＭで抽出され、合わせた有機層は、ＨＣｌ（１Ｎ）、炭酸水素ナトリウム飽和水溶液およびブラインで洗浄される。その溶液は、硫酸ナトリウムで乾燥される。濾過し溶媒を除去すると、粗アルデヒドが得られる。さらなる精製は、クロマトグラフィーにより達成される。

This starting material is dissolved in a mixture of organic solvents (eg, methanol, DCM and pyridine). The solution is cooled to −78 ° C. and ozone is bubbled through the solution until the blue color persists. Excess ozone is removed from the nitrogen stream. The reaction mixture is warmed to room temperature and thiourea is added. Stirring at room temperature is continued. The reaction mixture is filtered and partitioned between DCM and water. The aqueous layer is extracted with DCM and the combined organic layers are washed with HCl (1N), saturated aqueous sodium bicarbonate, and brine. The solution is dried with sodium sulfate. Filtration and removal of the solvent gives the crude aldehyde. Further purification is achieved by chromatography.

  The product of Step 1 is dissolved in an organic solvent (eg, benzene). Trifluoromethanesulfonyl chloride and dichlorotris (triphenylphosphine) ruthenium are added and the solution is degassed. The reaction mixture was prepared according to J. Chem. Soc. Perkin Trans. 1, 1994, 1339-1346 and heated at 120 ° C. At the end of the reaction, the mixture is cooled to room temperature and the solvent is removed in vacuo. Further purification of the product is achieved by chromatography.

  (Synthesis of olefin and linker for phosphonate)

フェンアセトアルデヒド（５．３ｇ、１５．８ｍｍｏｌ）を、トルエン（５０ｍＬ）中にて、１００℃で、２−（トリフェニル−ホスファニリデン）−プロピオンアルデヒド（６．８ｇ、２０．５ｍｍｏｌ）と共に、一晩加熱した。濃縮した後、その残留物をシリカゲルクロマトグラフィーで精製して、淡黄色固形物として、４．２４ｇ（７２％）の不飽和アルデヒドを得た。¹H NMR (300 MHz, CDCl₃) δ0.00 (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)。

Phenacetaldehyde (5.3 g, 15.8 mmol) was heated in toluene (50 mL) at 100 ° C. with 2- (triphenyl-phosphanylidene) -propionaldehyde (6.8 g, 20.5 mmol) overnight. did. After concentration, the residue was purified by silica gel chromatography to give 4.24 g (72%) of unsaturated aldehyde as a pale yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.00 (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).

このトリメチルシリルエチル保護アルデヒドは、Ｔｅｔｒａｈｅｄｒｏｎ，１９９５，５１，２０９９で報告されたもののような手順に従って、溶媒（例えば、アセトニトリル）中で、塩基（例えば、トリエチルアミン）の存在下にて、ヒドロキシホスホネートを生じさせるために、亜リン酸ジエチルで処理される。このヒドロキシホスホネートは、Ｏ−アルキル化され、次いで、その保護基は、トリフルオロ酢酸またはフッ化テトラブチルアンモニウムのいずれかで処理することにより、除去されて、所望のメトキシホスホネート類似物が産生される。

This trimethylsilylethyl protected aldehyde gives a hydroxyphosphonate in the presence of a base (eg triethylamine) in a solvent (eg acetonitrile) according to a procedure such as that reported in Tetrahedron, 1995, 51, 2099. For the treatment with diethyl phosphite. The hydroxyphosphonate is O-alkylated and the protecting group is then removed by treatment with either trifluoroacetic acid or tetrabutylammonium fluoride to produce the desired methoxyphosphonate analog. .

  Alternatively, the aldehyde is mixed with diethyl phosphonate (2-aminoethyl) and treated with a reducing agent (eg, sodium triacetoxyborohydride) to produce an aminophosphonate analog.

４−［６−メトキシ−７−メチル−３−オキソ−４−（２−トリメチルシラニル−エトキシ）−１，３−ジヒドロ−イソベンゾフラン−５−イル］−２−メチル−ブタ−２−エナール（１０３ｍｇ、０．２７ｍｍｏｌ）のメタノール（５ｍＬ）溶液を、０℃まで冷却した。ＣｅＣｌ_３の溶液（０．６８ｍＬ、ＭｅＯＨ：Ｈ_２Ｏ、９：１）を加え、続いて、ＬｉＢＨ_４（０．１４ｍＬ、２Ｍ ＴＨＦ溶液０．２８ｍｍｏｌ）を加えた。氷浴を取り除き、その反応混合物を室温まで温めた。この反応混合物をさらに４０分間攪拌し、それから、ＴＬＣにより、出発アルデヒドが完全に消費されたことが明らかとなった。１Ｎ ＨＣｌ水溶液（０．５ｍＬ）を加えることにより、その反応物をワークアップし、その生成物をＣＨ_２Ｃｌ_２で抽出した。その有機層を飽和炭酸水素ナトリウム水溶液およびブラインで洗浄した。この有機層を減圧下にて濃縮し、その残留物をシリカゲルクロマトグラフィーで精製して、透明液体として、１００ｍｇ（９７％）の生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.00 (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)。

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. A solution of CeCl ₃ (0.68 mL, MeOH: H ₂ O, 9: 1) was added followed by LiBH ₄ (0.14 mL, 0.2M mmol in 2M THF). The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for an additional 40 minutes, after which time TLC revealed complete consumption of the starting aldehyde. The reaction was worked up by adding 1N aqueous HCl (0.5 mL) and the product was extracted with CH ₂ Cl ₂ . The organic layer was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give 100 mg (97%) of product as a clear liquid. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.00 (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).

重合体で支持したトリフェニルホスフィンは、１時間にわたって、ＤＣＭで浸漬される。引き続いて、このアリルアルコールおよび四臭化炭素が加えられる。この反応が完結したとき、その混合物は、濾過され、その濾液は、濃縮される。その臭化物は、必要に応じて、クロマトグラフィーで精製される。

The polymer supported triphenylphosphine is soaked in DCM for 1 hour. Subsequently, the allyl alcohol and carbon tetrabromide are added. When the reaction is complete, the mixture is filtered and the filtrate is concentrated. The bromide is purified by chromatography if necessary.

この臭化アリルは、ＷＯ ９５／２２５３８で記述されたもののような手順に従って、不活性有機溶媒（例えば、ジメチルホルムアミド）中にて、ジエトキシホスホリル酢酸エチルのアルカリ金属塩（これは、ジエトキシホスホリル酢酸エチルとナトリウムヘキサメチルジシラジドまたは水素化ナトリウムとを反応させることにより、調製した）で処理されて、ホスホン酸エトキシカルボニルが得られる。そのカルボン酸エステル基は、アミドの形成およびエステルの還元に通常利用される方法に従って、そのカルボン酸アミド基およびヒドロキシメチル基の両方に変換される。例えば、このカルボン酸エステルは、水酸化リチウム水溶液でケン化される。その酸は、クロロギ酸エチルで活性化され、そしてホウ水素化ナトリウムで還元されて、保護基を除去した後、そのホスホン酸ヒドロキシメチル類似物が産生される。この酸はまた、その塩化アシルに変換され、次いで、エチルアミンと反応されて、そのアミド類似物が得られる。

This allyl bromide is prepared from an alkali metal salt of ethyl diethoxyphosphorylacetate (which is diethoxyphosphoryl) in an inert organic solvent (eg dimethylformamide) according to procedures such as those described in WO 95/22538. Treatment with ethyl acetate and sodium hexamethyldisilazide or sodium hydride) provides ethoxycarbonyl phosphonate. The carboxylic ester group is converted to both the carboxylic amide group and the hydroxymethyl group according to methods commonly used for amide formation and ester reduction. For example, the carboxylic acid ester is saponified with an aqueous lithium hydroxide solution. The acid is activated with ethyl chloroformate and reduced with sodium borohydride to produce the hydroxymethyl phosphonate analog after removal of the protecting group. The acid is also converted to the acyl chloride and then reacted with ethylamine to give the amide analog.

このアリールアセトアルデヒドは、Ｓｙｎｔｈｅｓｉｓ，１９９９，２８２で報告されたもののような手順に従って、２−（ジエトキシホスホリル）−ブタ−３−エン酸エチルエステルとカップリングされて、その２−ビニル置換エステルが産生される。その２−ビニル基は、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．１９９８，３９，８６２１で記述されたもののようなシクロプロパン化条件下にて、その２−シクロプロピル基に変換される。このエステルは、そのアルコールに変換され、これは、必要に応じて、さらに、下記のような反応を受け得、種々のホスホネート含有ミコフェノール酸類似物が産生される。

This arylacetaldehyde is coupled with 2- (diethoxyphosphoryl) -but-3-enoic acid ethyl ester according to a procedure such as that reported in Synthesis, 1999, 282 to produce the 2-vinyl substituted ester. Is done. The 2-vinyl group is disclosed in Tetrahedron Lett. Converted to its 2-cyclopropyl group under cyclopropanation conditions such as those described in 1998,39,8621. This ester is converted to its alcohol, which can optionally undergo further reactions as described below to produce various phosphonate-containing mycophenolic acid analogs.

このアリルアルコールは、塩基（例えば、リチウムｔ−ブトキシド）の存在下にて、溶媒（例えば、ジメチルホルムアミド）中にて、ブロモメチルホスホン酸ジイソプロピルエステルで処理される。次いで、そのフェノール保護基は、トリフルオロ酢酸で処理することにより、除去される。

This allyl alcohol is treated with bromomethylphosphonic acid diisopropyl ester in a solvent (eg, dimethylformamide) in the presence of a base (eg, lithium t-butoxide). The phenol protecting group is then removed by treatment with trifluoroacetic acid.

あるいは、このフェンアセトアルデヒドは、Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９８７，５２，８４９に報告されるような手順に従って、そのアリルホスホニウム塩に変換される。次いで、このホスホニウム塩は、市販の３，３，３−トリフルオロ−２−オキソ−プロピオン酸エチルエステルおよび塩基（例えば、水素化ナトリウム）で処理されて、その２−トリフルオロメチル置換エステルが産生される。このエステルは、そのアルコールに変換され、これは、必要に応じて、先に記述した反応を受けて、ホスホネート基を含有する種々の鎖を備えたミコフェノール酸類似物が産生される。

Alternatively, this phenacetaldehyde is described in J. Org. Org. Chem. Converted to its allylphosphonium salt according to the procedure reported in 1987, 52, 849. The phosphonium salt is then treated with commercially available 3,3,3-trifluoro-2-oxo-propionic acid ethyl ester and a base (eg, sodium hydride) to produce the 2-trifluoromethyl substituted ester. Is done. The ester is converted to the alcohol, which, if necessary, undergoes the reactions described above to produce mycophenolic acid analogs with various chains containing phosphonate groups.

（Ｒ_４の変種の導入）

(Introduction of R ₄ variants)

このエノン（合成は、Ｔｅｔｒａｈｅｄｒｏｎ，１９８５，４１，４８８１−４８８９で概説されている）およびジエン（Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，１９８９，３７，２９４８−２９５１）は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９６、３９，４１８１−４１９６の手順に従って、有機溶媒（例えば、トルエン）に溶解され、室温で、２４時間攪拌され、さらに５時間にわたって、還流状態まで加熱される。その反応混合物は、室温まで冷却され、そして真空中で溶媒が除去される。その粗反応生成物は、クロマトグラフィーでさらに精製される。

This enone (the synthesis is reviewed in Tetrahedron, 1985, 41, 4881-4889) and diene (Chem. Pharm. Bull., 1989, 37, 2948-2951) are described in J. Am. Med. Chem. , 1996, 39, 4181-4196, dissolved in an organic solvent (eg, toluene), stirred at room temperature for 24 hours, and heated to reflux for an additional 5 hours. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. The crude reaction product is further purified by chromatography.

  The product of step 1 is Med. Chem. , 1996, 39, 4181-4196, is dissolved in an organic solvent (eg, DCM) and m-chloroperbenzoic acid is added. At the end of the reaction, the solution is poured into an aqueous sodium hydrogen sulfite solution. The organic layer is washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. Filtration and evaporation of the solvent yields the crude product.

  The crude product is described in J. Org. Med. Chem. , 1996, 39, 4181-4196, and dissolved in an organic solvent (eg, toluene) and treated with dichlorodicyanoquinone (DDQ). At the end of the reaction, the solvent is removed in vacuo and the crude material is further purified by chromatography.

  The product is described in J. Org. Med. Chem. , 1996, 39, 46-55, and dissolved in an organic solvent (eg, DCM) and treated with boron trichloride at reflux temperature. At the end of the reaction, the solution is washed with aqueous HCl. This solution is dried over sodium sulfate. Removal of the solvent yields the crude reaction product. Further purification is achieved by chromatography.

  The product of the previous step and triphenylphosphine are dissolved in an organic solvent (eg, tetrahydrofuran (THF). Diisopropyl azodicarboxylate (DIAD) is added dropwise at 0 ° C. A THF solution of 2-trimethylsilylethanol is added. At the end of the reaction, the solvent is removed in vacuo, and the crude reaction solid is extracted with a mixture of organic solvents (eg, hexane and diethyl ether). The washings are combined and the solvent removed in vacuo The desired product is further purified by chromatography and separated from the undesired regio isomers.

この出発物質は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９６，３９，４１８１−４１９６の手順に従って、有機溶媒（例えば、ジメチルホルムアミド（ＤＭＦ）に溶解され、そしてＮ−クロロスクシンイミドと反応される。この出発物質が消費された後、その反応混合物は、水に注がれ、その生成物は、ジエチルエーテルで抽出される。合わせた有機層は、硫酸ナトリウムで乾燥される。濾過し溶媒を蒸発させると、粗反応生成物が得られる。さらなる精製は、クロマトグラフィーにより達成される。

This starting material is described in J. Am. Med. Chem. , 1996, 39, 4181-4196, 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 The product is poured into water and the product is extracted with diethyl ether, the combined organic layers are dried over sodium sulfate, filtered and the solvent is evaporated to give the crude reaction product. Achieved by chromatography.

この出発物質は、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９６６，８８，５８５５−５８６６の手順に従って、有機溶媒（例えば、ベンゼン）に溶解され、そしてジメチルスルホキシド（ＤＭＳＯ）、ジシクロヘキシルカルボジイミド（ＤＣＣ）およびオルトリン酸と反応される。この反応の終わりに，その懸濁液は、濾過され、その有機層は、炭酸水素ナトリウム水溶液で洗浄され、そして硫酸ナトリウムで乾燥される。濾過し、そして溶媒を蒸発させると、粗製物質が生じる。さらなる精製は、クロマトグラフィーにより達成される。

This starting material is described in J. Am. Am. Chem. Soc. , 1966, 88, 5855-5866, dissolved in an organic solvent (eg, benzene) and reacted with dimethyl sulfoxide (DMSO), dicyclohexylcarbodiimide (DCC) and orthophosphoric acid. At the end of the reaction, the suspension is filtered and the organic layer is washed with aqueous sodium bicarbonate and dried over sodium sulfate. Filtration and evaporation of the solvent yields a crude material. Further purification is achieved by chromatography.

  The product of Step 1 was obtained from Chem. Rev. 1962, 62, 347-404 are dissolved in an organic solvent (eg DCM or THF) and treated with Raney nickel. When all starting material is consumed, the reaction is filtered and the solvent is removed in vacuo. Further purification is achieved by chromatography.

この出発物質は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９６，３９，４１８１−４１９６の手順に従って、有機溶媒（例えば、ＤＣＭおよび臭素）に溶解される。この反応の終わりに、さらなるＤＣＭが追加され、その溶液は、チオ硫酸ナトリウム水溶液およびブラインで洗浄される。その有機層は、硫酸ナトリウムで乾燥される。濾過し、そして溶媒を蒸発させると、粗製物質が得られる。さらなる精製は、シリカゲルクロマトグラフィーにより達成される。

This starting material is described in J. Am. Med. Chem. , 1996, 39, 4181-4196, dissolved in an organic solvent (eg, DCM and bromine). At the end of the reaction, additional DCM is added and the solution is washed with aqueous sodium thiosulfate and brine. The organic layer is dried with sodium sulfate. Filtration and evaporation of the solvent gives the crude material. Further purification is achieved by silica gel chromatography.

  This starting material, lithium chloride, triphenylarsine, tributylvinyltin and tris (dibenzylideneacetone) dipalladium (0) -chloroform adducts are described in Med. Chem. , 1996, 39, 4181-4196, in an organic solvent (eg, N-methylpyrrolidinone) at a high temperature of about 55 ° C. At the end of the reaction, the mixture is cooled to room temperature and poured into a mixture of ice, potassium fluoride, water and ethyl acetate. Stirring is continued for 1 hour. The suspension is filtered through celite and extracted with ethyl acetate. The combined organic extracts are dried with sodium sulfate. The solvent is removed in vacuo and the crude material is further purified by chromatography.

  The product of step 2 is dissolved in a mixture of organic solvents (eg, 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 in vacuo and the crude reaction is filtered through silica gel. Further purification is achieved by chromatography.

この出発物質は、有機溶媒（例えば、ＤＭＦ）に溶解される。Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９６，３９，４１８１−４１９６の手順に従って、炭酸カリウムおよび臭化アリルが加えられ、そして室温での攪拌が継続される。全ての出発物質が消費されると、ＨＣｌ水溶液およびジエチルエーテルが加えられ、その有機層が集められ、そして真空中で溶媒が除去される。

This starting material is dissolved in an organic solvent (eg, DMF). J. et al. Med. Chem. , 1996, 39, 4181-4196, potassium carbonate and allyl bromide are added and stirring at room temperature is continued. When all starting material is consumed, aqueous HCl and diethyl ether are added, the organic layer is collected, and the solvent is removed in vacuo.

  The crude material is dissolved in N, N-diethylaniline and the reaction mixture is heated at an elevated temperature of about 180 ° C. At the end of the reaction, the mixture is cooled to room temperature and poured into a mixture of aqueous HCl (2N) and ethyl acetate. The organic layer is washed with aqueous HCl (2N) and dried over sodium sulfate. Filtration and removal of the solvent yields the crude product. Further purification is achieved by chromatography.

  The product of step 2 is dissolved in a mixture of organic solvents (eg, methanol, DCM and pyridine). The solution is cooled to −78 ° C. and ozone is bubbled through the solution until the blue color persists. Excess ozone is removed from the nitrogen stream. The reaction mixture is warmed to room temperature and thiourea is added. Stirring at room temperature is continued. The reaction mixture is filtered and partitioned between DCM and water. The aqueous layer is extracted with DCM and the combined organic layers are washed with HCl (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 is achieved by chromatography.

  This aldehyde can be obtained from Chem. Rev. , 1989, 89, 863-927, are dissolved in an organic solvent (eg, THF) and reacted with triphenylphosphonium secondary propyl bromide and potassium tertiary butoxide. At the end of the reaction, the solvent is removed in vacuo and the crude material is purified by chromatography.

  ((A) Introduction of linker into phosphonate)

ここで図示したフェノールは、必要に応じて、特別な試薬でアルキル化され得る。必要に応じて、そのホスホネート部分は、このような試薬の一部となる。あるいは、それは、次の工程にて、種々の手段（そのうちの３つは、上で図示している）により、導入される。例えば、ハロゲン化アルキルは、溶媒（例えば、トルエン）中にて、（または他のＡｒｂｕｚｏｖ反応条件で：Ｅｎｇｅｌ，Ｒ．，「Ｓｙｎｔｈｅｓｉｓ ｏｆ Ｃａｒｂｏｎ−ｐｈｏｓｐｈｏｒｕｓ Ｂｏｎｄｓ」、ＣＲＣ ｐｒｅｓｓ，１９８８を参照）、亜リン酸トリエチルと共に加熱され得る。あるいは、エポキシドは、ホスフィン酸ジアルキルのアニオンと反応され得る。さらに他の例では、このホスホネート試薬は、求電子試薬（例えば、アセチリドアニオン）であり得、オキシ塩化リンと縮合され得、その中間体であるジクロロホスホネートは、エタノールでクエンチされて、所望のホスホン酸のジエチルエステルが産生される。

The phenols illustrated here can be alkylated with special reagents, if desired. If necessary, the phosphonate moiety becomes part of such a reagent. Alternatively, it is introduced by various means (three of which are illustrated above) in the next step. For example, alkyl halides can be prepared in a solvent (eg, toluene) (or under other Arbuzov reaction conditions: Engel, R., “Synthesis of Carbon-phosphorus Bonds”, CRC press, 1988), phosphorous Can be heated with triethyl acid. Alternatively, the epoxide can be reacted with an anion of a dialkyl phosphinate. In yet another example, the phosphonate reagent can be an electrophile (eg, an acetylide anion) and can be condensed with phosphorus oxychloride, the intermediate dichlorophosphonate being quenched with ethanol to give the desired phosphonate. The diethyl ester of the acid is produced.

(Example 333)
Certain compounds of the invention can be prepared as follows.

（［４−（６−エチル−４−ヒドロキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−ホスホン酸）
この生成物は、本明細書中（例えば、実施例２９２および３１７）で記述したものと類似の方法を使用して、調製した。ＭＳ（ネガティブモード）：３６９．３［Ｍ^＋−１］。

([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 292 and 317). MS (negative mode): 369.3 [M ⁺ -1].

(Example 333A)
Certain compounds of the invention can be prepared as follows.

（２−｛［４−（６−エチル−４−ヒドロキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルオキシメチル］−フェノキシ−ホスフィノイルアミノ｝−プロピオン酸エチルエステル）
本明細書中（例えば、実施例３０２）で記述したものと類似の方法使用して、実施例３３３から出発して、所望生成物を調製した。ＭＳ（ポジティブモード）：５４６．３［Ｍ^＋＋１］＆５６８．３［Ｍ^＋＋Ｎａ］。

(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 333 using methods similar to those described herein (eg, Example 302). MS (positive mode): 546.3 [M ⁺ +1] & 568.3 [M ⁺ + Na].

(Example 334)
Certain compounds of the invention can be prepared as follows.

（２−（｛２−［４−（６−エチル−４−ヒドロキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルアミノ］−エチル｝−フェノキシ−ホスフィノイルアミノ）−プロピオン酸エチルエステル）
この生成物は、還元アミノ化工程において、本明細書中（例えば、実施例３０９および３３３）で記述したものと類似の方法を使用して、２−［（２−アミノ−エチル）−フェノキシ−ホスフィノイルアミノ］−プロピオン酸エチルエステルを使用して調製した。ＭＳ（ポジティブモード）：５５９．４［Ｍ^＋＋１］＆５８１．３［Ｍ^＋＋Ｎａ］。

(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)
This product is used in the reductive amination step using methods similar to those described herein (eg, Examples 309 and 333) using 2-[(2-amino-ethyl) -phenoxy- Prepared using phosphinoylamino] -propionic acid ethyl ester. MS (positive mode): 559.4 [M ⁺ +1] & 581.3 [M ⁺ + Na].

(Example 335)
Certain compounds of the invention can be prepared as follows.

（２−（（１−エトキシカルボニル−エチルアミノ）−｛２−［４−（６−エチル−４−ヒドロキシ−７−メチル−３−オキソ−１，３−ジヒドロ−イソベンゾフラン−５−イル）−２−メチル−ブタ−２−エニルアミノ］−エチル｝−ホスフィノイルアミノ）−プロピオン酸エチルエステル）
この生成物は、還元アミノ化工程において、本明細書中（例えば、実施例３３４）で記述したものと類似の方法により、２−［（２−アミノエチル）−（１−エトキシカルボニル−エチルアミノ）−ホスフィノイルアミノ］−プロピオン酸エチルエステルを使用して調製した。ＭＳ（ポジティブモード）：５８２．４［Ｍ^＋＋１］＆６０４．３［Ｍ^＋＋Ｎａ］。

(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)
This product is converted into 2-[(2-aminoethyl)-(1-ethoxycarbonyl-ethylamino) in a reductive amination step by a method analogous to that described herein (eg, Example 334). ) -Phosphinoylamino] -propionic acid ethyl ester. MS (positive mode): 582.4 [M ⁺ +1] & 604.3 [M ⁺ + Na].

(Example 336)
((2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -methyl) -phosphonic acid diethyl ester)

４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−安息香酸半塩酸塩二水和物（６７．０ｍｇ、１７７μｍｏｌ）のＤＭＦ（３．０ｍＬ）溶液に、シアノホスホン酸ジエチル（３４．８μＬ、２３０μｍｏｌ）およびジイソプロピルエチルアミン（ヒューニッヒ塩基、ＤＩＥＡ、３０．４μＬ、１７７μｍｏｌ）を加えた。この溶液を、室温で、４時間攪拌し、そのとき、ホスホン酸ジエチル（アミノメチル）（４５．４ｍｇ、１７７μｍｏｌ）を加えた。出発物質の完全な消費が認められたとき、この溶液を、さらに４時間攪拌した。真空中で溶媒を除去し、その残留物をシリカゲルクロマトグラフィー（これは、ＭｅＯＨ−ＣＨ_２Ｃｌ_２（１０〜３０％）を使用する）で精製することにより、この反応物をワークアップした。このクロマトグラフィー工程から集めた生成物は、次の反応に進めるのに十分に純粋であった。少量の生成物（２０ｍｇ）をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で再精製して、１２．９ｍｇ（７６％）の純粋生成物を得た。¹H NMR (300 MHz, DMSO-d₆) δ1.19 (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). ³¹P (121.4 MHz, DMSO-d₆) δ 23.4. MS (m/z)475.2 [M+H]⁺, 597.2 [M+Na]⁺。

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 cyanophosphone. Diethyl acid (34.8 μL, 230 μmol) and diisopropylethylamine (Hunig base, DIEA, 30.4 μL, 177 μmol) were added. The solution was stirred at room temperature for 4 hours, at which time diethyl phosphonate (aminomethyl) (45.4 mg, 177 μmol) was added. When complete consumption of starting material was observed, the solution was stirred for an additional 4 hours. The reaction was worked up by removing the solvent in vacuo and purifying the residue by silica gel chromatography, which uses MeOH—CH ₂ Cl ₂ (10-30%). The product collected from this chromatography step was pure enough to proceed to the next reaction. A small amount of product (20 mg) was repurified with RP HPLC on a _C18 column (which uses H ₂ O / acetonitrile (2-95%)) to give 12.9 mg (76%) pure product I got a thing. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.19 (t, 6H, J = 7.2 Hz), 3.21 (s, 3H), 3.70 (m, 2H), 4.00 (q, 4H, J = 7.2 Hz ), 4.81 (s, 2H), 6.81 (d, 2H, J = 9 Hz), 7.71 (d, 2H, J = 9 Hz), 8.40 (br s, 1H), 8.61 (s, 1H). ³¹ P (121.4 MHz, DMSO-d ₆ ) δ 23.4. MS (m / z) 475.2 [M + H] ⁺ , 597.2 [M + Na] ⁺ .

(Example 337)
((2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -methyl) -phosphonic acid)

粗（２−｛４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−ベンゾイルアミノ｝−エチル）−ホスホン酸ジエチルエステルのポストシリカカラムクロマトグラフィー（６０ｍｇ、１２６μｍｏｌ）の無水ＤＭＦ（０．９０ｍＬ）溶液に、室温で、臭化トリメチルシリル（ブロモトリメチルシラン、ＴＭＳＢｒ、１３０．６μＬ、１，０１０μｍｏｌ）を加えた。次いで、この溶液を、７０℃で、４．０時間加熱し、その後、その反応混合物を室温まで冷却した。真空中にて、溶媒の容量を約７００μＬまで減らし、そしてＨ_２Ｏ（１００μＬ）で希釈した。この溶液をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で精製して、黄色固形物として、２６．８ｍｇ（５１％）の所望化合物を得た。¹H NMR (300 MHz, DMSO-d₆) δ3.18 (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]⁺。

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid diethyl ester post silica column chromatography (60 mg, 126 μmol) Trimethylsilyl bromide (bromotrimethylsilane, TMSBr, 130.6 μL, 1,010 μmol) was added to an anhydrous DMF (0.90 mL) solution at room temperature. The solution was then heated at 70 ° C. for 4.0 hours, after which the reaction mixture was cooled to room temperature. In vacuo, the solvent volume was reduced to about 700 μL and diluted with H ₂ O (100 μL). The solution is purified by RP HPLC on a _C18 column (which uses H ₂ O / acetonitrile (2-95%)) to yield 26.8 mg (51%) of the desired compound as a yellow solid. Obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.18 (s, 3H), 3.50 (m, 2H), 4.77 (s, 2H), 6.79 (d, 2H, J = 9 Hz), 7.79 (d , 2H, J = 9 Hz), 8.07 (br s, 1H), 8.56 (s, 1H); MS (m / z) 419.2 [M + H] ⁺ .

(Example 338)
((2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid diethyl ester)

４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−安息香酸半塩酸塩二水和物（６１．２ｍｇ、１６１μｍｏｌ）のＤＭＦ（２．８ｍＬ）溶液に、シアノホスホン酸ジエチル（３１．８μＬ、２１０μｍｏｌ）およびＤＩＥＡ（２７．８μＬ、１６１μｍｏｌ）を加えた。この溶液を、室温で、４時間攪拌し、そのとき、ホスホン酸ジエチル（アミノエチル）（４３．８ｍｇ、１６１μｍｏｌ）を加えた。この溶液を、さらに３時間攪拌し、その時点までに、出発物質が完全に消費されたことが認められた。真空中で溶媒を除去し、その残留物をシリカゲルクロマトグラフィー（これは、ＭｅＯＨ−ＣＨ_２Ｃｌ_２（１０〜３０％）を使用する）で精製することにより、この反応物をワークアップした。このクロマトグラフィー工程から集めた生成物は、次の反応に進めるのに十分に純粋であった。少量の生成物（３２ｍｇ）をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で再精製して、１９ｍｇ（７０％）の純粋生成物を得た。¹H NMR (300 MHz, DMSO-d₆) δ1.21 (t, 6H, J= 7 Hz), 1.95- 2.05 (m, 2H), 3.20 (s, 3H), 3.13- 3.22 (m, 2H),3.98 (appt 七重線にする, 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). ³¹P (121.4 MHz, DMSO-d₆)δ 28.9. MS (m/z) 489.2 [M+H]⁺, 511.2 [M+Na]⁺。

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) was added cyanophosphone. Diethyl acid (31.8 μL, 210 μmol) and DIEA (27.8 μL, 161 μmol) were added. The solution was stirred at room temperature for 4 hours, at which time diethyl (aminoethyl) phosphonate (43.8 mg, 161 μmol) was added. The solution was stirred for an additional 3 hours by which time it was observed that the starting material had been completely consumed. The reaction was worked up by removing the solvent in vacuo and purifying the residue by silica gel chromatography, which uses MeOH—CH ₂ Cl ₂ (10-30%). The product collected from this chromatography step was pure enough to proceed to the next reaction. A small amount of product (32 mg) was repurified with RP HPLC on a _C18 column (which uses H ₂ O / acetonitrile (2-95%)) to give 19 mg (70%) of pure product. Obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.21 (t, 6H, J = 7 Hz), 1.95- 2.05 (m, 2H), 3.20 (s, 3H), 3.13- 3.22 (m, 2H) , 3.98 (appt 7-wire, 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 ) δ 28.9. MS (m / z) 489.2 [M + H] ⁺ , 511.2 [M + Na] ⁺ .

(Example 339)
((2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid)

粗（２−｛４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−ベンゾイルアミノ｝−エチル）−ホスホン酸ジエチルエステルのポストシリカカラムクロマトグラフィー（６１ｍｇ、１２５μｍｏｌ）の無水ＤＭＦ（１．００ｍＬ）溶液に、室温で、ＴＭＳＢｒ（１２９．０μＬ、９９９．２μｍｏｌ）を加えた。次いで、この溶液を、７０℃で、５．５時間加熱し、そのとき、ＬＣＭＳ分析により、この反応が９０％完結したことが立証された。その反応混合物を室温まで冷却し、さらに１２時間攪拌した。真空中で溶媒を除去し、その残留物をＤＭＦ／Ｈ_２Ｏ（８００μＬ、１：１）および１Ｎ ＮａＯＨ水溶液（１５μＬ）に溶解することにより、この反応物をワークアップした。その生成物をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で精製して、黄色固形物として、２９ｍｇ（５３％）の所望化合物を得た。¹H NMR (300 MHz, DMSO-d₆) δ1.67- 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). ³¹P (121.4 MHz, DMSO-d₆) δ 23.0. MS(m/z) 431.3 [M-H]^-。

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid diethyl ester post silica column chromatography (61 mg, 125 μmol) To an anhydrous DMF (1.00 mL) solution, TMSBr (129.0 μL, 999.2 μmol) was added at room temperature. The solution was then heated at 70 ° C. for 5.5 hours, at which time LCMS analysis demonstrated that the reaction was 90% complete. The reaction mixture was cooled to room temperature and stirred for an additional 12 hours. The reaction was worked up by removing the solvent in vacuo and dissolving the residue in DMF / H ₂ O (800 μL, 1: 1) and 1N aqueous NaOH (15 μL). The product was purified by RP HPLC on a _C18 column (using H ₂ O / acetonitrile (2-95%)) to give 29 mg (53%) of the desired compound as a yellow solid. It was. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.67- 1.85 (m, 2H), 3.19 (s, 3H), 3.25- 3.40 (m, 2H), 4.76 (s, 2H), 6.71 (br s , 2H), 5.80 (d, 2H, J = 9 Hz), 7.64 (d, 2H, J = 9 Hz), 7.73 (br s, 2H), 8.15 (br s, 1H), 8.56 (s, 1H) ³¹ P (121.4 MHz, DMSO-d ₆ ) δ 23.0. MS (m / z) 431.3 [MH] ⁻ .

(Example 340)
((2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -propyl) -phosphonic acid diethyl ester)

４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−安息香酸半塩酸塩二水和物（６１．２ｍｇ、１６１μｍｏｌ）のＤＭＦ（２．８ｍＬ）溶液に、シアノホスホン酸ジエチル（３１．８μＬ、２１０μｍｏｌ）およびＤＩＥＡ（２７．８μＬ、１６１μｍｏｌ）を加えた。この溶液を、室温で、３時間攪拌し、そのとき、ホスホン酸ジエチル（アミノプロピル）（３４．９ｍｇ、１２２．６μｍｏｌ）を加えた。この溶液を、さらに２時間攪拌すると、出発物質が完全に消費されたことが認められた。真空中で溶媒を除去し、その残留物をシリカゲルクロマトグラフィー（これは、ＭｅＯＨ−ＣＨ_２Ｃｌ_２（１０〜３０％）を使用する）で精製することにより、この反応物をワークアップした。このクロマトグラフィー工程から集めた生成物（６５．５ｍｇ）は、次の反応に進めるのに十分に純粋であった。少量（３２．８ｍｇ）をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で再精製して、２３．２ｍｇ（７５％）の純粋生成物を得た。¹H NMR (300 MHz, DMSO-d₆) δ1.20 (t, 6H, J= 7.2 Hz), 1.64- 1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H), 3.98(appt septet, 4H, J= 7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J= 9 Hz), 7.68 (d, 2H,J= 9 Hz), 8.17 (br s, 1H), 8.70 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆)δ 31.9; MS (m/z) 503.2 [M+H]⁺。

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) was added cyanophosphone. Diethyl acid (31.8 μL, 210 μmol) and DIEA (27.8 μL, 161 μmol) were added. The solution was stirred at room temperature for 3 hours, at which time diethyl phosphonate (aminopropyl) (34.9 mg, 122.6 μmol) was added. The solution was stirred for an additional 2 hours and it was found that the starting material was completely consumed. The reaction was worked up by removing the solvent in vacuo and purifying the residue by silica gel chromatography, which uses MeOH—CH ₂ Cl ₂ (10-30%). The product collected from this chromatography step (65.5 mg) was pure enough to proceed to the next reaction. A small amount (32.8 mg) was repurified with RP HPLC on a _C18 column (which uses H ₂ O / acetonitrile (2-95%)) to yield 23.2 mg (75%) of pure product. Got. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.20 (t, 6H, J = 7.2 Hz), 1.64- 1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H), 3.98 (appt septet, 4H, J = 7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J = 9 Hz), 7.68 (d, 2H, J = 9 Hz), 8.17 (br s, 1H) , 8.70 (s, 1H); ³¹ P (121.4 MHz, DMSO-d ₆ ) δ 31.9; MS (m / z) 503.2 [M + H] ⁺ .

(Example 341)
((2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -propyl) -phosphonic acid)

粗（２−｛４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−ベンゾイルアミノ｝−プロピル）−ホスホン酸ジエチルエステルのポストシリカカラムクロマトグラフィー（３２．２ｍｇ、６６．２μｍｏｌ）の無水ＤＭＦ（０．５０ｍＬ）溶液に、室温で、ＴＭＳＢｒ（６８．０μＬ、５２９．６μｍｏｌ）を加えた。次いで、この溶液を、７０℃で、１．０時間加熱し、そのとき、ＬＣＭＳ分析により、この反応が完結したことが立証された。その反応混合物を室温まで冷却し、そして水（６０μＬ）およびメタノール（６０μＬ）を加えた。この粗反応混合物をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で精製して、黄色固形物として、１１．２ｍｇ（３８％）の所望化合物を得た。¹H NMR (300 MHz, DMSO-d₆) δ1.50 (m, 2H), 1.61 (m, 2H), 3.22 (s, 3H), 3.25- 3.40 (m, 2H), 4.84 (s, 2H),6.80 (d, 2H, J= 9 Hz), 7.69 (d, 2H, J= 9 Hz), 8.20 (br s, 1H), 8.69 (s, 1H). ³¹P(121.4 MHz, DMSO-d₆) δ 26.3. MS (m/z) 447.3 [M-H]^-。

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -propyl) -phosphonic acid diethyl ester post silica column chromatography (32.2 mg, 66 .2 μmol) in anhydrous DMF (0.50 mL) at room temperature was added TMSBr (68.0 μL, 529.6 μmol). The solution was then heated at 70 ° C. for 1.0 hour, at which time LCMS analysis demonstrated that the reaction was 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 as a yellow solid. A compound was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.50 (m, 2H), 1.61 (m, 2H), 3.22 (s, 3H), 3.25- 3.40 (m, 2H), 4.84 (s, 2H) , 6.80 (d, 2H, J = 9 Hz), 7.69 (d, 2H, J = 9 Hz), 8.20 (br s, 1H), 8.69 (s, 1H). ³¹ P (121.4 MHz, DMSO-d ₆ ) δ 26.3. MS (m / z) 447.3 [MH] ⁻ .

(Example 342)
(2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] benzoylamino} -ethyl) phenoxyphosphinoyloxy] propionic acid ethyl ester [diastereomeric mixture at phosphorus] )

４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−安息香酸半塩酸塩二水和物（６０．０ｍｇ、１５８．３μｍｏｌ）のＤＭＦ（２．５ｍＬ）溶液に、シアノホスホン酸ジエチル（３１．２μＬ、２０５．７μｍｏｌ）およびＤＩＥＡ（８１．８μＬ、４７４．９μｍｏｌ）を加えた。この溶液を、室温で、３．５時間攪拌し、そのとき、（Ｓ）−２−［（２−アミノエチル）フェノキシホスフィノイルオキシ］−プロピオン酸エチルエステル一酢酸塩（５７．１ｍｇ、１５８．３μｍｏｌ；リンにおけるジアステレオマー混合物）のＤＭＦ（２００μＬ）溶液を加えた。この溶液を、さらに１．５時間攪拌すると、出発物質が完全に消費されたことが認められた。真空中で溶媒を除去し、その粗製物質をシリカゲルクロマトグラフィー（これは、ＭｅＯＨ−ＣＨ_２Ｃｌ_２（１０〜３０％）を使用する）で精製した。少量の生成物（２４．８ｍｇ）をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で再精製して、１５．８ｍｇ（６５％）の純粋生成物を得た。¹H NMR (300 MHz, DMSO-d₆) δ1.17 - 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); ³¹P (121.4MHz, DMSO-d₆) δ 26.6, 27.4. MS (m/z) 609.2 [M+H]⁺。

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (60.0 mg, 158.3 μmol) in DMF (2.5 mL), Diethyl cyanophosphonate (31.2 μL, 205.7 μmol) and DIEA (81.8 μL, 474.9 μmol) were added. The solution was stirred at room temperature for 3.5 hours when (S) -2-[(2-aminoethyl) phenoxyphosphinoyloxy] -propionic acid ethyl ester monoacetate (57.1 mg, 158 .3 μmol; a mixture of diastereomers in phosphorus) in DMF (200 μL) was added. The solution was stirred for an additional 1.5 hours and it was found that the starting material was completely consumed. The solvent was removed in vacuo and the crude material was purified by silica gel chromatography (which uses MeOH—CH ₂ Cl ₂ (10-30%)). A small amount of product (24.8 mg) was re-purified with RP HPLC on a _C18 column (which uses H ₂ O / acetonitrile (2-95%)) to give 15.8 mg (65%) of A pure product was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.17-1.27 (m, 3H), 1.32 (d, 2H, J = 7.5 Hz), 1.42 (d, 1H, J = 7.5 Hz) 2.27 (m, 2H), 3.19 (s, 3H), 3.53 (m, 2H), 4.08-4.14 (m, 2H), 4.77 (s, 2H), 4.98 (m, 1H), 6.72 (br s, 1H), 6.81 ( d, 2H, J = 9 Hz), 7.21 (m, 3H), 7.36 (m, 2H), 7.66 (d, 2H, J = 9 Hz), 8.26 (br s, 1H), 8.56 (s, 1H) ³¹ P (121.4 MHz, DMSO-d ₆ ) δ 26.6, 27.4. MS (m / z) 609.2 [M + H] ⁺ .

(Example 343)
(2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] benzoylamino} -ethyl) phenoxyphosphinoyloxy] -propionic acid [diastereomeric mixture at phosphorus])

２−［（２−｛４−［（２，４−ジアミノプテリジン−６−イルメチル）メチル−アミノ］ベンゾイルアミノ｝エチル）フェノキシ−ホスフィノイルオキシ］プロピオン酸エチルエステル（リンにおけるジアステレオマーの混合物；４０．０ｍｇ、６５．７μｍｏｌ）のＤＭＦ（０．４ｍＬ）、アセトニトリル（０．２ｍＬ）および水（０．２ｍＬ）溶液に、水酸化ナトリウム水溶液（１Ｎ、１３１．４μＬ）を加えた。この溶液を、室温で、４時間攪拌した。真空中で溶媒を除去し、その粗生成物をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で精製して、２３．７ｍｇ（７１．３％）の純粋生成物を得た。¹H NMR (300 MHz, DMSO-d₆) δ1.30 (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 (brs, 1H), 8.63 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 25.1. MS (m/z) 505.2 [M+H]⁺。

2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methyl-amino] benzoylamino} ethyl) phenoxy-phosphinoyloxy] propionic acid ethyl ester (mixture of diastereomers at phosphorus To a solution of 40.0 mg, 65.7 μmol) in 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 room 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 give 23.7 mg (71. 3%) pure product was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.30 (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 (brs, 1H), 8.63 (s, 1H); ³¹ P (121.4 MHz, DMSO-d ₆ ) δ 25.1. MS (m / z) 505.2 [M + H] ⁺ .

(Example 343A)
(2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] benzoylamino} ethyl) phenoxyphosphinoyloxy] propionic acid ethyl ester [diastereoisomerically pure in phosphorus ])

４−［（２，４−ジアミノプテリジン−６−イルメチル）−メチル−アミノ］安息香酸半塩酸塩二水和物（１０１．９ｍｇ、２６８．９μｍｏｌ）のＤＭＦ（３．３ｍＬ）溶液に、シアノホスホン酸ジエチル（５３．０μＬ、３４９．５μｍｏｌ）およびＤＩＥＡ（１３８．０μＬ、８０６．７μｍｏｌ）を加えた。この溶液を、室温で、２．５時間攪拌し、そのとき、（Ｓ）−２−［（２−アミノエチル）フェノキシホスフィノイルオキシ］−プロピオン酸エチルエステル一酢酸塩（リンにおいてジアステレオ異性的に純粋；２６８．９μｍｏｌ）のＤＭＦ（５００μＬ）溶液を加えた。この溶液を、さらに３０分間攪拌すると、出発物質が完全に消費されたことが認められた。真空中で溶媒を除去し、その粗製物質をシリカゲルクロマトグラフィー（これは、ＭｅＯＨ−ＣＨ_２Ｃｌ_２（１０〜３０％）を使用する）で精製した。少量の生成物（４０．０ｍｇ）をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で再精製して、２８．７ｍｇ（７５．１％）の純粋生成物を得た。¹H NMR (300 MHz, DMSO-d₆) δ1.15 (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 (brs, 1H), 8.71 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.6. MS (m/z) 609.2 [M+H]⁺。

To a solution of 4-[(2,4-diaminopteridin-6-ylmethyl) -methyl-amino] benzoic acid hemihydrochloride dihydrate (101.9 mg, 268.9 μmol) in DMF (3.3 mL) was added cyanophosphone. Diethyl acid (53.0 μL, 349.5 μmol) and DIEA (138.0 μL, 806.7 μmol) were added. This solution was stirred at room temperature for 2.5 hours, when (S) -2-[(2-aminoethyl) phenoxyphosphinoyloxy] -propionic acid ethyl ester monoacetate (diastereoisomerism at phosphorus). Pure; 268.9 μmol) in DMF (500 μL) was added. The solution was stirred for an additional 30 minutes and it was found that the starting material was completely consumed. The solvent was removed in vacuo and the crude material was purified by silica gel chromatography (which uses MeOH—CH ₂ Cl ₂ (10-30%)). A small amount of product (40.0 mg) was repurified on RP HPLC on a _C18 column (which uses H ₂ O / acetonitrile (2-95%)) to give 28.7 mg (75.1%). ) Pure product was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.15 (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 (brs, 1H), 8.71 (s, 1H); ³¹ P (121.4 MHz, DMSO-d ₆ ) δ 26.6 MS (m / z) 609.2 [M + H] ⁺ .

(Example 344)
(2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] benzoylamino} -ethyl) -phenoxyphosphinoylamino] propionic acid ethyl ester (of diastereomers in phosphorus blend))

４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−安息香酸半塩酸塩二水和物（３９．６ｍｇ、１０４．０μｍｏｌ）のＤＭＦ（１．２ｍＬ）の溶液に、シアノホスホン酸ジエチル（２０．６μＬ、１３６．１μｍｏｌ）およびＤＩＥＡ（３６．０μＬ、２０９．４μｍｏｌ）を加えた。この溶液を、室温で、３時間攪拌し、そのとき、ＤＭＦ（２００μＬ）中の（Ｓ）−２−［（２−アミノエチル）フェノキシホスフィノイルアミノ］プロピオン酸エチルエステル一酢酸塩（リンにおけるジアステレオマーの混合物；１０４．０μｍｏｌ）を加えた。この溶液を３０分間攪拌すると、出発物質が完全に消費されたことが認められた。その反応物のアリコート（６６％）をシリカゲルクロマトグラフィー（これは、ＭｅＯＨ−ＣＨ_２Ｃｌ_２（１０〜３０％）を使用する）で精製して、２７．２ｍｇの粗生成物を得た。少量の生成物（１０ｍｇ）をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で再精製して、４．２ｍｇ（２６％）の純粋生成物を得た。¹H NMR (300 MHz, DMSO-d₆) δ1.11 (t, 3H, J= 6.9 Hz), 1.18 (d, 3H, J= 7.2 Hz), 2.06- 2.17 (m, 2H), 3.20 (s,3H), 3.51 (m, 2H), 3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80(d, 2H, J= 9 Hz), 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.59 (s, 1H) ³¹P (121.4 MHz, DMSO-d₆)δ 29.5, 30.1. MS (m/z) 608.2 [M+H]⁺。

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (39.6 mg, 104.0 μmol) in DMF (1.2 mL). , Diethyl cyanophosphonate (20.6 μL, 136.1 μmol) and DIEA (36.0 μL, 209.4 μmol) were added. This solution was stirred at room temperature for 3 hours, when (S) -2-[(2-aminoethyl) phenoxyphosphinoylamino] propionic acid ethyl ester monoacetate (in phosphorus) in DMF (200 μL). A mixture of diastereomers; 104.0 μmol) was added. The solution was stirred for 30 minutes and it was found that the starting material was completely consumed. An aliquot (66%) of the reaction 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 repurified on RP HPLC on a _C18 column (which uses H ₂ O / acetonitrile (2-95%)) to yield 4.2 mg (26%) pure product I got a thing. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.11 (t, 3H, J = 6.9 Hz), 1.18 (d, 3H, J = 7.2 Hz), 2.06- 2.17 (m, 2H), 3.20 (s , 3H), 3.51 (m, 2H), 3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80 (d, 2H, J = 9 Hz) , 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d, 2H, J = 9 Hz), 8.20 (br s, 1H), 8.59 (s, 1H) ³¹ P (121.4 MHz, DMSO-d ₆ ) δ 29.5, 30.1. MS (m / z) 608.2 [M + H] ⁺ .

(Example 345)
(2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6- (diethoxy-phosphoryl) -hexanoic acid)

４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−安息香酸半塩酸塩二水和物（６３．０ｍｇ、１６６．２μｍｏｌ）のＤＭＦ（２．８ｍＬ）溶液に、ホスホン酸ジエチルシアノ（３０．８μＬ、１９９．４μｍｏｌ）およびＤＩＥＡ（８５．８μＬ、４９８．６μｍｏｌ）を加えた。この溶液を、室温で、３．５時間攪拌し、そのとき、（Ｌ）−２−アミノ−６−ジエチルホスホナトヘキサン酸（４４．３ｍｇ、１６６．２μｍｏｌ）を加えた。この溶液を、さらに４８時間攪拌した。真空中で溶媒を除去し、その残留物をシリカゲルクロマトグラフィー（これは、ＭｅＯＨ−ＣＨ_２Ｃｌ_２（１０〜３０％）を使用する）で精製することにより、この反応物をワークアップした。このクロマトグラフィー工程から集めた生成物（８７ｍｇ）は、次の反応に進めるのに十分に純粋であった。生成物のアリコート（５１．０ｍｇ）をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で再精製して、２４．７ｍｇ（４４％）の純粋生成物を得た。¹H NMR (300 MHz, DMSO-d₆) δ1.18 (t, 6H, J= 6.9 Hz), 1.42 (m, 4H), 1.65 (m, 4H), 3.20 (s, 3H), 3.92 (m,4H), 4.29 (m, 1H), 4.78 (s, 2H), 6.72 (br s, 1H), 6.81 (d, 2H, J= 9 Hz), 7.73(d, 2H, J= 9 Hz), 8.14 (d, 1H, J = 7.8 Hz), 8.56 (s, 1H); ³¹P(121.4 MHz, DMSO-d₆) δ 31.8; MS (m/z) 574.3 [M]⁺。

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (63.0 mg, 166.2 μmol) in DMF (2.8 mL), Diethylcyanophosphonate (30.8 μL, 199.4 μmol) and DIEA (85.8 μL, 498.6 μmol) were added. The solution was stirred at room temperature for 3.5 hours, at which time (L) -2-amino-6-diethylphosphonatohexanoic acid (44.3 mg, 166.2 μmol) was added. The solution was stirred for an additional 48 hours. The reaction was worked up by removing the solvent in vacuo and purifying the residue by silica gel chromatography, which uses MeOH—CH ₂ Cl ₂ (10-30%). The product collected from this chromatography step (87 mg) was pure enough to proceed to the next reaction. An aliquot of the product (51.0 mg) was re-purified with RP HPLC on a _C18 column (which uses H ₂ O / acetonitrile (2-95%)) to yield 24.7 mg (44%) A pure product was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.18 (t, 6H, J = 6.9 Hz), 1.42 (m, 4H), 1.65 (m, 4H), 3.20 (s, 3H), 3.92 (m , 4H), 4.29 (m, 1H), 4.78 (s, 2H), 6.72 (br s, 1H), 6.81 (d, 2H, J = 9 Hz), 7.73 (d, 2H, J = 9 Hz), 8.14 (d, 1H, J = 7.8 Hz), 8.56 (s, 1H); ³¹ P (121.4 MHz, DMSO-d ₆ ) δ 31.8; MS (m / z) 574.3 [M] ⁺ .

(Example 346)
(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] benzoylamino} -6- (phosphoryl) hexanoic acid)

粗（２−｛４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−ベンゾイルアミノ｝）−２’（Ｌ）−（６’−（ホスホン酸ジエチルエステル）ヘキサン酸）のポストシリカカラムクロマトグラフィー（２０ｍｇ、３４．６μｍｏｌ）の無水ＤＭＦ（０．６０ｍＬ）溶液に、室温で、ＴＭＳＢｒ（１８．０μＬ、１３９．２μｍｏｌ）を加えた。この溶液を、７０℃で、１８時間攪拌し、その後、その反応混合物を室温まで冷却した。真空中で溶媒を除去し、そしてＤＭＦ（４００μＬ）および水（６０μＬ）に溶解した。この溶液をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（２〜９５％）を使用する）で精製して、黄色固形物として、８．９ｍｇ（４９％）の生成物を得た。¹H NMR (300 MHz, DMSO-d₆) δ1.45 (m, 6H), 1.75 (m, 2H), 3.20 (s, 3H), 4.25 (m, 1H), 4.77 (s, 2H), 6.62 (brs, 1H), 6.80 (d, 2H, J= 8.7 Hz), 7.73 (d, 2H, J= 8.7 Hz), 8.14 (br s, 1H), 8.55(s, 1H); MS (m/z) 519.2 [M+H]⁺。

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino})-2 '(L)-(6'-(phosphonic acid diethyl ester) hexanoic acid TMSBr (18.0 μL, 139.2 μmol) was added to an anhydrous DMF (0.60 mL) solution of post silica column chromatography (20 mg, 34.6 μmol) at room temperature. The solution was stirred at 70 ° C. for 18 hours, after which the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and dissolved in DMF (400 μL) and water (60 μL). The solution was purified by RP HPLC on a _C18 column (which uses H ₂ O / acetonitrile (2-95%)) to give 8.9 mg (49%) of product as a yellow solid. Obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.45 (m, 6H), 1.75 (m, 2H), 3.20 (s, 3H), 4.25 (m, 1H), 4.77 (s, 2H), 6.62 (brs, 1H), 6.80 (d, 2H, J = 8.7 Hz), 7.73 (d, 2H, J = 8.7 Hz), 8.14 (br s, 1H), 8.55 (s, 1H); MS (m / z ) 519.2 [M + H] ⁺ .

(Example 347)
(2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 ′-(phosphonic acid monophenyl) hexanoic acid)

このエチル−ＴＭＳエステルは、適当な条件下にて加水分解されて、本発明の対応する酸が得られる。

This ethyl-TMS ester is hydrolyzed under suitable conditions to give the corresponding acid of the present invention.

  The intermediate 2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 ′-(phosphonic acid monophenyl) -hexanoic acid TMS ethanol is It can be prepared as follows.

  (A. (L) -2-Cbz-amino-hexanoic acid-6-phosphonic acid)

（Ｌ）−２−アミノ−６−（ジエトキシホスホニル）ヘキサン酸（１０６ｍｇ、３９６．８μｍｏｌ）の無水ＤＭＦ（２．００ｍＬ）懸濁液に、室温で、ＴＭＳＢｒ（３０７．０μＬ、２，３８１．０μｍｏｌ）を加えた。次いで、この溶液を、７０℃で、２時間加熱し、その後、その反応混合物を室温まで冷却した。真空中で溶媒を除去した。その粗製物質を水（０．２５ｍＬ）およびＮａＯＨ（１Ｎ、２．５０ｍＬ）に溶解した。クロロギ酸ベンジル（７９．３μＬ、５５５．５μｍｏｌ）を加え、そして室温での攪拌を継続した。２時間後、この溶液をエーテル（２ｍＬ）で洗浄し、その水層をＨＣｌ水溶液でｐＨ１まで酸性化した。この水層をＥｔＯＡｃ（３×５ｍＬ）で抽出した。合わせた有機抽出物を硫酸ナトリウムで乾燥した。溶媒を濾過し蒸発させると、粗生成物が得られ、これは、さらに変換するのに十分に純粋であった。¹H NMR (300 MHz, DMSO-d₆) δ1.42 - 1.65 (m, 8H), 3.90 (m, 1H), 5.02 (s, 2H), 7.32 (s, 5H), 7.55 (m, 1H),7.94 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.5; MS (m/z)345.6 [M+H]⁺。

To a suspension of (L) -2-amino-6- (diethoxyphosphonyl) hexanoic acid (106 mg, 396.8 μmol) in anhydrous DMF (2.00 mL) at room temperature, TMSBr (307.0 μL, 2,381). 0.0 μmol) 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 in vacuo. The crude material was dissolved in water (0.25 mL) and NaOH (1N, 2.50 mL). Benzyl chloroformate (79.3 μL, 555.5 μmol) was added and stirring at room temperature was continued. After 2 hours, the solution was washed with ether (2 mL) and the aqueous layer was acidified to pH 1 with aqueous HCl. This aqueous layer 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 ) δ1.42-1.65 (m, 8H), 3.90 (m, 1H), 5.02 (s, 2H), 7.32 (s, 5H), 7.55 (m, 1H) , 7.94 (s, 1H); ³¹ P (121.4 MHz, DMSO-d ₆ ) δ 26.5; MS (m / z) 345.6 [M + H] ⁺ .

  (B. (L) -2-Amino-hexanoic acid 2'TMS ethyl ester-6-phosphonic acid monophenyl ester)

（Ｌ）−２−Ｃｂｚ−アミノ−ヘキサン酸-６−ホスホン酸（１３７．３ｍｇ、３９７．９μｍｏｌ）の２−ＴＭＳエタノール（２．５ｍＬ）溶液に、塩化アセチル（５０μＬ）を加えた。室温での攪拌を継続した。２２時間後、完全な変換が認められた。真空中で溶媒を除去した。その粗製物質は、次の工程に十分に純粋であった。

Acetyl chloride (50 μL) was added to a solution of (L) -2-Cbz-amino-hexanoic acid-6-phosphonic acid (137.3 mg, 397.9 μmol) in 2-TMS ethanol (2.5 mL). Stirring at room temperature was continued. After 22 hours, complete conversion was observed. The solvent was removed in vacuo. The crude material was pure enough for the next step.

  Half of this crude material (198.9 μmol) was dissolved in toluene (3.0 mL) at room temperature. Thionyl chloride (167.2 mg, 1,416.0 μmol) was added and the reaction mixture was heated at 70 ° C. (oil bath). After 4 hours, the reaction was cooled to room temperature and the solvent was removed in vacuo. This crude material was redissolved in methylene chloride (2.0 mL) and a solution of phenol (36.6 mg, 389.0 μmol) and DIEA (67.0 μL, 389.0 μmol) in methylene chloride (1.0 mL) was added. . Stirring at room temperature was continued. After 4 hours, the solvent was removed in vacuo.

  This crude material was dissolved in tetrahydrofuran (THF) (3.0 mL) and aqueous sodium hydroxide (1N, 0.885 mL) was added. Stirring at room temperature was continued. After 14 hours, the solvent was removed in vacuo to give crude phosphonic acid monophenyl ester (63.8 mg). This material was dissolved in 2-TMS ethanol (1.0 mL) and acetyl chloride (20 μL) was added. Stirring at room temperature was continued. After 22 hours, complete conversion to its carboxylate ester was observed. The solvent was removed in vacuo. This material was pure enough for the next step.

  Half of this crude material (75 μmol) was dissolved in ethanol (1.5 mL). Pd / C (5%, 20 mg) was added and the reaction was placed in a hydrogen gas atmosphere. After 1.5 hours, celite was added and the crude reaction mixture was filtered through celite. The solvent was removed in vacuo and the crude material was used in the next step without further purification.

  (C. 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 '-(phosphonic acid monophenyl) -hexanoic acid TMS ethanol ester)

４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−安息香酸半塩酸塩二水和物（２２．７ｍｇ、６０．０μｍｏｌ）のＤＭＦ（０．８０ｍＬ）溶液に、ホスホン酸ジエチルシアノ（１２．４μＬ、７８．０μｍｏｌ）およびＤＩＥＡ（３１．０μＬ、１８０．０μｍｏｌ）を加えた。この溶液を、室温で、１時間攪拌し、そのとき、（Ｌ）−２−アミノ−６−モノフェノキシホスホナトヘキサン酸２’ＴＭＳエチルエステル（７０．５μｍｏｌ）（これは、ＤＭＦ（０．２ｍＬ）に懸濁した）を加えた。この溶液を、さらに３．５時間攪拌した。その粗反応混合物をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（５〜９５％）を使用する）で精製して、１９．４ｍｇ（４６％）の２−｛４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−ベンゾイルアミノ｝−６’−（ホスホン酸モノフェニル）−ヘキサン酸ＴＭＳエタノールエステルを得た。¹H NMR (300 MHz, DMSO-d₆) δ0.0 (s, 9H), 0.91 (t, 2H, J= 8.1 Hz), 1.42 - 1.53 (m, 4H), 1.67 -1.76 (m, 4H),3.24 (s, 3H), 4.10 (t, 2H, J= 8.1 Hz), 4.29 (m, 1H), 4.86 (s, 2H), 6.81 (d, 2H,J= 9 Hz), 7.12 (m, 3H), 7. 31 (m, 2H), 7.74 (d, 2H, J= 9 Hz), 8.14 (d, 1H, J =7.8 Hz), 8.71 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.2; MS (m/z) 695.2 [M]⁺。

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (22.7 mg, 60.0 μmol) in DMF (0.80 mL), Diethylcyanophosphonate (12.4 μL, 78.0 μmol) and DIEA (31.0 μL, 180.0 μmol) were added. The solution was stirred at room temperature for 1 hour, when (L) -2-amino-6-monophenoxyphosphonatohexanoic acid 2′TMS ethyl ester (70.5 μmol) (this was DMF (0.2 mL Suspended) was added. 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 yield 19.4 mg (46%) of 2- {4- [ (2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 '-(phosphonic acid monophenyl) -hexanoic acid TMS ethanol ester was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ0.0 (s, 9H), 0.91 (t, 2H, J = 8.1 Hz), 1.42-1.53 (m, 4H), 1.67 -1.76 (m, 4H) , 3.24 (s, 3H), 4.10 (t, 2H, J = 8.1 Hz), 4.29 (m, 1H), 4.86 (s, 2H), 6.81 (d, 2H, J = 9 Hz), 7.12 (m, 3H), 7.31 (m, 2H), 7.74 (d, 2H, J = 9 Hz), 8.14 (d, 1H, J = 7.8 Hz), 8.71 (s, 1H); ³¹ P (121.4 MHz, DMSO -d ₆ ) δ 26.2; MS (m / z) 695.2 [M] ⁺ .

(Example 347A)
(4-[(2,4-Diamino-pteridin-6-ylmethyl) methylamino] benzoylamino} -6 ′-(monophenylmono (S) lactic acid-ethyl phosphonate) hexanoic acid)

このエチル−ＴＭＳエステルは、適当な条件下にて加水分解されて、本発明の対応する酸が得られる。

This ethyl-TMS ester is hydrolyzed under suitable conditions to give the corresponding acid of the present invention.

  Intermediate {2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 '-(monophenylmono (S) lactic acid-ethyl phosphonate)- Hexanoic acid TMS ethanol ester can be prepared as follows.

  (A. 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 ′-(monophenylmono (S) lactic acid-ethyl phosphonate) -hexane Acid TMS ethanol ester)

２−｛４−［（２，４−ジアミノ−プテリジン−６−イルメチル）−メチル−アミノ］−ベンゾイルアミノ｝−６’−（ホスホン酸モノフェニル）−ヘキサン酸ＴＭＳエタノールエステル（１４．５ｍｇ、２０．８μｍｏｌ、実施例２２５）のＤＭＦ（０．７０ｍＬ）溶液に、ＰｙＢＯＰ（３２．４ｍｇ、６２．４μｍｏｌ）、ＤＩＥＡ（２１．４ｍｇ、１６６．４μｍｏｌ）および（Ｓ）乳酸エチル（１９．６ｍｇ、１６６．４μｍｏｌ）を加えた。その反応混合物を、室温で、１時間攪拌した。この粗反応混合物をＣ_１８カラム上のＲＰ ＨＰＬＣ（これは、Ｈ_２Ｏ／アセトニトリル（５〜９５％）を使用する）で精製して、リンにおけるジアステレオマーの混合物（約４：１）として、１３．５ｍｇ（８１％）の純粋生成物を得た。¹H NMR (300 MHz, CDCl₃) δ0.0 (s, 9H), 1.02 (t, 2H, J= 8.7 Hz), 1.23 (t, 3H, J= 9.3 Hz), 1.35 (d, 2.4H,J= 6.6 Hz), 1.42 - 1.53 (m, 4.6H), 1.67 -1.86 (m, 4H), 3.14 (s, 3H), 4.03 -4.27 (m, 4H), 4.71 (br s, 3H), 4.98 (m, 0.8H), 5.10 (m, 0.2H), 6.57 (d, 2H, J=7.5 Hz), 7.00 (m, 1H), 7.16 (m, 3H), 7. 30 (m, 2H), 7.63 (d, 2H, J= 7.5 Hz),8.43 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 30.5, 29.2; MS(m/z) 795.2 [M]⁺。

2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 '-(phosphonic acid monophenyl) -hexanoic acid TMS ethanol ester (14.5 mg, 20 .8 μmol, Example 225) in DMF (0.70 mL) was added to 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%)) as a mixture of diastereomers in phosphorus (about 4: 1). 13.5 mg (81%) of pure product was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.0 (s, 9H), 1.02 (t, 2H, J = 8.7 Hz), 1.23 (t, 3H, J = 9.3 Hz), 1.35 (d, 2.4H, J = 6.6 Hz), 1.42-1.53 (m, 4.6H), 1.67 -1.86 (m, 4H), 3.14 (s, 3H), 4.03 -4.27 (m, 4H), 4.71 (br s, 3H), 4.98 (m, 0.8H), 5.10 (m, 0.2H), 6.57 (d, 2H, J = 7.5 Hz), 7.00 (m, 1H), 7.16 (m, 3H), 7.30 (m, 2H), 7.63 (d, 2H, J = 7.5 Hz), 8.43 (s, 1H); ³¹ P (121.4 MHz, DMSO-d ₆ ) δ 30.5, 29.2; MS (m / z) 795.2 [M] ⁺ .

(Example 348)
By way of example and not limitation, embodiments of the invention are named below in tabular form (Table 100). These embodiments are of the general formula “MBF”:

ＭＢＦの各実施形態は、置換した核（Ｓｃ）として描写されている。Ｓｃは、本明細書中の式１〜１５１（ここで、Ａ^０は、ＳｃがＬｇに共有結合する点である）だけでなく、以下の表１．１〜１．５で記述されている。表１００で記述された実施形態について、Ｓｃは、一定の数字で指定された核であり、そして各置換基は、英字または数字で指定されている。表１．１〜１．５は、表１００の実施形態を形成する際に使用される核の一覧表である。各核（Ｓｃ）は、表１．１〜１．５の数字で指定され、そしてこの指定は、まず、各実施形態名で見える。同様に、表１０．１〜１０．１９および２０．１〜２０．３６は、再度、英字および数字の名称により、それぞれ、選択した結合基（Ｌｇ）およびプロドラッグ（Ｐｄ^１およびＰｄ^２）置換基を列挙する。従って、式ＭＢＦの化合物は、本明細書中の式１〜１５１に基づいたＳｃ基を有する化合物だけでなく、以下の表１００に従った化合物を含む。全ての場合において、式ＭＢＦの化合物は、以下の表で示したＬｇ基、Ｐｄ^１基およびＰｄ^２基を有する。

Each embodiment of MBF is depicted as a substituted nucleus (Sc). Sc is described in Tables 1.1-1.5 below, as well as in Formulas 1-151 herein, where A ⁰ is the point where Sc is covalently bonded to Lg. . For the embodiment described in Table 100, Sc is a nucleus designated by a constant number, and each substituent is designated by a letter or number. Tables 1.1-1.5 are a list of nuclei used in forming the embodiment of Table 100. Each nucleus (Sc) is designated by the numbers in Tables 1.1-1.5, and this designation is first visible in each embodiment name. Similarly, Tables 10.1 to 10.19 and 20.1 to 20.36 again show selected linking group (Lg) and prodrug (Pd ¹ and Pd ² ) substitutions by letters and numbers, respectively. List groups. Accordingly, compounds of formula MBF include compounds according to Table 100 below as well as compounds having Sc groups based on formulas 1-151 herein. In all cases, the compound of formula MBF has the Lg, Pd ¹ and Pd ² groups shown in the table below.

Therefore, each embodiment nominated in Table 100 nominates the linking group (Lg) from Tables 10.1 to 10.19, following the numbers nominating the origin of the nuclei in Tables 1.1 to 1.5. And the numbers indicating the ^two prodrug groups (Pd ¹ and Pd ² ) from Tables 20.1-20.36. In the illustrated tabular form, each embodiment of the table 100 appears as a name having the following notation:

各Ｓｃ基は、波形符号（「〜」）を有して示される。この波形符号は、ＳｃがＬｇに共有結合する点である。結合基（Ｌｇ）のＱ^１およびＱ^２は、基または原子を表わすのではなく、単に、結合性の名称であることが理解されるべきである。Ｑ^１は、核（Ｓｃ）への共有結合部位であり、そしてＱ^２は、式ＭＢＦのリン原子への共有結合部位である。各プロドラッグ基（Ｐｄ^１およびＰｄ^２）は、波形符号（「〜」）で、ＭＢＦのリン原子に共有結合される。表１０．１〜１０．１９および２０．１〜２０．３６の一部の実施形態は、英字および数字（表１０．１〜１０．１９）または数字および英字（表２０．１〜２０．３６）の組合せとして、指定され得る。例えば、ＢＪ１およびＢＪ２に対する表１０の入力が存在している。いずれにしても、表１０．１〜１０．１９の入力は、常に、英字から開始し、そして表２０．１〜２０．３６のものは、常に、数字から開始する。核（Ｓｃ）が大括弧（［］）に囲まれて示され、この括弧から外側に共有結合が伸長するとき、ＳｃがＬｇに共有結合する点は、Ｓｃ上の任意の置換可能な部位であり得る。この結合点の選択は、本明細書中で記述する。限定ではなく例として、この結合点は、スキームおよび実施例で描写したものから選択される。

Each Sc group is indicated with a waveform code (“˜”). This waveform code is a point where Sc is covalently bonded to Lg. It is to be understood that Q ¹ and Q ² of the linking group (Lg) do not represent groups or atoms, but are simply names of bonding. Q ¹ is a covalent binding site to the nucleus (Sc) and Q ² is a covalent binding site 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 waveform code (“˜”). Some embodiments of Tables 10.1 to 10.19 and 20.1 to 20.36 include letters and numbers (Tables 10.1 to 10.19) or numbers and letters (Tables 20.1 to 20.36). ) May be specified. For example, there are entries in Table 10 for BJ1 and BJ2. In any case, the entries in Tables 10.1 to 10.19 always start with a letter, and those in Tables 20.1 to 20.36 always start with a number. When the nucleus (Sc) is shown surrounded by square brackets ([]) and a covalent bond extends from the bracket, Sc is covalently bonded to Lg at any substitutable site on Sc. possible. This selection of attachment points is described herein. By way of example and not limitation, this point of attachment is selected from those depicted in the schemes and examples.

（表１００）
1.Bのプロドラッグ
1.B.228.228; 1.B.228.229; 1.B.228.230; 1.B.228.231; 1.B.228.236; 1.B.228.237;1.B.228.238; 1.B.228.239; 1.B.228.154; 1.B.228.157; 1.B.228.166; 1.B.228.169;1.B.228.172; 1.B.228.175; 1.B.228.240; 1.B.228.244; 1.B.229.228; 1.B.229.229;1.B.229.230; 1.B.229.231; 1.B.229.236; 1.B.229.237; 1.B.229.238; 1.B.229.239;1.B.229.154; 1.B.229.157; 1.B.229.166; 1.B.229.169; 1.B.229.172; 1.B.229.175;1.B.229.240; 1.B.229.244; 1.B.230.228; 1.B.230.229; 1.B.230.230; 1.B.230.231;1.B.230.236; 1.B.230.237; 1.B.230.238; 1.B.230.239; 1.B.230.154; 1.B.230.157;1.B.230.166; 1.B.230.169; 1.B.230.172; 1.B.230.175; 1.B.230.240; 1.B.230.244;1.B.231.228; 1.B.231.229; 1.B.231.230; 1.B.231.231; 1.B.231.236; 1.B.231.237;1.B.231.238; 1.B.231.239; 1.B.231.154; 1.B.231.157; 1.B.231.166; 1.B.231.169;1.B.231.172; 1.B.231.175; 1.B.231.240; 1.B.231.244; 1.B.236.228; 1.B.236.229;1.B.236.230; 1.B.236.231; 1.B.236.236; 1.B.236.237; 1.B.236.238; 1.B.236.239;1.B.236.154; 1.B.236.157; 1.B.236.166; 1.B.236.169; 1.B.236.172; 1.B.236.175;1.B.236.240; 1.B.236.244; 1.B.237.228; 1.B.237.229; 1.B.237.230; 1.B.237.231;1.B.237.236; 1.B.237.237; 1.B.237.238; 1.B.237.239; 1.B.237.154; 1.B.237.157;1.B.237.166; 1.B.237.169; 1.B.237.172; 1.B.237.175; 1.B.237.240; 1.B.237.244;1.B.238.228; 1.B.238.229; 1.B.238.230; 1.B.238.231; 1.B.238.236; 1.B.238.237;1.B.238.238; 1.B.238.239; 1.B.238.154; 1.B.238.157; 1.B.238.166; 1.B.238.169;1.B.238.172; 1.B.238.175; 1.B.238.240; 1.B.238.244; 1.B.239.228; 1.B.239.229;1.B.239.230; 1.B.239.231; 1.B.239.236; 1.B.239.237; 1.B.239.238; 1.B.239.239;1.B.239.154; 1.B.239.157; 1.B.239.166; 1.B.239.169; 1.B.239.172; 1.B.239.175;1.B.239.240; 1.B.239.244; 1.B.154.228; 1.B.154.229; 1.B.154.230; 1.B.154.231;1.B.154.236; 1.B.154.237; 1.B.154.238; 1.B.154.239; 1.B.154.154; 1.B.154.157;1.B.154.166; 1.B.154.169; 1.B.154.172; 1.B.154.175; 1.B.154.240; 1.B.154.244;1.B.157.228; 1.B.157.229; 1.B.157.230; 1.B.157.231; 1.B.157.236; 1.B.157.237;1.B.157.238; 1.B.157.239; 1.B.157.154; 1.B.157.157; 1.B.157.166; 1.B.157.169;1.B.157.172; 1.B.157.175; 1.B.157.240; 1.B.157.244; 1.B.166.228; 1.B.166.229;1.B.166.230; 1.B.166.231; 1.B.166.236; 1.B.166.237; 1.B.166.238; 1.B.166.239;1.B.166.154; 1.B.166.157; 1.B.166.166; 1.B.166.169; 1.B.166.172; 1.B.166.175;1.B.166.240; 1.B.166.244; 1.B.169.228; 1.B.169.229; 1.B.169.230; 1.B.169.231;1.B.169.236; 1.B.169.237; 1.B.169.238; 1.B.169.239; 1.B.169.154; 1.B.169.157;1.B.169.166; 1.B.169.169; 1.B.169.172; 1.B.169.175; 1.B.169.240; 1.B.169.244;1.B.172.228; 1.B.172.229; 1.B.172.230; 1.B.172.231; 1.B.172.236; 1.B.172.237;1.B.172.238; 1.B.172.239; 1.B.172.154; 1.B.172.157; 1.B.172.166; 1.B.172.169;1.B.172.172; 1.B.172.175; 1.B.172.240; 1.B.172.244; 1.B.175.228; 1.B.175.229;1.B.175.230; 1.B.175.231; 1.B.175.236; 1.B.175.237; 1.B.175.238; 1.B.175.239;1.B.175.154; 1.B.175.157; 1.B.175.166; 1.B.175.169; 1.B.175.172; 1.B.175.175;1.B.175.240; 1.B.175.244; 1.B.240.228; 1.B.240.229; 1.B.240.230; 1.B.240.231;1.B.240.236; 1.B.240.237; 1.B.240.238; 1.B.240.239; 1.B.240.154; 1.B.240.157;1.B.240.166; 1.B.240.169; 1.B.240.172; 1.B.240.175; 1.B.240.240; 1.B.240.244;1.B.244.228; 1.B.244.229; 1.B.244.230; 1.B.244.231; 1.B.244.236; 1.B.244.237;1.B.244.238; 1.B.244.239; 1.B.244.154; 1.B.244.157; 1.B.244.166; 1.B.244.169;1.B.244.172; 1.B.244.175; 1.B.244.240; 1.B.244.244;

1.Dのプロドラッグ
1.D.228.228;1.D.228.229; 1.D.228.230; 1.D.228.231; 1.D.228.236; 1.D.228.237; 1.D.228.238;1.D.228.239; 1.D.228.154; 1.D.228.157; 1.D.228.166; 1.D.228.169; 1.D.228.172;1.D.228.175; 1.D.228.240; 1.D.228.244; 1.D.229.228; 1.D.229.229; 1.D.229.230;1.D.229.231; 1.D.229.236; 1.D.229.237; 1.D.229.238; 1.D.229.239; 1.D.229.154;1.D.229.157; 1.D.229.166; 1.D.229.169; 1.D.229.172; 1.D.229.175; 1.D.229.240;1.D.229.244; 1.D.230.228; 1.D.230.229; 1.D.230.230; 1.D.230.231; 1.D.230.236;1.D.230.237; 1.D.230.238; 1.D.230.239; 1.D.230.154; 1.D.230.157; 1.D.230.166;1.D.230.169; 1.D.230.172; 1.D.230.175; 1.D.230.240; 1.D.230.244; 1.D.231.228;1.D.231.229; 1.D.231.230; 1.D.231.231; 1.D.231.236; 1.D.231.237; 1.D.231.238;1.D.231.239; 1.D.231.154; 1.D.231.157; 1.D.231.166; 1.D.231.169; 1.D.231.172;1.D.231.175; 1.D.231.240; 1.D.231.244; 1.D.236.228; 1.D.236.229; 1.D.236.230;1.D.236.231; 1.D.236.236; 1.D.236.237; 1.D.236.238; 1.D.236.239; 1.D.236.154;1.D.236.157; 1.D.236.166; 1.D.236.169; 1.D.236.172; 1.D.236.175; 1.D.236.240;1.D.236.244; 1.D.237.228; 1.D.237.229; 1.D.237.230; 1.D.237.231; 1.D.237.236;1.D.237.237; 1.D.237.238; 1.D.237.239; 1.D.237.154; 1.D.237.157; 1.D.237.166;1.D.237.169; 1.D.237.172; 1.D.237.175; 1.D.237.240; 1.D.237.244; 1.D.238.228;1.D.238.229; 1.D.238.230; 1.D.238.231; 1.D.238.236; 1.D.238.237; 1.D.238.238;1.D.238.239; 1.D.238.154; 1.D.238.157; 1.D.238.166; 1.D.238.169; 1.D.238.172;1.D.238.175; 1.D.238.240; 1.D.238.244; 1.D.239.228; 1.D.239.229; 1.D.239.230;1.D.239.231; 1.D.239.236; 1.D.239.237; 1.D.239.238; 1.D.239.239; 1.D.239.154;1.D.239.157; 1.D.239.166; 1.D.239.169; 1.D.239.172; 1.D.239.175; 1.D.239.240;1.D.239.244; 1.D.154.228; 1.D.154.229; 1.D.154.230; 1.D.154.231; 1.D.154.236;1.D.154.237; 1.D.154.238; 1.D.154.239; 1.D.154.154; 1.D.154.157; 1.D.154.166;1.D.154.169; 1.D.154.172; 1.D.154.175; 1.D.154.240; 1.D.154.244; 1.D.157.228;1.D.157.229; 1.D.157.230; 1.D.157.231; 1.D.157.236; 1.D.157.237; 1.D.157.238;1.D.157.239; 1.D.157.154; 1.D.157.157; 1.D.157.166; 1.D.157.169; 1.D.157.172;1.D.157.175; 1.D.157.240; 1.D.157.244; 1.D.166.228; 1.D.166.229; 1.D.166.230;1.D.166.231; 1.D.166.236; 1.D.166.237; 1.D.166.238; 1.D.166.239; 1.D.166.154;1.D.166.157; 1.D.166.166; 1.D.166.169; 1.D.166.172; 1.D.166.175; 1.D.166.240;1.D.166.244; 1.D.169.228; 1.D.169.229; 1.D.169.230; 1.D.169.231; 1.D.169.236;1.D.169.237; 1.D.169.238; 1.D.169.239; 1.D.169.154; 1.D.169.157; 1.D.169.166;1.D.169.169; 1.D.169.172; 1.D.169.175; 1.D.169.240; 1.D.169.244; 1.D.172.228;1.D.172.229; 1.D.172.230; 1.D.172.231; 1.D.172.236; 1.D.172.237; 1.D.172.238;1.D.172.239; 1.D.172.154; 1.D.172.157; 1.D.172.166; 1.D.172.169; 1.D.172.172;1.D.172.175; 1.D.172.240; 1.D.172.244; 1.D.175.228; 1.D.175.229; 1.D.175.230;1.D.175.231; 1.D.175.236; 1.D.175.237; 1.D.175.238; 1.D.175.239; 1.D.175.154;1.D.175.157; 1.D.175.166; 1.D.175.169; 1.D.175.172; 1.D.175.175; 1.D.175.240;1.D.175.244; 1.D.240.228; 1.D.240.229; 1.D.240.230; 1.D.240.231; 1.D.240.236;1.D.240.237; 1.D.240.238; 1.D.240.239; 1.D.240.154; 1.D.240.157; 1.D.240.166;1.D.240.169; 1.D.240.172; 1.D.240.175; 1.D.240.240; 1.D.240.244; 1.D.244.228;1.D.244.229; 1.D.244.230; 1.D.244.231; 1.D.244.236; 1.D.244.237; 1.D.244.238;1.D.244.239; 1.D.244.154; 1.D.244.157; 1.D.244.166; 1.D.244.169; 1.D.244.172;1.D.244.175; 1.D.244.240; 1.D.244.244;

1.Eのプロドラッグ
1.E.228.228; 1.E.228.229; 1.E.228.230; 1.E.228.231; 1.E.228.236; 1.E.228.237;1.E.228.238; 1.E.228.239; 1.E.228.154; 1.E.228.157; 1.E.228.166; 1.E.228.169;1.E.228.172; 1.E.228.175; 1.E.228.240; 1.E.228.244; 1.E.229.228; 1.E.229.229;1.E.229.230; 1.E.229.231; 1.E.229.236; 1.E.229.237; 1.E.229.238; 1.E.229.239;1.E.229.154; 1.E.229.157; 1.E.229.166; 1.E.229.169; 1.E.229.172; 1.E.229.175;1.E.229.240; 1.E.229.244; 1.E.230.228; 1.E.230.229; 1.E.230.230; 1.E.230.231;1.E.230.236; 1.E.230.237; 1.E.230.238; 1.E.230.239; 1.E.230.154; 1.E.230.157;1.E.230.166; 1.E.230.169; 1.E.230.172; 1.E.230.175; 1.E.230.240; 1.E.230.244;1.E.231.228; 1.E.231.229; 1.E.231.230; 1.E.231.231; 1.E.231.236; 1.E.231.237;1.E.231.238; 1.E.231.239; 1.E.231.154; 1.E.231.157; 1.E.231.166; 1.E.231.169;1.E.231.172; 1.E.231.175; 1.E.231.240; 1.E.231.244; 1.E.236.228; 1.E.236.229;1.E.236.230; 1.E.236.231; 1.E.236.236; 1.E.236.237; 1.E.236.238; 1.E.236.239;1.E.236.154; 1.E.236.157; 1.E.236.166; 1.E.236.169; 1.E.236.172; 1.E.236.175;1.E.236.240; 1.E.236.244; 1.E.237.228; 1.E.237.229; 1.E.237.230; 1.E.237.231;1.E.237.236; 1.E.237.237; 1.E.237.238; 1.E.237.239; 1.E.237.154; 1.E.237.157;1.E.237.166; 1.E.237.169; 1.E.237.172; 1.E.237.175; 1.E.237.240; 1.E.237.244;1.E.238.228; 1.E.238.229; 1.E.238.230; 1.E.238.231; 1.E.238.236; 1.E.238.237;1.E.238.238; 1.E.238.239; 1.E.238.154; 1.E.238.157; 1.E.238.166; 1.E.238.169;1.E.238.172; 1.E.238.175; 1.E.238.240; 1.E.238.244; 1.E.239.228; 1.E.239.229;1.E.239.230; 1.E.239.231; 1.E.239.236; 1.E.239.237; 1.E.239.238; 1.E.239.239;1.E.239.154; 1.E.239.157; 1.E.239.166; 1.E.239.169; 1.E.239.172; 1.E.239.175;1.E.239.240; 1.E.239.244; 1.E.154.228; 1.E.154.229; 1.E.154.230; 1.E.154.231;1.E.154.236; 1.E.154.237; 1.E.154.238; 1.E.154.239; 1.E.154.154; 1.E.154.157;1.E.154.166; 1.E.154.169; 1.E.154.172; 1.E.154.175; 1.E.154.240; 1.E.154.244;1.E.157.228; 1.E.157.229; 1.E.157.230; 1.E.157.231; 1.E.157.236; 1.E.157.237;1.E.157.238; 1.E.157.239; 1.E.157.154; 1.E.157.157; 1.E.157.166; 1.E.157.169;1.E.157.172; 1.E.157.175; 1.E.157.240; 1.E.157.244; 1.E.166.228; 1.E.166.229;1.E.166.230; 1.E.166.231; 1.E.166.236; 1.E.166.237; 1.E.166.238; 1.E.166.239;1.E.166.154; 1.E.166.157; 1.E.166.166; 1.E.166.169; 1.E.166.172; 1.E.166.175;1.E.166.240; 1.E.166.244; 1.E.169.228; 1.E.169.229; 1.E.169.230; 1.E.169.231;1.E.169.236; 1.E.169.237; 1.E.169.238; 1.E.169.239; 1.E.169.154; 1.E.169.157;1.E.169.166; 1.E.169.169; 1.E.169.172; 1.E.169.175; 1.E.169.240; 1.E.169.244;1.E.172.228; 1.E.172.229; 1.E.172.230; 1.E.172.231; 1.E.172.236; 1.E.172.237;1.E.172.238; 1.E.172.239; 1.E.172.154; 1.E.172.157; 1.E.172.166; 1.E.172.169;1.E.172.172; 1.E.172.175; 1.E.172.240; 1.E.172.244; 1.E.175.228; 1.E.175.229; 1.E.175.230;1.E.175.231; 1.E.175.236; 1.E.175.237; 1.E.175.238; 1.E.175.239; 1.E.175.154;1.E.175.157; 1.E.175.166; 1.E.175.169; 1.E.175.172; 1.E.175.175; 1.E.175.240;1.E.175.244; 1.E.240.228; 1.E.240.229; 1.E.240.230; 1.E.240.231; 1.E.240.236;1.E.240.237; 1.E.240.238; 1.E.240.239; 1.E.240.154; 1.E.240.157; 1.E.240.166;1.E.240.169; 1.E.240.172; 1.E.240.175; 1.E.240.240; 1.E.240.244; 1.E.244.228;1.E.244.229; 1.E.244.230; 1.E.244.231; 1.E.244.236; 1.E.244.237; 1.E.244.238;1.E.244.239; 1.E.244.154; 1.E.244.157; 1.E.244.166; 1.E.244.169; 1.E.244.172;1.E.244.175; 1.E.244.240; 1.E.244.244;

1.Gのプロドラッグ
1.G.228.228; 1.G.228.229; 1.G.228.230; 1.G.228.231; 1.G.228.236; 1.G.228.237;1.G.228.238; 1.G.228.239; 1.G.228.154; 1.G.228.157; 1.G.228.166; 1.G.228.169;1.G.228.172; 1.G.228.175; 1.G.228.240; 1.G.228.244; 1.G.229.228; 1.G.229.229;1.G.229.230; 1.G.229.231; 1.G.229.236; 1.G.229.237; 1.G.229.238; 1.G.229.239;1.G.229.154; 1.G.229.157; 1.G.229.166; 1.G.229.169; 1.G.229.172; 1.G.229.175;1.G.229.240; 1.G.229.244; 1.G.230.228; 1.G.230.229; 1.G.230.230; 1.G.230.231;1.G.230.236; 1.G.230.237; 1.G.230.238; 1.G.230.239; 1.G.230.154; 1.G.230.157;1.G.230.166; 1.G.230.169; 1.G.230.172; 1.G.230.175; 1.G.230.240; 1.G.230.244;1.G.231.228; 1.G.231.229; 1.G.231.230; 1.G.231.231; 1.G.231.236; 1.G.231.237;1.G.231.238; 1.G.231.239; 1.G.231.154; 1.G.231.157; 1.G.231.166; 1.G.231.169;1.G.231.172; 1.G.231.175; 1.G.231.240; 1.G.231.244; 1.G.236.228; 1.G.236.229;1.G.236.230; 1.G.236.231; 1.G.236.236; 1.G.236.237; 1.G.236.238; 1.G.236.239;1.G.236.154; 1.G.236.157; 1.G.236.166; 1.G.236.169; 1.G.236.172; 1.G.236.175;1.G.236.240; 1.G.236.244; 1.G.237.228; 1.G.237.229; 1.G.237.230; 1.G.237.231;1.G.237.236; 1.G.237.237; 1.G.237.238; 1.G.237.239; 1.G.237.154; 1.G.237.157;1.G.237.166; 1.G.237.169; 1.G.237.172; 1.G.237.175; 1.G.237.240; 1.G.237.244;1.G.238.228; 1.G.238.229; 1.G.238.230; 1.G.238.231; 1.G.238.236; 1.G.238.237;1.G.238.238; 1.G.238.239; 1.G.238.154; 1.G.238.157; 1.G.238.166; 1.G.238.169;1.G.238.172; 1.G.238.175; 1.G.238.240; 1.G.238.244; 1.G.239.228; 1.G.239.229;1.G.239.230; 1.G.239.231; 1.G.239.236; 1.G.239.237; 1.G.239.238; 1.G.239.239;1.G.239.154; 1.G.239.157; 1.G.239.166; 1.G.239.169; 1.G.239.172; 1.G.239.175;1.G.239.240; 1.G.239.244; 1.G.154.228; 1.G.154.229; 1.G.154.230; 1.G.154.231;1.G.154.236; 1.G.154.237; 1.G.154.238; 1.G.154.239; 1.G.154.154; 1.G.154.157;1.G.154.166; 1.G.154.169; 1.G.154.172; 1.G.154.175; 1.G.154.240; 1.G.154.244;1.G.157.228; 1.G.157.229; 1.G.157.230; 1.G.157.231; 1.G.157.236; 1.G.157.237;1.G.157.238; 1.G.157.239; 1.G.157.154; 1.G.157.157; 1.G.157.166; 1.G.157.169;1.G.157.172; 1.G.157.175; 1.G.157.240; 1.G.157.244; 1.G.166.228; 1.G.166.229;1.G.166.230; 1.G.166.231; 1.G.166.236; 1.G.166.237; 1.G.166.238; 1.G.166.239;1.G.166.154; 1.G.166.157; 1.G.166.166; 1.G.166.169; 1.G.166.172; 1.G.166.175;1.G.166.240; 1.G.166.244; 1.G.169.228; 1.G.169.229; 1.G.169.230; 1.G.169.231;1.G.169.236; 1.G.169.237; 1.G.169.238; 1.G.169.239; 1.G.169.154; 1.G.169.157;1.G.169.166; 1.G.169.169; 1.G.169.172; 1.G.169.175; 1.G.169.240; 1.G.169.244;1.G.172.228; 1.G.172.229; 1.G.172.230; 1.G.172.231; 1.G.172.236; 1.G.172.237;1.G.172.238; 1.G.172.239; 1.G.172.154; 1.G.172.157; 1.G.172.166; 1.G.172.169;1.G.172.172; 1.G.172.175; 1.G.172.240; 1.G.172.244; 1.G.175.228; 1.G.175.229;1.G.175.230; 1.G.175.231; 1.G.175.236; 1.G.175.237; 1.G.175.238; 1.G.175.239;1.G.175.154; 1.G.175.157; 1.G.175.166; 1.G.175.169; 1.G.175.172; 1.G.175.175;1.G.175.240; 1.G.175.244; 1.G.240.228; 1.G.240.229; 1.G.240.230; 1.G.240.231;1.G.240.236; 1.G.240.237; 1.G.240.238; 1.G.240.239; 1.G.240.154; 1.G.240.157;1.G.240.166; 1.G.240.169; 1.G.240.172; 1.G.240.175; 1.G.240.240; 1.G.240.244;1.G.244.228; 1.G.244.229; 1.G.244.230; 1.G.244.231; 1.G.244.236; 1.G.244.237;1.G.244.238; 1.G.244.239; 1.G.244.154; 1.G.244.157; 1.G.244.166; 1.G.244.169;1.G.244.172; 1.G.244.175; 1.G.244.240; 1.G.244.244;

1.Iのプロドラッグ
1.I.228.228; 1.I.228.229; 1.I.228.230; 1.I.228.231; 1.I.228.236; 1.I.228.237;1.I.228.238; 1.I.228.239; 1.I.228.154; 1.I.228.157; 1.I.228.166; 1.I.228.169;1.I.228.172; 1.I.228.175; 1.I.228.240; 1.I.228.244; 1.I.229.228; 1.I.229.229;1.I.229.230; 1.I.229.231; 1.I.229.236; 1.I.229.237; 1.I.229.238; 1.I.229.239;1.I.229.154; 1.I.229.157; 1.I.229.166; 1.I.229.169; 1.I.229.172; 1.I.229.175; 1.I.229.240;1.I.229.244; 1.I.230.228; 1.I.230.229; 1.I.230.230; 1.I.230.231; 1.I.230.236;1.I.230.237; 1.I.230.238; 1.I.230.239; 1.I.230.154; 1.I.230.157; 1.I.230.166;1.I.230.169; 1.I.230.172; 1.I.230.175; 1.I.230.240; 1.I.230.244; 1.I.231.228;1.I.231.229; 1.I.231.230; 1.I.231.231; 1.I.231.236; 1.I.231.237; 1.I.231.238;1.I.231.239; 1.I.231.154; 1.I.231.157; 1.I.231.166; 1.I.231.169; 1.I.231.172;1.I.231.175; 1.I.231.240; 1.I.231.244; 1.I.236.228; 1.I.236.229; 1.I.236.230;1.I.236.231; 1.I.236.236; 1.I.236.237; 1.I.236.238; 1.I.236.239; 1.I.236.154;1.I.236.157; 1.I.236.166; 1.I.236.169; 1.I.236.172; 1.I.236.175; 1.I.236.240;1.I.236.244; 1.I.237.228; 1.I.237.229; 1.I.237.230; 1.I.237.231; 1.I.237.236;1.I.237.237; 1.I.237.238; 1.I.237.239; 1.I.237.154; 1.I.237.157; 1.I.237.166;1.I.237.169; 1.I.237.172; 1.I.237.175; 1.I.237.240; 1.I.237.244; 1.I.238.228;1.I.238.229; 1.I.238.230; 1.I.238.231; 1.I.238.236; 1.I.238.237; 1.I.238.238;1.I.238.239; 1.I.238.154; 1.I.238.157; 1.I.238.166; 1.I.238.169; 1.I.238.172;1.I.238.175; 1.I.238.240; 1.I.238.244; 1.I.239.228; 1.I.239.229; 1.I.239.230;1.I.239.231; 1.I.239.236; 1.I.239.237; 1.I.239.238; 1.I.239.239; 1.I.239.154;1.I.239.157; 1.I.239.166; 1.I.239.169; 1.I.239.172; 1.I.239.175; 1.I.239.240;1.I.239.244; 1.I.154.228; 1.I.154.229; 1.I.154.230; 1.I.154.231; 1.I.154.236;1.I.154.237; 1.I.154.238; 1.I.154.239; 1.I.154.154; 1.I.154.157; 1.I.154.166;1.I.154.169; 1.I.154.172; 1.I.154.175; 1.I.154.240; 1.I.154.244; 1.I.157.228;1.I.157.229; 1.I.157.230; 1.I.157.231; 1.I.157.236; 1.I.157.237; 1.I.157.238;1.I.157.239; 1.I.157.154; 1.I.157.157; 1.I.157.166; 1.I.157.169; 1.I.157.172;1.I.157.175; 1.I.157.240; 1.I.157.244; 1.I.166.228; 1.I.166.229; 1.I.166.230;1.I.166.231; 1.I.166.236; 1.I.166.237; 1.I.166.238; 1.I.166.239; 1.I.166.154;1.I.166.157; 1.I.166.166; 1.I.166.169; 1.I.166.172; 1.I.166.175; 1.I.166.240;1.I.166.244; 1.I.169.228; 1.I.169.229; 1.I.169.230; 1.I.169.231; 1.I.169.236;1.I.169.237; 1.I.169.238; 1.I.169.239; 1.I.169.154; 1.I.169.157; 1.I.169.166;1.I.169.169; 1.I.169.172; 1.I.169.175; 1.I.169.240; 1.I.169.244; 1.I.172.228;1.I.172.229; 1.I.172.230; 1.I.172.231; 1.I.172.236; 1.I.172.237; 1.I.172.238;1.I.172.239; 1.I.172.154; 1.I.172.157; 1.I.172.166; 1.I.172.169; 1.I.172.172;1.I.172.175; 1.I.172.240; 1.I.172.244; 1.I.175.228; 1.I.175.229; 1.I.175.230;1.I.175.231; 1.I.175.236; 1.I.175.237; 1.I.175.238; 1.I.175.239; 1.I.175.154;1.I.175.157; 1.I.175.166; 1.I.175.169; 1.I.175.172; 1.I.175.175; 1.I.175.240;1.I.175.244; 1.I.240.228; 1.I.240.229; 1.I.240.230; 1.I.240.231; 1.I.240.236;1.I.240.237; 1.I.240.238; 1.I.240.239; 1.I.240.154; 1.I.240.157; 1.I.240.166;1.I.240.169; 1.I.240.172; 1.I.240.175; 1.I.240.240; 1.I.240.244; 1.I.244.228;1.I.244.229; 1.I.244.230; 1.I.244.231; 1.I.244.236; 1.I.244.237; 1.I.244.238;1.I.244.239; 1.I.244.154; 1.I.244.157; 1.I.244.166; 1.I.244.169; 1.I.244.172;1.I.244.175; 1.I.244.240; 1.I.244.244;

1.Jのプロドラッグ
1.J.228.228; 1.J.228.229; 1.J.228.230; 1.J.228.231; 1.J.228.236; 1.J.228.237;1.J.228.238; 1.J.228.239; 1.J.228.154; 1.J.228.157; 1.J.228.166; 1.J.228.169;1.J.228.172; 1.J.228.175; 1.J.228.240; 1.J.228.244; 1.J.229.228; 1.J.229.229;1.J.229.230; 1.J.229.231; 1.J.229.236; 1.J.229.237; 1.J.229.238; 1.J.229.239;1.J.229.154; 1.J.229.157; 1.J.229.166; 1.J.229.169; 1.J.229.172; 1.J.229.175;1.J.229.240; 1.J.229.244; 1.J.230.228; 1.J.230.229; 1.J.230.230; 1.J.230.231;1.J.230.236; 1.J.230.237; 1.J.230.238; 1.J.230.239; 1.J.230.154; 1.J.230.157;1.J.230.166; 1.J.230.169; 1.J.230.172; 1.J.230.175; 1.J.230.240; 1.J.230.244; 1.J.231.228;1.J.231.229; 1.J.231.230; 1.J.231.231; 1.J.231.236; 1.J.231.237; 1.J.231.238;1.J.231.239; 1.J.231.154; 1.J.231.157; 1.J.231.166; 1.J.231.169; 1.J.231.172;1.J.231.175; 1.J.231.240; 1.J.231.244; 1.J.236.228; 1.J.236.229; 1.J.236.230;1.J.236.231; 1.J.236.236; 1.J.236.237; 1.J.236.238; 1.J.236.239; 1.J.236.154;1.J.236.157; 1.J.236.166; 1.J.236.169; 1.J.236.172; 1.J.236.175; 1.J.236.240;1.J.236.244; 1.J.237.228; 1.J.237.229; 1.J.237.230; 1.J.237.231; 1.J.237.236;1.J.237.237; 1.J.237.238; 1.J.237.239; 1.J.237.154; 1.J.237.157; 1.J.237.166;1.J.237.169; 1.J.237.172; 1.J.237.175; 1.J.237.240; 1.J.237.244; 1.J.238.228;1.J.238.229; 1.J.238.230; 1.J.238.231; 1.J.238.236; 1.J.238.237; 1.J.238.238;1.J.238.239; 1.J.238.154; 1.J.238.157; 1.J.238.166; 1.J.238.169; 1.J.238.172;1.J.238.175; 1.J.238.240; 1.J.238.244; 1.J.239.228; 1.J.239.229; 1.J.239.230;1.J.239.231; 1.J.239.236; 1.J.239.237; 1.J.239.238; 1.J.239.239; 1.J.239.154;1.J.239.157; 1.J.239.166; 1.J.239.169; 1.J.239.172; 1.J.239.175; 1.J.239.240; 1.J.239.244;1.J.154.228; 1.J.154.229; 1.J.154.230; 1.J.154.231; 1.J.154.236; 1.J.154.237;1.J.154.238; 1.J.154.239; 1.J.154.154; 1.J.154.157; 1.J.154.166; 1.J.154.169;1.J.154.172; 1.J.154.175; 1.J.154.240; 1.J.154.244; 1.J.157.228; 1.J.157.229;1.J.157.230; 1.J.157.231; 1.J.157.236; 1.J.157.237; 1.J.157.238; 1.J.157.239;1.J.157.154; 1.J.157.157; 1.J.157.166; 1.J.157.169; 1.J.157.172; 1.J.157.175;1.J.157.240; 1.J.157.244; 1.J.166.228; 1.J.166.229; 1.J.166.230; 1.J.166.231;1.J.166.236; 1.J.166.237; 1.J.166.238; 1.J.166.239; 1.J.166.154; 1.J.166.157;1.J.166.166; 1.J.166.169; 1.J.166.172; 1.J.166.175; 1.J.166.240; 1.J.166.244;1.J.169.228; 1.J.169.229; 1.J.169.230; 1.J.169.231; 1.J.169.236; 1.J.169.237;1.J.169.238; 1.J.169.239; 1.J.169.154; 1.J.169.157; 1.J.169.166; 1.J.169.169;1.J.169.172; 1.J.169.175; 1.J.169.240; 1.J.169.244; 1.J.172.228; 1.J.172.229;1.J.172.230; 1.J.172.231; 1.J.172.236; 1.J.172.237; 1.J.172.238; 1.J.172.239;1.J.172.154; 1.J.172.157; 1.J.172.166; 1.J.172.169; 1.J.172.172; 1.J.172.175;1.J.172.240; 1.J.172.244; 1.J.175.228; 1.J.175.229; 1.J.175.230; 1.J.175.231;1.J.175.236; 1.J.175.237; 1.J.175.238; 1.J.175.239; 1.J.175.154; 1.J.175.157;1.J.175.166; 1.J.175.169; 1.J.175.172; 1.J.175.175; 1.J.175.240; 1.J.175.244;1.J.240.228; 1.J.240.229; 1.J.240.230; 1.J.240.231; 1.J.240.236; 1.J.240.237;1.J.240.238; 1.J.240.239; 1.J.240.154; 1.J.240.157; 1.J.240.166; 1.J.240.169;1.J.240.172; 1.J.240.175; 1.J.240.240; 1.J.240.244; 1.J.244.228; 1.J.244.229;1.J.244.230; 1.J.244.231; 1.J.244.236; 1.J.244.237; 1.J.244.238; 1.J.244.239;1.J.244.154; 1.J.244.157; 1.J.244.166; 1.J.244.169; 1.J.244.172; 1.J.244.175;1.J.244.240; 1.J.244.244;

1.Lのプロドラッグ
1.L.228.228; 1.L.228.229; 1.L.228.230; 1.L.228.231; 1.L.228.236; 1.L.228.237;1.L.228.238; 1.L.228.239; 1.L.228.154; 1.L.228.157; 1.L.228.166; 1.L.228.169;1.L.228.172; 1.L.228.175; 1.L.228.240; 1.L.228.244; 1.L.229.228; 1.L.229.229;1.L.229.230; 1.L.229.231; 1.L.229.236; 1.L.229.237; 1.L.229.238; 1.L.229.239;1.L.229.154; 1.L.229.157; 1.L.229.166; 1.L.229.169; 1.L.229.172; 1.L.229.175;1.L.229.240; 1.L.229.244; 1.L.230.228; 1.L.230.229; 1.L.230.230; 1.L.230.231;1.L.230.236; 1.L.230.237; 1.L.230.238; 1.L.230.239; 1.L.230.154; 1.L.230.157;1.L.230.166; 1.L.230.169; 1.L.230.172; 1.L.230.175; 1.L.230.240; 1.L.230.244;1.L.231.228; 1.L.231.229; 1.L.231.230; 1.L.231.231; 1.L.231.236; 1.L.231.237;1.L.231.238; 1.L.231.239; 1.L.231.154; 1.L.231.157; 1.L.231.166; 1.L.231.169;1.L.231.172; 1.L.231.175; 1.L.231.240; 1.L.231.244; 1.L.236.228; 1.L.236.229;1.L.236.230; 1.L.236.231; 1.L.236.236; 1.L.236.237; 1.L.236.238; 1.L.236.239;1.L.236.154; 1.L.236.157; 1.L.236.166; 1.L.236.169; 1.L.236.172; 1.L.236.175;1.L.236.240; 1.L.236.244; 1.L.237.228; 1.L.237.229; 1.L.237.230; 1.L.237.231;1.L.237.236; 1.L.237.237; 1.L.237.238; 1.L.237.239; 1.L.237.154; 1.L.237.157;1.L.237.166; 1.L.237.169; 1.L.237.172; 1.L.237.175; 1.L.237.240; 1.L.237.244;1.L.238.228; 1.L.238.229; 1.L.238.230; 1.L.238.231; 1.L.238.236; 1.L.238.237;1.L.238.238; 1.L.238.239; 1.L.238.154; 1.L.238.157; 1.L.238.166; 1.L.238.169;1.L.238.172; 1.L.238.175; 1.L.238.240; 1.L.238.244; 1.L.239.228; 1.L.239.229;1.L.239.230; 1.L.239.231; 1.L.239.236; 1.L.239.237; 1.L.239.238; 1.L.239.239;1.L.239.154; 1.L.239.157; 1.L.239.166; 1.L.239.169; 1.L.239.172; 1.L.239.175;1.L.239.240; 1.L.239.244; 1.L.154.228; 1.L.154.229; 1.L.154.230; 1.L.154.231;1.L.154.236; 1.L.154.237; 1.L.154.238; 1.L.154.239; 1.L.154.154; 1.L.154.157;1.L.154.166; 1.L.154.169; 1.L.154.172; 1.L.154.175; 1.L.154.240; 1.L.154.244;1.L.157.228; 1.L.157.229; 1.L.157.230; 1.L.157.231; 1.L.157.236; 1.L.157.237;1.L.157.238; 1.L.157.239; 1.L.157.154; 1.L.157.157; 1.L.157.166; 1.L.157.169;1.L.157.172; 1.L.157.175; 1.L.157.240; 1.L.157.244; 1.L.166.228; 1.L.166.229;1.L.166.230; 1.L.166.231; 1.L.166.236; 1.L.166.237; 1.L.166.238; 1.L.166.239;1.L.166.154; 1.L.166.157; 1.L.166.166; 1.L.166.169; 1.L.166.172; 1.L.166.175;1.L.166.240; 1.L.166.244; 1.L.169.228; 1.L.169.229; 1.L.169.230; 1.L.169.231;1.L.169.236; 1.L.169.237; 1.L.169.238; 1.L.169.239; 1.L.169.154; 1.L.169.157;1.L.169.166; 1.L.169.169; 1.L.169.172; 1.L.169.175; 1.L.169.240; 1.L.169.244;1.L.172.228; 1.L.172.229; 1.L.172.230; 1.L.172.231; 1.L.172.236; 1.L.172.237;1.L.172.238; 1.L.172.239; 1.L.172.154; 1.L.172.157; 1.L.172.166; 1.L.172.169;1.L.172.172; 1.L.172.175; 1.L.172.240; 1.L.172.244; 1.L.175.228; 1.L.175.229;1.L.175.230; 1.L.175.231; 1.L.175.236; 1.L.175.237; 1.L.175.238; 1.L.175.239;1.L.175.154; 1.L.175.157; 1.L.175.166; 1.L.175.169; 1.L.175.172; 1.L.175.175;1.L.175.240; 1.L.175.244; 1.L.240.228; 1.L.240.229; 1.L.240.230; 1.L.240.231;1.L.240.236; 1.L.240.237; 1.L.240.238; 1.L.240.239; 1.L.240.154; 1.L.240.157;1.L.240.166; 1.L.240.169; 1.L.240.172; 1.L.240.175; 1.L.240.240; 1.L.240.244;1.L.244.228; 1.L.244.229; 1.L.244.230; 1.L.244.231; 1.L.244.236; 1.L.244.237;1.L.244.238; 1.L.244.239; 1.L.244.154; 1.L.244.157; 1.L.244.166; 1.L.244.169;1.L.244.172; 1.L.244.175; 1.L.244.240; 1.L.244.244;

1.Oのプロドラッグ
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.O.228.154; 1.O.228.157; 1.O.228.166; 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.O.230.229; 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.O.238.244; 1.O.239.228; 1.O.239.229;1.O.239.230; 1.O.239.231; 1.O.239.236; 1.O.239.237; 1.O.239.238; 1.O.239.239;1.O.239.154; 1.O.239.157; 1.O.239.166; 1.O.239.169; 1.O.239.172; 1.O.239.175;1.O.239.240; 1.O.239.244; 1.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.157.169;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.240.157; 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のプロドラッグ
1.P.228.228; 1.P.228.229; 1.P.228.230; 1.P.228.231; 1.P.228.236; 1.P.228.237;1.P.228.238; 1.P.228.239; 1.P.228.154; 1.P.228.157; 1.P.228.166; 1.P.228.169;1.P.228.172; 1.P.228.175; 1.P.228.240; 1.P.228.244; 1.P.229.228; 1.P.229.229;1.P.229.230; 1.P.229.231; 1.P.229.236; 1.P.229.237; 1.P.229.238; 1.P.229.239;1.P.229.154; 1.P.229.157; 1.P.229.166; 1.P.229.169; 1.P.229.172; 1.P.229.175;1.P.229.240; 1.P.229.244; 1.P.230.228; 1.P.230.229; 1.P.230.230; 1.P.230.231;1.P.230.236; 1.P.230.237; 1.P.230.238; 1.P.230.239; 1.P.230.154; 1.P.230.157;1.P.230.166; 1.P.230.169; 1.P.230.172; 1.P.230.175; 1.P.230.240; 1.P.230.244;1.P.231.228; 1.P.231.229; 1.P.231.230; 1.P.231.231; 1.P.231.236; 1.P.231.237;1.P.231.238; 1.P.231.239; 1.P.231.154; 1.P.231.157; 1.P.231.166; 1.P.231.169;1.P.231.172; 1.P.231.175; 1.P.231.240; 1.P.231.244; 1.P.236.228; 1.P.236.229;1.P.236.230; 1.P.236.231; 1.P.236.236; 1.P.236.237; 1.P.236.238; 1.P.236.239;1.P.236.154; 1.P.236.157; 1.P.236.166; 1.P.236.169; 1.P.236.172; 1.P.236.175;1.P.236.240; 1.P.236.244; 1.P.237.228; 1.P.237.229; 1.P.237.230; 1.P.237.231;1.P.237.236; 1.P.237.237; 1.P.237.238; 1.P.237.239; 1.P.237.154; 1.P.237.157;1.P.237.166; 1.P.237.169; 1.P.237.172; 1.P.237.175; 1.P.237.240; 1.P.237.244;1.P.238.228; 1.P.238.229; 1.P.238.230; 1.P.238.231; 1.P.238.236; 1.P.238.237;1.P.238.238; 1.P.238.239; 1.P.238.154; 1.P.238.157; 1.P.238.166; 1.P.238.169;1.P.238.172; 1.P.238.175; 1.P.238.240; 1.P.238.244; 1.P.239.228; 1.P.239.229;1.P.239.230; 1.P.239.231; 1.P.239.236; 1.P.239.237; 1.P.239.238; 1.P.239.239;1.P.239.154; 1.P.239.157; 1.P.239.166; 1.P.239.169; 1.P.239.172; 1.P.239.175;1.P.239.240; 1.P.239.244; 1.P.154.228; 1.P.154.229; 1.P.154.230; 1.P.154.231;1.P.154.236; 1.P.154.237; 1.P.154.238; 1.P.154.239; 1.P.154.154; 1.P.154.157;1.P.154.166; 1.P.154.169; 1.P.154.172; 1.P.154.175; 1.P.154.240; 1.P.154.244;1.P.157.228; 1.P.157.229; 1.P.157.230; 1.P.157.231; 1.P.157.236; 1.P.157.237;1.P.157.238; 1.P.157.239; 1.P.157.154; 1.P.157.157; 1.P.157.166; 1.P.157.169;1.P.157.172; 1.P.157.175; 1.P.157.240; 1.P.157.244; 1.P.166.228; 1.P.166.229;1.P.166.230; 1.P.166.231; 1.P.166.236; 1.P.166.237; 1.P.166.238; 1.P.166.239;1.P.166.154; 1.P.166.157; 1.P.166.166; 1.P.166.169; 1.P.166.172; 1.P.166.175;1.P.166.240; 1.P.166.244; 1.P.169.228; 1.P.169.229; 1.P.169.230; 1.P.169.231;1.P.169.236; 1.P.169.237; 1.P.169.238; 1.P.169.239; 1.P.169.154; 1.P.169.157;1.P.169.166; 1.P.169.169; 1.P.169.172; 1.P.169.175; 1.P.169.240; 1.P.169.244;1.P.172.228; 1.P.172.229; 1.P.172.230; 1.P.172.231; 1.P.172.236; 1.P.172.237;1.P.172.238; 1.P.172.239; 1.P.172.154; 1.P.172.157; 1.P.172.166; 1.P.172.169;1.P.172.172; 1.P.172.175; 1.P.172.240; 1.P.172.244; 1.P.175.228; 1.P.175.229;1.P.175.230; 1.P.175.231; 1.P.175.236; 1.P.175.237; 1.P.175.238; 1.P.175.239;1.P.175.154; 1.P.175.157; 1.P.175.166; 1.P.175.169; 1.P.175.172; 1.P.175.175;1.P.175.240; 1.P.175.244; 1.P.240.228; 1.P.240.229; 1.P.240.230; 1.P.240.231;1.P.240.236; 1.P.240.237; 1.P.240.238; 1.P.240.239; 1.P.240.154; 1.P.240.157;1.P.240.166; 1.P.240.169; 1.P.240.172; 1.P.240.175; 1.P.240.240; 1.P.240.244;1.P.244.228; 1.P.244.229; 1.P.244.230; 1.P.244.231; 1.P.244.236; 1.P.244.237;1.P.244.238; 1.P.244.239; 1.P.244.154; 1.P.244.157; 1.P.244.166; 1.P.244.169;1.P.244.172; 1.P.244.175; 1.P.244.240; 1.P.244.244;

1.Uのプロドラッグ
1.U.228.228;1.U.228.229; 1.U.228.230; 1.U.228.231; 1.U.228.236; 1.U.228.237; 1.U.228.238;1.U.228.239; 1.U.228.154; 1.U.228.157; 1.U.228.166; 1.U.228.169; 1.U.228.172;1.U.228.175; 1.U.228.240; 1.U.228.244; 1.U.229.228; 1.U.229.229; 1.U.229.230;1.U.229.231; 1.U.229.236; 1.U.229.237; 1.U.229.238; 1.U.229.239; 1.U.229.154;1.U.229.157; 1.U.229.166; 1.U.229.169; 1.U.229.172; 1.U.229.175; 1.U.229.240;1.U.229.244; 1.U.230.228; 1.U.230.229; 1.U.230.230; 1.U.230.231; 1.U.230.236;1.U.230.237; 1.U.230.238; 1.U.230.239; 1.U.230.154; 1.U.230.157; 1.U.230.166;1.U.230.169; 1.U.230.172; 1.U.230.175; 1.U.230.240; 1.U.230.244; 1.U.231.228;1.U.231.229; 1.U.231.230; 1.U.231.231; 1.U.231.236; 1.U.231.237; 1.U.231.238;1.U.231.239; 1.U.231.154; 1.U.231.157; 1.U.231.166; 1.U.231.169; 1.U.231.172;1.U.231.175; 1.U.231.240; 1.U.231.244; 1.U.236.228; 1.U.236.229; 1.U.236.230;1.U.236.231; 1.U.236.236; 1.U.236.237; 1.U.236.238; 1.U.236.239; 1.U.236.154;1.U.236.157; 1.U.236.166; 1.U.236.169; 1.U.236.172; 1.U.236.175; 1.U.236.240;1.U.236.244; 1.U.237.228; 1.U.237.229; 1.U.237.230; 1.U.237.231; 1.U.237.236;1.U.237.237; 1.U.237.238; 1.U.237.239; 1.U.237.154; 1.U.237.157; 1.U.237.166;1.U.237.169; 1.U.237.172; 1.U.237.175; 1.U.237.240; 1.U.237.244; 1.U.238.228;1.U.238.229; 1.U.238.230; 1.U.238.231; 1.U.238.236; 1.U.238.237; 1.U.238.238;1.U.238.239; 1.U.238.154; 1.U.238.157; 1.U.238.166; 1.U.238.169; 1.U.238.172;1.U.238.175; 1.U.238.240; 1.U.238.244; 1.U.239.228; 1.U.239.229; 1.U.239.230;1.U.239.231; 1.U.239.236; 1.U.239.237; 1.U.239.238; 1.U.239.239; 1.U.239.154;1.U.239.157; 1.U.239.166; 1.U.239.169; 1.U.239.172; 1.U.239.175; 1.U.239.240;1.U.239.244; 1.U.154.228; 1.U.154.229; 1.U.154.230; 1.U.154.231; 1.U.154.236;1.U.154.237; 1.U.154.238; 1.U.154.239; 1.U.154.154; 1.U.154.157; 1.U.154.166;1.U.154.169; 1.U.154.172; 1.U.154.175; 1.U.154.240; 1.U.154.244; 1.U.157.228;1.U.157.229; 1.U.157.230; 1.U.157.231; 1.U.157.236; 1.U.157.237; 1.U.157.238;1.U.157.239; 1.U.157.154; 1.U.157.157; 1.U.157.166; 1.U.157.169; 1.U.157.172;1.U.157.175; 1.U.157.240; 1.U.157.244; 1.U.166.228; 1.U.166.229; 1.U.166.230;1.U.166.231; 1.U.166.236; 1.U.166.237; 1.U.166.238; 1.U.166.239; 1.U.166.154;1.U.166.157; 1.U.166.166; 1.U.166.169; 1.U.166.172; 1.U.166.175; 1.U.166.240;1.U.166.244; 1.U.169.228; 1.U.169.229; 1.U.169.230; 1.U.169.231; 1.U.169.236;1.U.169.237; 1.U.169.238; 1.U.169.239; 1.U.169.154; 1.U.169.157; 1.U.169.166;1.U.169.169; 1.U.169.172; 1.U.169.175; 1.U.169.240; 1.U.169.244; 1.U.172.228;1.U.172.229; 1.U.172.230; 1.U.172.231; 1.U.172.236; 1.U.172.237; 1.U.172.238;1.U.172.239; 1.U.172.154; 1.U.172.157; 1.U.172.166; 1.U.172.169; 1.U.172.172;1.U.172.175; 1.U.172.240; 1.U.172.244; 1.U.175.228; 1.U.175.229; 1.U.175.230;1.U.175.231; 1.U.175.236; 1.U.175.237; 1.U.175.238; 1.U.175.239; 1.U.175.154;1.U.175.157; 1.U.175.166; 1.U.175.169; 1.U.175.172; 1.U.175.175; 1.U.175.240;1.U.175.244; 1.U.240.228; 1.U.240.229; 1.U.240.230; 1.U.240.231; 1.U.240.236;1.U.240.237; 1.U.240.238; 1.U.240.239; 1.U.240.154; 1.U.240.157; 1.U.240.166;1.U.240.169; 1.U.240.172; 1.U.240.175; 1.U.240.240; 1.U.240.244; 1.U.244.228;1.U.244.229; 1.U.244.230; 1.U.244.231; 1.U.244.236; 1.U.244.237; 1.U.244.238;1.U.244.239; 1.U.244.154; 1.U.244.157; 1.U.244.166; 1.U.244.169; 1.U.244.172;1.U.244.175; 1.U.244.240; 1.U.244.244;

1.Wのプロドラッグ
1.W.228.228; 1.W.228.229; 1.W.228.230; 1.W.228.231; 1.W.228.236; 1.W.228.237;1.W.228.238; 1.W.228.239; 1.W.228.154; 1.W.228.157; 1.W.228.166; 1.W.228.169;1.W.228.172; 1.W.228.175; 1.W.228.240; 1.W.228.244; 1.W.229.228; 1.W.229.229;1.W.229.230; 1.W.229.231; 1.W.229.236; 1.W.229.237; 1.W.229.238; 1.W.229.239;1.W.229.154; 1.W.229.157; 1.W.229.166; 1.W.229.169; 1.W.229.172; 1.W.229.175;1.W.229.240; 1.W.229.244; 1.W.230.228; 1.W.230.229; 1.W.230.230; 1.W.230.231;1.W.230.236; 1.W.230.237; 1.W.230.238; 1.W.230.239; 1.W.230.154; 1.W.230.157;1.W.230.166; 1.W.230.169; 1.W.230.172; 1.W.230.175; 1.W.230.240; 1.W.230.244;1.W.231.228; 1.W.231.229; 1.W.231.230; 1.W.231.231; 1.W.231.236; 1.W.231.237;1.W.231.238; 1.W.231.239; 1.W.231.154; 1.W.231.157; 1.W.231.166; 1.W.231.169;1.W.231.172; 1.W.231.175; 1.W.231.240; 1.W.231.244; 1.W.236.228; 1.W.236.229;1.W.236.230; 1.W.236.231; 1.W.236.236; 1.W.236.237; 1.W.236.238; 1.W.236.239;1.W.236.154; 1.W.236.157; 1.W.236.166; 1.W.236.169; 1.W.236.172; 1.W.236.175;1.W.236.240; 1.W.236.244; 1.W.237.228; 1.W.237.229; 1.W.237.230; 1.W.237.231;1.W.237.236; 1.W.237.237; 1.W.237.238; 1.W.237.239; 1.W.237.154; 1.W.237.157;1.W.237.166; 1.W.237.169; 1.W.237.172; 1.W.237.175; 1.W.237.240; 1.W.237.244;1.W.238.228; 1.W.238.229; 1.W.238.230; 1.W.238.231; 1.W.238.236; 1.W.238.237;1.W.238.238; 1.W.238.239; 1.W.238.154; 1.W.238.157; 1.W.238.166; 1.W.238.169;1.W.238.172; 1.W.238.175; 1.W.238.240; 1.W.238.244; 1.W.239.228; 1.W.239.229;1.W.239.230; 1.W.239.231; 1.W.239.236; 1.W.239.237; 1.W.239.238; 1.W.239.239;1.W.239.154; 1.W.239.157; 1.W.239.166; 1.W.239.169; 1.W.239.172; 1.W.239.175;1.W.239.240; 1.W.239.244; 1.W.154.228; 1.W.154.229; 1.W.154.230; 1.W.154.231;1.W.154.236; 1.W.154.237; 1.W.154.238; 1.W.154.239; 1.W.154.154; 1.W.154.157;1.W.154.166; 1.W.154.169; 1.W.154.172; 1.W.154.175; 1.W.154.240; 1.W.154.244;1.W.157.228; 1.W.157.229; 1.W.157.230; 1.W.157.231; 1.W.157.236; 1.W.157.237;1.W.157.238; 1.W.157.239; 1.W.157.154; 1.W.157.157; 1.W.157.166; 1.W.157.169;1.W.157.172; 1.W.157.175; 1.W.157.240; 1.W.157.244; 1.W.166.228; 1.W.166.229;1.W.166.230; 1.W.166.231; 1.W.166.236; 1.W.166.237; 1.W.166.238; 1.W.166.239;1.W.166.154; 1.W.166.157; 1.W.166.166; 1.W.166.169; 1.W.166.172; 1.W.166.175;1.W.166.240; 1.W.166.244; 1.W.169.228; 1.W.169.229; 1.W.169.230; 1.W.169.231;1.W.169.236; 1.W.169.237; 1.W.169.238; 1.W.169.239; 1.W.169.154; 1.W.169.157;1.W.169.166; 1.W.169.169; 1.W.169.172; 1.W.169.175; 1.W.169.240; 1.W.169.244; 1.W.172.228;1.W.172.229; 1.W.172.230; 1.W.172.231; 1.W.172.236; 1.W.172.237; 1.W.172.238;1.W.172.239; 1.W.172.154; 1.W.172.157; 1.W.172.166; 1.W.172.169; 1.W.172.172;1.W.172.175; 1.W.172.240; 1.W.172.244; 1.W.175.228; 1.W.175.229; 1.W.175.230;1.W.175.231; 1.W.175.236; 1.W.175.237; 1.W.175.238; 1.W.175.239; 1.W.175.154;1.W.175.157; 1.W.175.166; 1.W.175.169; 1.W.175.172; 1.W.175.175; 1.W.175.240;1.W.175.244; 1.W.240.228; 1.W.240.229; 1.W.240.230; 1.W.240.231; 1.W.240.236;1.W.240.237; 1.W.240.238; 1.W.240.239; 1.W.240.154; 1.W.240.157; 1.W.240.166;1.W.240.169; 1.W.240.172; 1.W.240.175; 1.W.240.240; 1.W.240.244; 1.W.244.228;1.W.244.229; 1.W.244.230; 1.W.244.231; 1.W.244.236; 1.W.244.237; 1.W.244.238;1.W.244.239; 1.W.244.154; 1.W.244.157; 1.W.244.166; 1.W.244.169; 1.W.244.172;1.W.244.175; 1.W.244.240; 1.W.244.244;

1.Yのプロドラッグ
1.Y.228.228; 1.Y.228.229; 1.Y.228.230; 1.Y.228.231; 1.Y.228.236; 1.Y.228.237;1.Y.228.238; 1.Y.228.239; 1.Y.228.154; 1.Y.228.157; 1.Y.228.166; 1.Y.228.169;1.Y.228.172; 1.Y.228.175; 1.Y.228.240; 1.Y.228.244; 1.Y.229.228; 1.Y.229.229;1.Y.229.230; 1.Y.229.231; 1.Y.229.236; 1.Y.229.237; 1.Y.229.238; 1.Y.229.239;1.Y.229.154; 1.Y.229.157; 1.Y.229.166; 1.Y.229.169; 1.Y.229.172; 1.Y.229.175;1.Y.229.240; 1.Y.229.244; 1.Y.230.228; 1.Y.230.229; 1.Y.230.230; 1.Y.230.231;1.Y.230.236; 1.Y.230.237; 1.Y.230.238; 1.Y.230.239; 1.Y.230.154; 1.Y.230.157;1.Y.230.166; 1.Y.230.169; 1.Y.230.172; 1.Y.230.175; 1.Y.230.240; 1.Y.230.244;1.Y.231.228; 1.Y.231.229; 1.Y.231.230; 1.Y.231.231; 1.Y.231.236; 1.Y.231.237;1.Y.231.238; 1.Y.231.239; 1.Y.231.154; 1.Y.231.157; 1.Y.231.166; 1.Y.231.169;1.Y.231.172; 1.Y.231.175; 1.Y.231.240; 1.Y.231.244; 1.Y.236.228; 1.Y.236.229;1.Y.236.230; 1.Y.236.231; 1.Y.236.236; 1.Y.236.237; 1.Y.236.238; 1.Y.236.239;1.Y.236.154; 1.Y.236.157; 1.Y.236.166; 1.Y.236.169; 1.Y.236.172; 1.Y.236.175;1.Y.236.240; 1.Y.236.244; 1.Y.237.228; 1.Y.237.229; 1.Y.237.230; 1.Y.237.231;1.Y.237.236; 1.Y.237.237; 1.Y.237.238; 1.Y.237.239; 1.Y.237.154; 1.Y.237.157;1.Y.237.166; 1.Y.237.169; 1.Y.237.172; 1.Y.237.175; 1.Y.237.240; 1.Y.237.244;1.Y.238.228; 1.Y.238.229; 1.Y.238.230; 1.Y.238.231; 1.Y.238.236; 1.Y.238.237;1.Y.238.238; 1.Y.238.239; 1.Y.238.154; 1.Y.238.157; 1.Y.238.166; 1.Y.238.169;1.Y.238.172; 1.Y.238.175; 1.Y.238.240; 1.Y.238.244; 1.Y.239.228; 1.Y.239.229;1.Y.239.230; 1.Y.239.231; 1.Y.239.236; 1.Y.239.237; 1.Y.239.238; 1.Y.239.239;1.Y.239.154; 1.Y.239.157; 1.Y.239.166; 1.Y.239.169; 1.Y.239.172; 1.Y.239.175;1.Y.239.240; 1.Y.239.244; 1.Y.154.228; 1.Y.154.229; 1.Y.154.230; 1.Y.154.231;1.Y.154.236; 1.Y.154.237; 1.Y.154.238; 1.Y.154.239; 1.Y.154.154; 1.Y.154.157;1.Y.154.166; 1.Y.154.169; 1.Y.154.172; 1.Y.154.175; 1.Y.154.240; 1.Y.154.244;1.Y.157.228; 1.Y.157.229; 1.Y.157.230; 1.Y.157.231; 1.Y.157.236; 1.Y.157.237;1.Y.157.238; 1.Y.157.239; 1.Y.157.154; 1.Y.157.157; 1.Y.157.166; 1.Y.157.169;1.Y.157.172; 1.Y.157.175; 1.Y.157.240; 1.Y.157.244; 1.Y.166.228; 1.Y.166.229;1.Y.166.230; 1.Y.166.231; 1.Y.166.236; 1.Y.166.237; 1.Y.166.238; 1.Y.166.239;1.Y.166.154; 1.Y.166.157; 1.Y.166.166; 1.Y.166.169; 1.Y.166.172; 1.Y.166.175;1.Y.166.240; 1.Y.166.244; 1.Y.169.228; 1.Y.169.229; 1.Y.169.230; 1.Y.169.231;1.Y.169.236; 1.Y.169.237; 1.Y.169.238; 1.Y.169.239; 1.Y.169.154; 1.Y.169.157;1.Y.169.166; 1.Y.169.169; 1.Y.169.172; 1.Y.169.175; 1.Y.169.240; 1.Y.169.244;1.Y.172.228; 1.Y.172.229; 1.Y.172.230; 1.Y.172.231; 1.Y.172.236; 1.Y.172.237;1.Y.172.238; 1.Y.172.239; 1.Y.172.154; 1.Y.172.157; 1.Y.172.166; 1.Y.172.169;1.Y.172.172; 1.Y.172.175; 1.Y.172.240; 1.Y.172.244; 1.Y.175.228; 1.Y.175.229;1.Y.175.230; 1.Y.175.231; 1.Y.175.236; 1.Y.175.237; 1.Y.175.238; 1.Y.175.239;1.Y.175.154; 1.Y.175.157; 1.Y.175.166; 1.Y.175.169; 1.Y.175.172; 1.Y.175.175;1.Y.175.240; 1.Y.175.244; 1.Y.240.228; 1.Y.240.229; 1.Y.240.230; 1.Y.240.231;1.Y.240.236; 1.Y.240.237; 1.Y.240.238; 1.Y.240.239; 1.Y.240.154; 1.Y.240.157;1.Y.240.166; 1.Y.240.169; 1.Y.240.172; 1.Y.240.175; 1.Y.240.240; 1.Y.240.244;1.Y.244.228; 1.Y.244.229; 1.Y.244.230; 1.Y.244.231; 1.Y.244.236; 1.Y.244.237;1.Y.244.238; 1.Y.244.239; 1.Y.244.154; 1.Y.244.157; 1.Y.244.166; 1.Y.244.169;1.Y.244.172; 1.Y.244.175; 1.Y.244.240; 1.Y.244.244;

2.Bのプロドラッグ
2.B.228.228; 2.B.228.229; 2.B.228.230; 2.B.228.231; 2.B.228.236; 2.B.228.237;2.B.228.238; 2.B.228.239; 2.B.228.154; 2.B.228.157; 2.B.228.166; 2.B.228.169; 2.B.228.172;2.B.228.175; 2.B.228.240; 2.B.228.244; 2.B.229.228; 2.B.229.229; 2.B.229.230;2.B.229.231; 2.B.229.236; 2.B.229.237; 2.B.229.238; 2.B.229.239; 2.B.229.154;2.B.229.157; 2.B.229.166; 2.B.229.169; 2.B.229.172; 2.B.229.175; 2.B.229.240;2.B.229.244; 2.B.230.228; 2.B.230.229; 2.B.230.230; 2.B.230.231; 2.B.230.236;2.B.230.237; 2.B.230.238; 2.B.230.239; 2.B.230.154; 2.B.230.157; 2.B.230.166;2.B.230.169; 2.B.230.172; 2.B.230.175; 2.B.230.240; 2.B.230.244; 2.B.231.228;2.B.231.229; 2.B.231.230; 2.B.231.231; 2.B.231.236; 2.B.231.237; 2.B.231.238;2.B.231.239; 2.B.231.154; 2.B.231.157; 2.B.231.166; 2.B.231.169; 2.B.231.172;2.B.231.175; 2.B.231.240; 2.B.231.244; 2.B.236.228; 2.B.236.229; 2.B.236.230;2.B.236.231; 2.B.236.236; 2.B.236.237; 2.B.236.238; 2.B.236.239; 2.B.236.154;2.B.236.157; 2.B.236.166; 2.B.236.169; 2.B.236.172; 2.B.236.175; 2.B.236.240;2.B.236.244; 2.B.237.228; 2.B.237.229; 2.B.237.230; 2.B.237.231; 2.B.237.236;2.B.237.237; 2.B.237.238; 2.B.237.239; 2.B.237.154; 2.B.237.157; 2.B.237.166;2.B.237.169; 2.B.237.172; 2.B.237.175; 2.B.237.240; 2.B.237.244; 2.B.238.228;2.B.238.229; 2.B.238.230; 2.B.238.231; 2.B.238.236; 2.B.238.237; 2.B.238.238;2.B.238.239; 2.B.238.154; 2.B.238.157; 2.B.238.166; 2.B.238.169; 2.B.238.172;2.B.238.175; 2.B.238.240; 2.B.238.244; 2.B.239.228; 2.B.239.229; 2.B.239.230;2.B.239.231; 2.B.239.236; 2.B.239.237; 2.B.239.238; 2.B.239.239; 2.B.239.154;2.B.239.157; 2.B.239.166; 2.B.239.169; 2.B.239.172; 2.B.239.175; 2.B.239.240;2.B.239.244; 2.B.154.228; 2.B.154.229; 2.B.154.230; 2.B.154.231; 2.B.154.236;2.B.154.237; 2.B.154.238; 2.B.154.239; 2.B.154.154; 2.B.154.157; 2.B.154.166;2.B.154.169; 2.B.154.172; 2.B.154.175; 2.B.154.240; 2.B.154.244; 2.B.157.228;2.B.157.229; 2.B.157.230; 2.B.157.231; 2.B.157.236; 2.B.157.237; 2.B.157.238;2.B.157.239; 2.B.157.154; 2.B.157.157; 2.B.157.166; 2.B.157.169; 2.B.157.172;2.B.157.175; 2.B.157.240; 2.B.157.244; 2.B.166.228; 2.B.166.229; 2.B.166.230;2.B.166.231; 2.B.166.236; 2.B.166.237; 2.B.166.238; 2.B.166.239; 2.B.166.154;2.B.166.157; 2.B.166.166; 2.B.166.169; 2.B.166.172; 2.B.166.175; 2.B.166.240;2.B.166.244; 2.B.169.228; 2.B.169.229; 2.B.169.230; 2.B.169.231; 2.B.169.236;2.B.169.237; 2.B.169.238; 2.B.169.239; 2.B.169.154; 2.B.169.157; 2.B.169.166;2.B.169.169; 2.B.169.172; 2.B.169.175; 2.B.169.240; 2.B.169.244; 2.B.172.228;2.B.172.229; 2.B.172.230; 2.B.172.231; 2.B.172.236; 2.B.172.237; 2.B.172.238;2.B.172.239; 2.B.172.154; 2.B.172.157; 2.B.172.166; 2.B.172.169; 2.B.172.172;2.B.172.175; 2.B.172.240; 2.B.172.244; 2.B.175.228; 2.B.175.229; 2.B.175.230;2.B.175.231; 2.B.175.236; 2.B.175.237; 2.B.175.238; 2.B.175.239; 2.B.175.154;2.B.175.157; 2.B.175.166; 2.B.175.169; 2.B.175.172; 2.B.175.175; 2.B.175.240;2.B.175.244; 2.B.240.228; 2.B.240.229; 2.B.240.230; 2.B.240.231; 2.B.240.236;2.B.240.237; 2.B.240.238; 2.B.240.239; 2.B.240.154; 2.B.240.157; 2.B.240.166;2.B.240.169; 2.B.240.172; 2.B.240.175; 2.B.240.240; 2.B.240.244; 2.B.244.228;2.B.244.229; 2.B.244.230; 2.B.244.231; 2.B.244.236; 2.B.244.237; 2.B.244.238;2.B.244.239; 2.B.244.154; 2.B.244.157; 2.B.244.166; 2.B.244.169; 2.B.244.172;2.B.244.175; 2.B.244.240; 2.B.244.244;

2.Dのプロドラッグ
2.D.228.228; 2.D.228.229; 2.D.228.230; 2.D.228.231; 2.D.228.236; 2.D.228.237;2.D.228.238; 2.D.228.239; 2.D.228.154; 2.D.228.157; 2.D.228.166; 2.D.228.169;2.D.228.172; 2.D.228.175; 2.D.228.240; 2.D.228.244; 2.D.229.228; 2.D.229.229;2.D.229.230; 2.D.229.231; 2.D.229.236; 2.D.229.237; 2.D.229.238; 2.D.229.239;2.D.229.154; 2.D.229.157; 2.D.229.166; 2.D.229.169; 2.D.229.172; 2.D.229.175;2.D.229.240; 2.D.229.244; 2.D.230.228; 2.D.230.229; 2.D.230.230; 2.D.230.231;2.D.230.236; 2.D.230.237; 2.D.230.238; 2.D.230.239; 2.D.230.154; 2.D.230.157;2.D.230.166; 2.D.230.169; 2.D.230.172; 2.D.230.175; 2.D.230.240; 2.D.230.244;2.D.231.228; 2.D.231.229; 2.D.231.230; 2.D.231.231; 2.D.231.236; 2.D.231.237;2.D.231.238; 2.D.231.239; 2.D.231.154; 2.D.231.157; 2.D.231.166; 2.D.231.169;2.D.231.172; 2.D.231.175; 2.D.231.240; 2.D.231.244; 2.D.236.228; 2.D.236.229;2.D.236.230; 2.D.236.231; 2.D.236.236; 2.D.236.237; 2.D.236.238; 2.D.236.239;2.D.236.154; 2.D.236.157; 2.D.236.166; 2.D.236.169; 2.D.236.172; 2.D.236.175;2.D.236.240; 2.D.236.244; 2.D.237.228; 2.D.237.229; 2.D.237.230; 2.D.237.231;2.D.237.236; 2.D.237.237; 2.D.237.238; 2.D.237.239; 2.D.237.154; 2.D.237.157;2.D.237.166; 2.D.237.169; 2.D.237.172; 2.D.237.175; 2.D.237.240; 2.D.237.244;2.D.238.228; 2.D.238.229; 2.D.238.230; 2.D.238.231; 2.D.238.236; 2.D.238.237;2.D.238.238; 2.D.238.239; 2.D.238.154; 2.D.238.157; 2.D.238.166; 2.D.238.169;2.D.238.172; 2.D.238.175; 2.D.238.240; 2.D.238.244; 2.D.239.228; 2.D.239.229;2.D.239.230; 2.D.239.231; 2.D.239.236; 2.D.239.237; 2.D.239.238; 2.D.239.239;2.D.239.154; 2.D.239.157; 2.D.239.166; 2.D.239.169; 2.D.239.172; 2.D.239.175;2.D.239.240; 2.D.239.244; 2.D.154.228; 2.D.154.229; 2.D.154.230; 2.D.154.231;2.D.154.236; 2.D.154.237; 2.D.154.238; 2.D.154.239; 2.D.154.154; 2.D.154.157;2.D.154.166; 2.D.154.169; 2.D.154.172; 2.D.154.175; 2.D.154.240; 2.D.154.244;2.D.157.228; 2.D.157.229; 2.D.157.230; 2.D.157.231; 2.D.157.236; 2.D.157.237;2.D.157.238; 2.D.157.239; 2.D.157.154; 2.D.157.157; 2.D.157.166; 2.D.157.169;2.D.157.172; 2.D.157.175; 2.D.157.240; 2.D.157.244; 2.D.166.228; 2.D.166.229;2.D.166.230; 2.D.166.231; 2.D.166.236; 2.D.166.237; 2.D.166.238; 2.D.166.239; 2.D.166.154;2.D.166.157; 2.D.166.166; 2.D.166.169; 2.D.166.172; 2.D.166.175; 2.D.166.240;2.D.166.244; 2.D.169.228; 2.D.169.229; 2.D.169.230; 2.D.169.231; 2.D.169.236;2.D.169.237; 2.D.169.238; 2.D.169.239; 2.D.169.154; 2.D.169.157; 2.D.169.166;2.D.169.169; 2.D.169.172; 2.D.169.175; 2.D.169.240; 2.D.169.244; 2.D.172.228;2.D.172.229; 2.D.172.230; 2.D.172.231; 2.D.172.236; 2.D.172.237; 2.D.172.238;2.D.172.239; 2.D.172.154; 2.D.172.157; 2.D.172.166; 2.D.172.169; 2.D.172.172;2.D.172.175; 2.D.172.240; 2.D.172.244; 2.D.175.228; 2.D.175.229; 2.D.175.230;2.D.175.231; 2.D.175.236; 2.D.175.237; 2.D.175.238; 2.D.175.239; 2.D.175.154;2.D.175.157; 2.D.175.166; 2.D.175.169; 2.D.175.172; 2.D.175.175; 2.D.175.240;2.D.175.244; 2.D.240.228; 2.D.240.229; 2.D.240.230; 2.D.240.231; 2.D.240.236;2.D.240.237; 2.D.240.238; 2.D.240.239; 2.D.240.154; 2.D.240.157; 2.D.240.166;2.D.240.169; 2.D.240.172; 2.D.240.175; 2.D.240.240; 2.D.240.244; 2.D.244.228;2.D.244.229; 2.D.244.230; 2.D.244.231; 2.D.244.236; 2.D.244.237; 2.D.244.238;2.D.244.239; 2.D.244.154; 2.D.244.157; 2.D.244.166; 2.D.244.169; 2.D.244.172;2.D.244.175; 2.D.244.240; 2.D.244.244;

2.Eのプロドラッグ
2.E.228.228; 2.E.228.229; 2.E.228.230; 2.E.228.231; 2.E.228.236; 2.E.228.237;2.E.228.238; 2.E.228.239; 2.E.228.154; 2.E.228.157; 2.E.228.166; 2.E.228.169;2.E.228.172; 2.E.228.175; 2.E.228.240; 2.E.228.244; 2.E.229.228; 2.E.229.229;2.E.229.230; 2.E.229.231; 2.E.229.236; 2.E.229.237; 2.E.229.238; 2.E.229.239;2.E.229.154; 2.E.229.157; 2.E.229.166; 2.E.229.169; 2.E.229.172; 2.E.229.175;2.E.229.240; 2.E.229.244; 2.E.230.228; 2.E.230.229; 2.E.230.230; 2.E.230.231;2.E.230.236; 2.E.230.237; 2.E.230.238; 2.E.230.239; 2.E.230.154; 2.E.230.157;2.E.230.166; 2.E.230.169; 2.E.230.172; 2.E.230.175; 2.E.230.240; 2.E.230.244;2.E.231.228; 2.E.231.229; 2.E.231.230; 2.E.231.231; 2.E.231.236; 2.E.231.237;2.E.231.238; 2.E.231.239; 2.E.231.154; 2.E.231.157; 2.E.231.166; 2.E.231.169;2.E.231.172; 2.E.231.175; 2.E.231.240; 2.E.231.244; 2.E.236.228; 2.E.236.229;2.E.236.230; 2.E.236.231; 2.E.236.236; 2.E.236.237; 2.E.236.238; 2.E.236.239;2.E.236.154; 2.E.236.157; 2.E.236.166; 2.E.236.169; 2.E.236.172; 2.E.236.175;2.E.236.240; 2.E.236.244; 2.E.237.228; 2.E.237.229; 2.E.237.230; 2.E.237.231;2.E.237.236; 2.E.237.237; 2.E.237.238; 2.E.237.239; 2.E.237.154; 2.E.237.157;2.E.237.166; 2.E.237.169; 2.E.237.172; 2.E.237.175; 2.E.237.240; 2.E.237.244;2.E.238.228; 2.E.238.229; 2.E.238.230; 2.E.238.231; 2.E.238.236; 2.E.238.237;2.E.238.238; 2.E.238.239; 2.E.238.154; 2.E.238.157; 2.E.238.166; 2.E.238.169;2.E.238.172; 2.E.238.175; 2.E.238.240; 2.E.238.244; 2.E.239.228; 2.E.239.229;2.E.239.230; 2.E.239.231; 2.E.239.236; 2.E.239.237; 2.E.239.238; 2.E.239.239;2.E.239.154; 2.E.239.157; 2.E.239.166; 2.E.239.169; 2.E.239.172; 2.E.239.175;2.E.239.240; 2.E.239.244; 2.E.154.228; 2.E.154.229; 2.E.154.230; 2.E.154.231;2.E.154.236; 2.E.154.237; 2.E.154.238; 2.E.154.239; 2.E.154.154; 2.E.154.157;2.E.154.166; 2.E.154.169; 2.E.154.172; 2.E.154.175; 2.E.154.240; 2.E.154.244;2.E.157.228; 2.E.157.229; 2.E.157.230; 2.E.157.231; 2.E.157.236; 2.E.157.237;2.E.157.238; 2.E.157.239; 2.E.157.154; 2.E.157.157; 2.E.157.166; 2.E.157.169;2.E.157.172; 2.E.157.175; 2.E.157.240; 2.E.157.244; 2.E.166.228; 2.E.166.229;2.E.166.230; 2.E.166.231; 2.E.166.236; 2.E.166.237; 2.E.166.238; 2.E.166.239;2.E.166.154; 2.E.166.157; 2.E.166.166; 2.E.166.169; 2.E.166.172; 2.E.166.175;2.E.166.240; 2.E.166.244; 2.E.169.228; 2.E.169.229; 2.E.169.230; 2.E.169.231;2.E.169.236; 2.E.169.237; 2.E.169.238; 2.E.169.239; 2.E.169.154; 2.E.169.157;2.E.169.166; 2.E.169.169; 2.E.169.172; 2.E.169.175; 2.E.169.240; 2.E.169.244;2.E.172.228; 2.E.172.229; 2.E.172.230; 2.E.172.231; 2.E.172.236; 2.E.172.237;2.E.172.238; 2.E.172.239; 2.E.172.154; 2.E.172.157; 2.E.172.166; 2.E.172.169;2.E.172.172; 2.E.172.175; 2.E.172.240; 2.E.172.244; 2.E.175.228; 2.E.175.229;2.E.175.230; 2.E.175.231; 2.E.175.236; 2.E.175.237; 2.E.175.238; 2.E.175.239;2.E.175.154; 2.E.175.157; 2.E.175.166; 2.E.175.169; 2.E.175.172; 2.E.175.175;2.E.175.240; 2.E.175.244; 2.E.240.228; 2.E.240.229; 2.E.240.230; 2.E.240.231;2.E.240.236; 2.E.240.237; 2.E.240.238; 2.E.240.239; 2.E.240.154; 2.E.240.157;2.E.240.166; 2.E.240.169; 2.E.240.172; 2.E.240.175; 2.E.240.240; 2.E.240.244;2.E.244.228; 2.E.244.229; 2.E.244.230; 2.E.244.231; 2.E.244.236; 2.E.244.237;2.E.244.238; 2.E.244.239; 2.E.244.154; 2.E.244.157; 2.E.244.166; 2.E.244.169;2.E.244.172; 2.E.244.175; 2.E.244.240; 2.E.244.244;

2.Gのプロドラッグ
2.G.228.228; 2.G.228.229; 2.G.228.230; 2.G.228.231; 2.G.228.236; 2.G.228.237;2.G.228.238; 2.G.228.239; 2.G.228.154; 2.G.228.157; 2.G.228.166; 2.G.228.169;2.G.228.172; 2.G.228.175; 2.G.228.240; 2.G.228.244; 2.G.229.228; 2.G.229.229;2.G.229.230; 2.G.229.231; 2.G.229.236; 2.G.229.237; 2.G.229.238; 2.G.229.239;2.G.229.154; 2.G.229.157; 2.G.229.166; 2.G.229.169; 2.G.229.172; 2.G.229.175;2.G.229.240; 2.G.229.244; 2.G.230.228; 2.G.230.229; 2.G.230.230; 2.G.230.231;2.G.230.236; 2.G.230.237; 2.G.230.238; 2.G.230.239; 2.G.230.154; 2.G.230.157;2.G.230.166; 2.G.230.169; 2.G.230.172; 2.G.230.175; 2.G.230.240; 2.G.230.244;2.G.231.228; 2.G.231.229; 2.G.231.230; 2.G.231.231; 2.G.231.236; 2.G.231.237;2.G.231.238; 2.G.231.239; 2.G.231.154; 2.G.231.157; 2.G.231.166; 2.G.231.169;2.G.231.172; 2.G.231.175; 2.G.231.240; 2.G.231.244; 2.G.236.228; 2.G.236.229;2.G.236.230; 2.G.236.231; 2.G.236.236; 2.G.236.237; 2.G.236.238; 2.G.236.239;2.G.236.154; 2.G.236.157; 2.G.236.166; 2.G.236.169; 2.G.236.172; 2.G.236.175;2.G.236.240; 2.G.236.244; 2.G.237.228; 2.G.237.229; 2.G.237.230; 2.G.237.231;2.G.237.236; 2.G.237.237; 2.G.237.238; 2.G.237.239; 2.G.237.154; 2.G.237.157;2.G.237.166; 2.G.237.169; 2.G.237.172; 2.G.237.175; 2.G.237.240; 2.G.237.244;2.G.238.228; 2.G.238.229; 2.G.238.230; 2.G.238.231; 2.G.238.236; 2.G.238.237;2.G.238.238; 2.G.238.239; 2.G.238.154; 2.G.238.157; 2.G.238.166; 2.G.238.169;2.G.238.172; 2.G.238.175; 2.G.238.240; 2.G.238.244; 2.G.239.228; 2.G.239.229;2.G.239.230; 2.G.239.231; 2.G.239.236; 2.G.239.237; 2.G.239.238; 2.G.239.239;2.G.239.154; 2.G.239.157; 2.G.239.166; 2.G.239.169; 2.G.239.172; 2.G.239.175;2.G.239.240; 2.G.239.244; 2.G.154.228; 2.G.154.229; 2.G.154.230; 2.G.154.231;2.G.154.236; 2.G.154.237; 2.G.154.238; 2.G.154.239; 2.G.154.154; 2.G.154.157;2.G.154.166; 2.G.154.169; 2.G.154.172; 2.G.154.175; 2.G.154.240; 2.G.154.244;2.G.157.228; 2.G.157.229; 2.G.157.230; 2.G.157.231; 2.G.157.236; 2.G.157.237;2.G.157.238; 2.G.157.239; 2.G.157.154; 2.G.157.157; 2.G.157.166; 2.G.157.169;2.G.157.172; 2.G.157.175; 2.G.157.240; 2.G.157.244; 2.G.166.228; 2.G.166.229;2.G.166.230; 2.G.166.231; 2.G.166.236; 2.G.166.237; 2.G.166.238; 2.G.166.239;2.G.166.154; 2.G.166.157; 2.G.166.166; 2.G.166.169; 2.G.166.172; 2.G.166.175;2.G.166.240; 2.G.166.244; 2.G.169.228; 2.G.169.229; 2.G.169.230; 2.G.169.231;2.G.169.236; 2.G.169.237; 2.G.169.238; 2.G.169.239; 2.G.169.154; 2.G.169.157;2.G.169.166; 2.G.169.169; 2.G.169.172; 2.G.169.175; 2.G.169.240; 2.G.169.244;2.G.172.228; 2.G.172.229; 2.G.172.230; 2.G.172.231; 2.G.172.236; 2.G.172.237;2.G.172.238; 2.G.172.239; 2.G.172.154; 2.G.172.157; 2.G.172.166; 2.G.172.169;2.G.172.172; 2.G.172.175; 2.G.172.240; 2.G.172.244; 2.G.175.228; 2.G.175.229;2.G.175.230; 2.G.175.231; 2.G.175.236; 2.G.175.237; 2.G.175.238; 2.G.175.239;2.G.175.154; 2.G.175.157; 2.G.175.166; 2.G.175.169; 2.G.175.172; 2.G.175.175;2.G.175.240; 2.G.175.244; 2.G.240.228; 2.G.240.229; 2.G.240.230; 2.G.240.231;2.G.240.236; 2.G.240.237; 2.G.240.238; 2.G.240.239; 2.G.240.154; 2.G.240.157;2.G.240.166; 2.G.240.169; 2.G.240.172; 2.G.240.175; 2.G.240.240; 2.G.240.244;2.G.244.228; 2.G.244.229; 2.G.244.230; 2.G.244.231; 2.G.244.236; 2.G.244.237;2.G.244.238; 2.G.244.239; 2.G.244.154; 2.G.244.157; 2.G.244.166; 2.G.244.169;2.G.244.172; 2.G.244.175; 2.G.244.240; 2.G.244.244;

2.Iのプロドラッグ
2.I.228.228; 2.I.228.229; 2.I.228.230; 2.I.228.231; 2.I.228.236; 2.I.228.237;2.I.228.238; 2.I.228.239; 2.I.228.154; 2.I.228.157; 2.I.228.166; 2.I.228.169;2.I.228.172; 2.I.228.175; 2.I.228.240; 2.I.228.244; 2.I.229.228; 2.I.229.229;2.I.229.230; 2.I.229.231; 2.I.229.236; 2.I.229.237; 2.I.229.238; 2.I.229.239;2.I.229.154; 2.I.229.157; 2.I.229.166; 2.I.229.169; 2.I.229.172; 2.I.229.175;2.I.229.240; 2.I.229.244; 2.I.230.228; 2.I.230.229; 2.I.230.230; 2.I.230.231;2.I.230.236; 2.I.230.237; 2.I.230.238; 2.I.230.239; 2.I.230.154; 2.I.230.157;2.I.230.166; 2.I.230.169; 2.I.230.172; 2.I.230.175; 2.I.230.240; 2.I.230.244;2.I.231.228; 2.I.231.229; 2.I.231.230; 2.I.231.231; 2.I.231.236; 2.I.231.237;2.I.231.238; 2.I.231.239; 2.I.231.154; 2.I.231.157; 2.I.231.166; 2.I.231.169;2.I.231.172; 2.I.231.175; 2.I.231.240; 2.I.231.244; 2.I.236.228; 2.I.236.229;2.I.236.230; 2.I.236.231; 2.I.236.236; 2.I.236.237; 2.I.236.238; 2.I.236.239;2.I.236.154; 2.I.236.157; 2.I.236.166; 2.I.236.169; 2.I.236.172; 2.I.236.175;2.I.236.240; 2.I.236.244; 2.I.237.228; 2.I.237.229; 2.I.237.230; 2.I.237.231;2.I.237.236; 2.I.237.237; 2.I.237.238; 2.I.237.239; 2.I.237.154; 2.I.237.157;2.I.237.166; 2.I.237.169; 2.I.237.172; 2.I.237.175; 2.I.237.240; 2.I.237.244;2.I.238.228; 2.I.238.229; 2.I.238.230; 2.I.238.231; 2.I.238.236; 2.I.238.237;2.I.238.238; 2.I.238.239; 2.I.238.154; 2.I.238.157; 2.I.238.166; 2.I.238.169;2.I.238.172; 2.I.238.175; 2.I.238.240; 2.I.238.244; 2.I.239.228; 2.I.239.229;2.I.239.230; 2.I.239.231; 2.I.239.236; 2.I.239.237; 2.I.239.238; 2.I.239.239;2.I.239.154; 2.I.239.157; 2.I.239.166; 2.I.239.169; 2.I.239.172; 2.I.239.175;2.I.239.240; 2.I.239.244; 2.I.154.228; 2.I.154.229; 2.I.154.230; 2.I.154.231;2.I.154.236; 2.I.154.237; 2.I.154.238; 2.I.154.239; 2.I.154.154; 2.I.154.157;2.I.154.166; 2.I.154.169; 2.I.154.172; 2.I.154.175; 2.I.154.240; 2.I.154.244;2.I.157.228; 2.I.157.229; 2.I.157.230; 2.I.157.231; 2.I.157.236; 2.I.157.237;2.I.157.238; 2.I.157.239; 2.I.157.154; 2.I.157.157; 2.I.157.166; 2.I.157.169;2.I.157.172; 2.I.157.175; 2.I.157.240; 2.I.157.244; 2.I.166.228; 2.I.166.229;2.I.166.230; 2.I.166.231; 2.I.166.236; 2.I.166.237; 2.I.166.238; 2.I.166.239;2.I.166.154; 2.I.166.157; 2.I.166.166; 2.I.166.169; 2.I.166.172; 2.I.166.175;2.I.166.240; 2.I.166.244; 2.I.169.228; 2.I.169.229; 2.I.169.230; 2.I.169.231; 2.I.169.236;2.I.169.237; 2.I.169.238; 2.I.169.239; 2.I.169.154; 2.I.169.157; 2.I.169.166;2.I.169.169; 2.I.169.172; 2.I.169.175; 2.I.169.240; 2.I.169.244; 2.I.172.228;2.I.172.229; 2.I.172.230; 2.I.172.231; 2.I.172.236; 2.I.172.237; 2.I.172.238;2.I.172.239; 2.I.172.154; 2.I.172.157; 2.I.172.166; 2.I.172.169; 2.I.172.172;2.I.172.175; 2.I.172.240; 2.I.172.244; 2.I.175.228; 2.I.175.229; 2.I.175.230;2.I.175.231; 2.I.175.236; 2.I.175.237; 2.I.175.238; 2.I.175.239; 2.I.175.154;2.I.175.157; 2.I.175.166; 2.I.175.169; 2.I.175.172; 2.I.175.175; 2.I.175.240;2.I.175.244; 2.I.240.228; 2.I.240.229; 2.I.240.230; 2.I.240.231; 2.I.240.236;2.I.240.237; 2.I.240.238; 2.I.240.239; 2.I.240.154; 2.I.240.157; 2.I.240.166;2.I.240.169; 2.I.240.172; 2.I.240.175; 2.I.240.240; 2.I.240.244; 2.I.244.228;2.I.244.229; 2.I.244.230; 2.I.244.231; 2.I.244.236; 2.I.244.237; 2.I.244.238;2.I.244.239; 2.I.244.154; 2.I.244.157; 2.I.244.166; 2.I.244.169; 2.I.244.172;2.I.244.175; 2.I.244.240; 2.I.244.244;

2.Jのプロドラッグ
2.J.228.228; 2.J.228.229; 2.J.228.230; 2.J.228.231; 2.J.228.236; 2.J.228.237;2.J.228.238; 2.J.228.239; 2.J.228.154; 2.J.228.157; 2.J.228.166; 2.J.228.169;2.J.228.172; 2.J.228.175; 2.J.228.240; 2.J.228.244; 2.J.229.228; 2.J.229.229;2.J.229.230; 2.J.229.231; 2.J.229.236; 2.J.229.237; 2.J.229.238; 2.J.229.239;2.J.229.154; 2.J.229.157; 2.J.229.166; 2.J.229.169; 2.J.229.172; 2.J.229.175;2.J.229.240; 2.J.229.244; 2.J.230.228; 2.J.230.229; 2.J.230.230; 2.J.230.231;2.J.230.236; 2.J.230.237; 2.J.230.238; 2.J.230.239; 2.J.230.154; 2.J.230.157;2.J.230.166; 2.J.230.169; 2.J.230.172; 2.J.230.175; 2.J.230.240; 2.J.230.244;2.J.231.228; 2.J.231.229; 2.J.231.230; 2.J.231.231; 2.J.231.236; 2.J.231.237;2.J.231.238; 2.J.231.239; 2.J.231.154; 2.J.231.157; 2.J.231.166; 2.J.231.169;2.J.231.172; 2.J.231.175; 2.J.231.240; 2.J.231.244; 2.J.236.228; 2.J.236.229;2.J.236.230; 2.J.236.231; 2.J.236.236; 2.J.236.237; 2.J.236.238; 2.J.236.239;2.J.236.154; 2.J.236.157; 2.J.236.166; 2.J.236.169; 2.J.236.172; 2.J.236.175;2.J.236.240; 2.J.236.244; 2.J.237.228; 2.J.237.229; 2.J.237.230; 2.J.237.231;2.J.237.236; 2.J.237.237; 2.J.237.238; 2.J.237.239; 2.J.237.154; 2.J.237.157;2.J.237.166; 2.J.237.169; 2.J.237.172; 2.J.237.175; 2.J.237.240; 2.J.237.244;2.J.238.228; 2.J.238.229; 2.J.238.230; 2.J.238.231; 2.J.238.236; 2.J.238.237;2.J.238.238; 2.J.238.239; 2.J.238.154; 2.J.238.157; 2.J.238.166; 2.J.238.169;2.J.238.172; 2.J.238.175; 2.J.238.240; 2.J.238.244; 2.J.239.228; 2.J.239.229;2.J.239.230; 2.J.239.231; 2.J.239.236; 2.J.239.237; 2.J.239.238; 2.J.239.239;2.J.239.154; 2.J.239.157; 2.J.239.166; 2.J.239.169; 2.J.239.172; 2.J.239.175;2.J.239.240; 2.J.239.244; 2.J.154.228; 2.J.154.229; 2.J.154.230; 2.J.154.231;2.J.154.236; 2.J.154.237; 2.J.154.238; 2.J.154.239; 2.J.154.154; 2.J.154.157;2.J.154.166; 2.J.154.169; 2.J.154.172; 2.J.154.175; 2.J.154.240; 2.J.154.244;2.J.157.228; 2.J.157.229; 2.J.157.230; 2.J.157.231; 2.J.157.236; 2.J.157.237;2.J.157.238; 2.J.157.239; 2.J.157.154; 2.J.157.157; 2.J.157.166; 2.J.157.169;2.J.157.172; 2.J.157.175; 2.J.157.240; 2.J.157.244; 2.J.166.228; 2.J.166.229;2.J.166.230; 2.J.166.231; 2.J.166.236; 2.J.166.237; 2.J.166.238; 2.J.166.239;2.J.166.154; 2.J.166.157; 2.J.166.166; 2.J.166.169; 2.J.166.172; 2.J.166.175;2.J.166.240; 2.J.166.244; 2.J.169.228; 2.J.169.229; 2.J.169.230; 2.J.169.231;2.J.169.236; 2.J.169.237; 2.J.169.238; 2.J.169.239; 2.J.169.154; 2.J.169.157;2.J.169.166; 2.J.169.169; 2.J.169.172; 2.J.169.175; 2.J.169.240; 2.J.169.244;2.J.172.228; 2.J.172.229; 2.J.172.230; 2.J.172.231; 2.J.172.236; 2.J.172.237;2.J.172.238; 2.J.172.239; 2.J.172.154; 2.J.172.157; 2.J.172.166; 2.J.172.169;2.J.172.172; 2.J.172.175; 2.J.172.240; 2.J.172.244; 2.J.175.228; 2.J.175.229;2.J.175.230; 2.J.175.231; 2.J.175.236; 2.J.175.237; 2.J.175.238; 2.J.175.239;2.J.175.154; 2.J.175.157; 2.J.175.166; 2.J.175.169; 2.J.175.172; 2.J.175.175;2.J.175.240; 2.J.175.244; 2.J.240.228; 2.J.240.229; 2.J.240.230; 2.J.240.231;2.J.240.236; 2.J.240.237; 2.J.240.238; 2.J.240.239; 2.J.240.154; 2.J.240.157;2.J.240.166; 2.J.240.169; 2.J.240.172; 2.J.240.175; 2.J.240.240; 2.J.240.244;2.J.244.228; 2.J.244.229; 2.J.244.230; 2.J.244.231; 2.J.244.236; 2.J.244.237;2.J.244.238; 2.J.244.239; 2.J.244.154; 2.J.244.157; 2.J.244.166; 2.J.244.169;2.J.244.172; 2.J.244.175; 2.J.244.240; 2.J.244.244;

2.Lのプロドラッグ
2.L.228.228;2.L.228.229; 2.L.228.230; 2.L.228.231; 2.L.228.236; 2.L.228.237; 2.L.228.238;2.L.228.239; 2.L.228.154; 2.L.228.157; 2.L.228.166; 2.L.228.169; 2.L.228.172;2.L.228.175; 2.L.228.240; 2.L.228.244; 2.L.229.228; 2.L.229.229; 2.L.229.230;2.L.229.231; 2.L.229.236; 2.L.229.237; 2.L.229.238; 2.L.229.239; 2.L.229.154;2.L.229.157; 2.L.229.166; 2.L.229.169; 2.L.229.172; 2.L.229.175; 2.L.229.240;2.L.229.244; 2.L.230.228; 2.L.230.229; 2.L.230.230; 2.L.230.231; 2.L.230.236;2.L.230.237; 2.L.230.238; 2.L.230.239; 2.L.230.154; 2.L.230.157; 2.L.230.166;2.L.230.169; 2.L.230.172; 2.L.230.175; 2.L.230.240; 2.L.230.244; 2.L.231.228;2.L.231.229; 2.L.231.230; 2.L.231.231; 2.L.231.236; 2.L.231.237; 2.L.231.238;2.L.231.239; 2.L.231.154; 2.L.231.157; 2.L.231.166; 2.L.231.169; 2.L.231.172;2.L.231.175; 2.L.231.240; 2.L.231.244; 2.L.236.228; 2.L.236.229; 2.L.236.230;2.L.236.231; 2.L.236.236; 2.L.236.237; 2.L.236.238; 2.L.236.239; 2.L.236.154;2.L.236.157; 2.L.236.166; 2.L.236.169; 2.L.236.172; 2.L.236.175; 2.L.236.240;2.L.236.244; 2.L.237.228; 2.L.237.229; 2.L.237.230; 2.L.237.231; 2.L.237.236;2.L.237.237; 2.L.237.238; 2.L.237.239; 2.L.237.154; 2.L.237.157; 2.L.237.166;2.L.237.169; 2.L.237.172; 2.L.237.175; 2.L.237.240; 2.L.237.244; 2.L.238.228;2.L.238.229; 2.L.238.230; 2.L.238.231; 2.L.238.236; 2.L.238.237; 2.L.238.238;2.L.238.239; 2.L.238.154; 2.L.238.157; 2.L.238.166; 2.L.238.169; 2.L.238.172;2.L.238.175; 2.L.238.240; 2.L.238.244; 2.L.239.228; 2.L.239.229; 2.L.239.230;2.L.239.231; 2.L.239.236; 2.L.239.237; 2.L.239.238; 2.L.239.239; 2.L.239.154;2.L.239.157; 2.L.239.166; 2.L.239.169; 2.L.239.172; 2.L.239.175; 2.L.239.240;2.L.239.244; 2.L.154.228; 2.L.154.229; 2.L.154.230; 2.L.154.231; 2.L.154.236;2.L.154.237; 2.L.154.238; 2.L.154.239; 2.L.154.154; 2.L.154.157; 2.L.154.166;2.L.154.169; 2.L.154.172; 2.L.154.175; 2.L.154.240; 2.L.154.244; 2.L.157.228;2.L.157.229; 2.L.157.230; 2.L.157.231; 2.L.157.236; 2.L.157.237; 2.L.157.238;2.L.157.239; 2.L.157.154; 2.L.157.157; 2.L.157.166; 2.L.157.169; 2.L.157.172;2.L.157.175; 2.L.157.240; 2.L.157.244; 2.L.166.228; 2.L.166.229; 2.L.166.230;2.L.166.231; 2.L.166.236; 2.L.166.237; 2.L.166.238; 2.L.166.239; 2.L.166.154;2.L.166.157; 2.L.166.166; 2.L.166.169; 2.L.166.172; 2.L.166.175; 2.L.166.240;2.L.166.244; 2.L.169.228; 2.L.169.229; 2.L.169.230; 2.L.169.231; 2.L.169.236;2.L.169.237; 2.L.169.238; 2.L.169.239; 2.L.169.154; 2.L.169.157; 2.L.169.166;2.L.169.169; 2.L.169.172; 2.L.169.175; 2.L.169.240; 2.L.169.244; 2.L.172.228;2.L.172.229; 2.L.172.230; 2.L.172.231; 2.L.172.236; 2.L.172.237; 2.L.172.238;2.L.172.239; 2.L.172.154; 2.L.172.157; 2.L.172.166; 2.L.172.169; 2.L.172.172;2.L.172.175; 2.L.172.240; 2.L.172.244; 2.L.175.228; 2.L.175.229; 2.L.175.230;2.L.175.231; 2.L.175.236; 2.L.175.237; 2.L.175.238; 2.L.175.239; 2.L.175.154;2.L.175.157; 2.L.175.166; 2.L.175.169; 2.L.175.172; 2.L.175.175; 2.L.175.240;2.L.175.244; 2.L.240.228; 2.L.240.229; 2.L.240.230; 2.L.240.231; 2.L.240.236;2.L.240.237; 2.L.240.238; 2.L.240.239; 2.L.240.154; 2.L.240.157; 2.L.240.166;2.L.240.169; 2.L.240.172; 2.L.240.175; 2.L.240.240; 2.L.240.244; 2.L.244.228;2.L.244.229; 2.L.244.230; 2.L.244.231; 2.L.244.236; 2.L.244.237; 2.L.244.238;2.L.244.239; 2.L.244.154; 2.L.244.157; 2.L.244.166; 2.L.244.169; 2.L.244.172;2.L.244.175; 2.L.244.240; 2.L.244.244;

2.Oのプロドラッグ
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.237.240; 2.O.237.244;2.O.238.228; 2.O.238.229; 2.O.238.230; 2.O.238.231; 2.O.238.236; 2.O.238.237;2.O.238.238; 2.O.238.239; 2.O.238.154; 2.O.238.157; 2.O.238.166; 2.O.238.169;2.O.238.172; 2.O.238.175; 2.O.238.240; 2.O.238.244; 2.O.239.228; 2.O.239.229;2.O.239.230; 2.O.239.231; 2.O.239.236; 2.O.239.237; 2.O.239.238; 2.O.239.239;2.O.239.154; 2.O.239.157; 2.O.239.166; 2.O.239.169; 2.O.239.172; 2.O.239.175;2.O.239.240; 2.O.239.244; 2.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.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.157.169; 2.O.157.172;2.O.157.175; 2.O.157.240; 2.O.157.244; 2.O.166.228; 2.O.166.229; 2.O.166.230;2.O.166.231; 2.O.166.236; 2.O.166.237; 2.O.166.238; 2.O.166.239; 2.O.166.154;2.O.166.157; 2.O.166.166; 2.O.166.169; 2.O.166.172; 2.O.166.175; 2.O.166.240;2.O.166.244; 2.O.169.228; 2.O.169.229; 2.O.169.230; 2.O.169.231; 2.O.169.236;2.O.169.237; 2.O.169.238; 2.O.169.239; 2.O.169.154; 2.O.169.157; 2.O.169.166;2.O.169.169; 2.O.169.172; 2.O.169.175; 2.O.169.240; 2.O.169.244; 2.O.172.228;2.O.172.229; 2.O.172.230; 2.O.172.231; 2.O.172.236; 2.O.172.237; 2.O.172.238;2.O.172.239; 2.O.172.154; 2.O.172.157; 2.O.172.166; 2.O.172.169; 2.O.172.172;2.O.172.175; 2.O.172.240; 2.O.172.244; 2.O.175.228; 2.O.175.229; 2.O.175.230;2.O.175.231; 2.O.175.236; 2.O.175.237; 2.O.175.238; 2.O.175.239; 2.O.175.154;2.O.175.157; 2.O.175.166; 2.O.175.169; 2.O.175.172; 2.O.175.175; 2.O.175.240;2.O.175.244; 2.O.240.228; 2.O.240.229; 2.O.240.230; 2.O.240.231; 2.O.240.236;2.O.240.237; 2.O.240.238; 2.O.240.239; 2.O.240.154; 2.O.240.157; 2.O.240.166;2.O.240.169; 2.O.240.172; 2.O.240.175; 2.O.240.240; 2.O.240.244; 2.O.244.228;2.O.244.229; 2.O.244.230; 2.O.244.231; 2.O.244.236; 2.O.244.237; 2.O.244.238;2.O.244.239; 2.O.244.154; 2.O.244.157; 2.O.244.166; 2.O.244.169; 2.O.244.172;2.O.244.175; 2.O.244.240; 2.O.244.244;

2.Pのプロドラッグ
2.P.228.228; 2.P.228.229; 2.P.228.230; 2.P.228.231; 2.P.228.236; 2.P.228.237;2.P.228.238; 2.P.228.239; 2.P.228.154; 2.P.228.157; 2.P.228.166; 2.P.228.169;2.P.228.172; 2.P.228.175; 2.P.228.240; 2.P.228.244; 2.P.229.228; 2.P.229.229;2.P.229.230; 2.P.229.231; 2.P.229.236; 2.P.229.237; 2.P.229.238; 2.P.229.239;2.P.229.154; 2.P.229.157; 2.P.229.166; 2.P.229.169; 2.P.229.172; 2.P.229.175;2.P.229.240; 2.P.229.244; 2.P.230.228; 2.P.230.229; 2.P.230.230; 2.P.230.231;2.P.230.236; 2.P.230.237; 2.P.230.238; 2.P.230.239; 2.P.230.154; 2.P.230.157;2.P.230.166; 2.P.230.169; 2.P.230.172; 2.P.230.175; 2.P.230.240; 2.P.230.244;2.P.231.228; 2.P.231.229; 2.P.231.230; 2.P.231.231; 2.P.231.236; 2.P.231.237;2.P.231.238; 2.P.231.239; 2.P.231.154; 2.P.231.157; 2.P.231.166; 2.P.231.169;2.P.231.172; 2.P.231.175; 2.P.231.240; 2.P.231.244; 2.P.236.228; 2.P.236.229;2.P.236.230; 2.P.236.231; 2.P.236.236; 2.P.236.237; 2.P.236.238; 2.P.236.239;2.P.236.154; 2.P.236.157; 2.P.236.166; 2.P.236.169; 2.P.236.172; 2.P.236.175;2.P.236.240; 2.P.236.244; 2.P.237.228; 2.P.237.229; 2.P.237.230; 2.P.237.231;2.P.237.236; 2.P.237.237; 2.P.237.238; 2.P.237.239; 2.P.237.154; 2.P.237.157;2.P.237.166; 2.P.237.169; 2.P.237.172; 2.P.237.175; 2.P.237.240; 2.P.237.244;2.P.238.228; 2.P.238.229; 2.P.238.230; 2.P.238.231; 2.P.238.236; 2.P.238.237;2.P.238.238; 2.P.238.239; 2.P.238.154; 2.P.238.157; 2.P.238.166; 2.P.238.169;2.P.238.172; 2.P.238.175; 2.P.238.240; 2.P.238.244; 2.P.239.228; 2.P.239.229;2.P.239.230; 2.P.239.231; 2.P.239.236; 2.P.239.237; 2.P.239.238; 2.P.239.239;2.P.239.154; 2.P.239.157; 2.P.239.166; 2.P.239.169; 2.P.239.172; 2.P.239.175;2.P.239.240; 2.P.239.244; 2.P.154.228; 2.P.154.229; 2.P.154.230; 2.P.154.231;2.P.154.236; 2.P.154.237; 2.P.154.238; 2.P.154.239; 2.P.154.154; 2.P.154.157;2.P.154.166; 2.P.154.169; 2.P.154.172; 2.P.154.175; 2.P.154.240; 2.P.154.244;2.P.157.228; 2.P.157.229; 2.P.157.230; 2.P.157.231; 2.P.157.236; 2.P.157.237;2.P.157.238; 2.P.157.239; 2.P.157.154; 2.P.157.157; 2.P.157.166; 2.P.157.169;2.P.157.172; 2.P.157.175; 2.P.157.240; 2.P.157.244; 2.P.166.228; 2.P.166.229;2.P.166.230; 2.P.166.231; 2.P.166.236; 2.P.166.237; 2.P.166.238; 2.P.166.239;2.P.166.154; 2.P.166.157; 2.P.166.166; 2.P.166.169; 2.P.166.172; 2.P.166.175;2.P.166.240; 2.P.166.244; 2.P.169.228; 2.P.169.229; 2.P.169.230; 2.P.169.231;2.P.169.236; 2.P.169.237; 2.P.169.238; 2.P.169.239; 2.P.169.154; 2.P.169.157;2.P.169.166; 2.P.169.169; 2.P.169.172; 2.P.169.175; 2.P.169.240; 2.P.169.244;2.P.172.228; 2.P.172.229; 2.P.172.230; 2.P.172.231; 2.P.172.236; 2.P.172.237;2.P.172.238; 2.P.172.239; 2.P.172.154; 2.P.172.157; 2.P.172.166; 2.P.172.169;2.P.172.172; 2.P.172.175; 2.P.172.240; 2.P.172.244; 2.P.175.228; 2.P.175.229;2.P.175.230; 2.P.175.231; 2.P.175.236; 2.P.175.237; 2.P.175.238; 2.P.175.239;2.P.175.154; 2.P.175.157; 2.P.175.166; 2.P.175.169; 2.P.175.172; 2.P.175.175;2.P.175.240; 2.P.175.244; 2.P.240.228; 2.P.240.229; 2.P.240.230; 2.P.240.231;2.P.240.236; 2.P.240.237; 2.P.240.238; 2.P.240.239; 2.P.240.154; 2.P.240.157;2.P.240.166; 2.P.240.169; 2.P.240.172; 2.P.240.175; 2.P.240.240; 2.P.240.244;2.P.244.228; 2.P.244.229; 2.P.244.230; 2.P.244.231; 2.P.244.236; 2.P.244.237;2.P.244.238; 2.P.244.239; 2.P.244.154; 2.P.244.157; 2.P.244.166; 2.P.244.169;2.P.244.172; 2.P.244.175; 2.P.244.240; 2.P.244.244;

2.Uのプロドラッグ
2.U.228.228; 2.U.228.229; 2.U.228.230; 2.U.228.231; 2.U.228.236; 2.U.228.237;2.U.228.238; 2.U.228.239; 2.U.228.154; 2.U.228.157; 2.U.228.166; 2.U.228.169;2.U.228.172; 2.U.228.175; 2.U.228.240; 2.U.228.244; 2.U.229.228; 2.U.229.229;2.U.229.230; 2.U.229.231; 2.U.229.236; 2.U.229.237; 2.U.229.238; 2.U.229.239;2.U.229.154; 2.U.229.157; 2.U.229.166; 2.U.229.169; 2.U.229.172; 2.U.229.175;2.U.229.240; 2.U.229.244; 2.U.230.228; 2.U.230.229; 2.U.230.230; 2.U.230.231;2.U.230.236; 2.U.230.237; 2.U.230.238; 2.U.230.239; 2.U.230.154; 2.U.230.157;2.U.230.166; 2.U.230.169; 2.U.230.172; 2.U.230.175; 2.U.230.240; 2.U.230.244;2.U.231.228; 2.U.231.229; 2.U.231.230; 2.U.231.231; 2.U.231.236; 2.U.231.237;2.U.231.238; 2.U.231.239; 2.U.231.154; 2.U.231.157; 2.U.231.166; 2.U.231.169;2.U.231.172; 2.U.231.175; 2.U.231.240; 2.U.231.244; 2.U.236.228; 2.U.236.229;2.U.236.230; 2.U.236.231; 2.U.236.236; 2.U.236.237; 2.U.236.238; 2.U.236.239;2.U.236.154; 2.U.236.157; 2.U.236.166; 2.U.236.169; 2.U.236.172; 2.U.236.175;2.U.236.240; 2.U.236.244; 2.U.237.228; 2.U.237.229; 2.U.237.230; 2.U.237.231;2.U.237.236; 2.U.237.237; 2.U.237.238; 2.U.237.239; 2.U.237.154; 2.U.237.157;2.U.237.166; 2.U.237.169; 2.U.237.172; 2.U.237.175; 2.U.237.240; 2.U.237.244;2.U.238.228; 2.U.238.229; 2.U.238.230; 2.U.238.231; 2.U.238.236; 2.U.238.237;2.U.238.238; 2.U.238.239; 2.U.238.154; 2.U.238.157; 2.U.238.166; 2.U.238.169;2.U.238.172; 2.U.238.175; 2.U.238.240; 2.U.238.244; 2.U.239.228; 2.U.239.229;2.U.239.230; 2.U.239.231; 2.U.239.236; 2.U.239.237; 2.U.239.238; 2.U.239.239;2.U.239.154; 2.U.239.157; 2.U.239.166; 2.U.239.169; 2.U.239.172; 2.U.239.175;2.U.239.240; 2.U.239.244; 2.U.154.228; 2.U.154.229; 2.U.154.230; 2.U.154.231;2.U.154.236; 2.U.154.237; 2.U.154.238; 2.U.154.239; 2.U.154.154; 2.U.154.157;2.U.154.166; 2.U.154.169; 2.U.154.172; 2.U.154.175; 2.U.154.240; 2.U.154.244;2.U.157.228; 2.U.157.229; 2.U.157.230; 2.U.157.231; 2.U.157.236; 2.U.157.237;2.U.157.238; 2.U.157.239; 2.U.157.154; 2.U.157.157; 2.U.157.166; 2.U.157.169;2.U.157.172; 2.U.157.175; 2.U.157.240; 2.U.157.244; 2.U.166.228; 2.U.166.229;2.U.166.230; 2.U.166.231; 2.U.166.236; 2.U.166.237; 2.U.166.238; 2.U.166.239;2.U.166.154; 2.U.166.157; 2.U.166.166; 2.U.166.169; 2.U.166.172; 2.U.166.175;2.U.166.240; 2.U.166.244; 2.U.169.228; 2.U.169.229; 2.U.169.230; 2.U.169.231;2.U.169.236; 2.U.169.237; 2.U.169.238; 2.U.169.239; 2.U.169.154; 2.U.169.157;2.U.169.166; 2.U.169.169; 2.U.169.172; 2.U.169.175; 2.U.169.240; 2.U.169.244;2.U.172.228; 2.U.172.229; 2.U.172.230; 2.U.172.231; 2.U.172.236; 2.U.172.237;2.U.172.238; 2.U.172.239; 2.U.172.154; 2.U.172.157; 2.U.172.166; 2.U.172.169;2.U.172.172; 2.U.172.175; 2.U.172.240; 2.U.172.244; 2.U.175.228; 2.U.175.229;2.U.175.230; 2.U.175.231; 2.U.175.236; 2.U.175.237; 2.U.175.238; 2.U.175.239;2.U.175.154; 2.U.175.157; 2.U.175.166; 2.U.175.169; 2.U.175.172; 2.U.175.175;2.U.175.240; 2.U.175.244; 2.U.240.228; 2.U.240.229; 2.U.240.230; 2.U.240.231;2.U.240.236; 2.U.240.237; 2.U.240.238; 2.U.240.239; 2.U.240.154; 2.U.240.157;2.U.240.166; 2.U.240.169; 2.U.240.172; 2.U.240.175; 2.U.240.240; 2.U.240.244;2.U.244.228; 2.U.244.229; 2.U.244.230; 2.U.244.231; 2.U.244.236; 2.U.244.237;2.U.244.238; 2.U.244.239; 2.U.244.154; 2.U.244.157; 2.U.244.166; 2.U.244.169;2.U.244.172; 2.U.244.175; 2.U.244.240; 2.U.244.244;

2.Wのプロドラッグ
2.W.228.228; 2.W.228.229; 2.W.228.230; 2.W.228.231; 2.W.228.236; 2.W.228.237;2.W.228.238; 2.W.228.239; 2.W.228.154; 2.W.228.157; 2.W.228.166; 2.W.228.169;2.W.228.172; 2.W.228.175; 2.W.228.240; 2.W.228.244; 2.W.229.228; 2.W.229.229;2.W.229.230; 2.W.229.231; 2.W.229.236; 2.W.229.237; 2.W.229.238; 2.W.229.239;2.W.229.154; 2.W.229.157; 2.W.229.166; 2.W.229.169; 2.W.229.172; 2.W.229.175;2.W.229.240; 2.W.229.244; 2.W.230.228; 2.W.230.229; 2.W.230.230; 2.W.230.231;2.W.230.236; 2.W.230.237; 2.W.230.238; 2.W.230.239; 2.W.230.154; 2.W.230.157;2.W.230.166; 2.W.230.169; 2.W.230.172; 2.W.230.175; 2.W.230.240; 2.W.230.244;2.W.231.228; 2.W.231.229; 2.W.231.230; 2.W.231.231; 2.W.231.236; 2.W.231.237;2.W.231.238; 2.W.231.239; 2.W.231.154; 2.W.231.157; 2.W.231.166; 2.W.231.169;2.W.231.172; 2.W.231.175; 2.W.231.240; 2.W.231.244; 2.W.236.228; 2.W.236.229;2.W.236.230; 2.W.236.231; 2.W.236.236; 2.W.236.237; 2.W.236.238; 2.W.236.239;2.W.236.154; 2.W.236.157; 2.W.236.166; 2.W.236.169; 2.W.236.172; 2.W.236.175;2.W.236.240; 2.W.236.244; 2.W.237.228; 2.W.237.229; 2.W.237.230; 2.W.237.231;2.W.237.236; 2.W.237.237; 2.W.237.238; 2.W.237.239; 2.W.237.154; 2.W.237.157;2.W.237.166; 2.W.237.169; 2.W.237.172; 2.W.237.175; 2.W.237.240; 2.W.237.244;2.W.238.228; 2.W.238.229; 2.W.238.230; 2.W.238.231; 2.W.238.236; 2.W.238.237;2.W.238.238; 2.W.238.239; 2.W.238.154; 2.W.238.157; 2.W.238.166; 2.W.238.169;2.W.238.172; 2.W.238.175; 2.W.238.240; 2.W.238.244; 2.W.239.228; 2.W.239.229;2.W.239.230; 2.W.239.231; 2.W.239.236; 2.W.239.237; 2.W.239.238; 2.W.239.239;2.W.239.154; 2.W.239.157; 2.W.239.166; 2.W.239.169; 2.W.239.172; 2.W.239.175;2.W.239.240; 2.W.239.244; 2.W.154.228; 2.W.154.229; 2.W.154.230; 2.W.154.231; 2.W.154.236;2.W.154.237; 2.W.154.238; 2.W.154.239; 2.W.154.154; 2.W.154.157; 2.W.154.166;2.W.154.169; 2.W.154.172; 2.W.154.175; 2.W.154.240; 2.W.154.244; 2.W.157.228;2.W.157.229; 2.W.157.230; 2.W.157.231; 2.W.157.236; 2.W.157.237; 2.W.157.238;2.W.157.239; 2.W.157.154; 2.W.157.157; 2.W.157.166; 2.W.157.169; 2.W.157.172;2.W.157.175; 2.W.157.240; 2.W.157.244; 2.W.166.228; 2.W.166.229; 2.W.166.230;2.W.166.231; 2.W.166.236; 2.W.166.237; 2.W.166.238; 2.W.166.239; 2.W.166.154;2.W.166.157; 2.W.166.166; 2.W.166.169; 2.W.166.172; 2.W.166.175; 2.W.166.240;2.W.166.244; 2.W.169.228; 2.W.169.229; 2.W.169.230; 2.W.169.231; 2.W.169.236;2.W.169.237; 2.W.169.238; 2.W.169.239; 2.W.169.154; 2.W.169.157; 2.W.169.166;2.W.169.169; 2.W.169.172; 2.W.169.175; 2.W.169.240; 2.W.169.244; 2.W.172.228;2.W.172.229; 2.W.172.230; 2.W.172.231; 2.W.172.236; 2.W.172.237; 2.W.172.238;2.W.172.239; 2.W.172.154; 2.W.172.157; 2.W.172.166; 2.W.172.169; 2.W.172.172;2.W.172.175; 2.W.172.240; 2.W.172.244; 2.W.175.228; 2.W.175.229; 2.W.175.230;2.W.175.231; 2.W.175.236; 2.W.175.237; 2.W.175.238; 2.W.175.239; 2.W.175.154;2.W.175.157; 2.W.175.166; 2.W.175.169; 2.W.175.172; 2.W.175.175; 2.W.175.240;2.W.175.244; 2.W.240.228; 2.W.240.229; 2.W.240.230; 2.W.240.231; 2.W.240.236;2.W.240.237; 2.W.240.238; 2.W.240.239; 2.W.240.154; 2.W.240.157; 2.W.240.166;2.W.240.169; 2.W.240.172; 2.W.240.175; 2.W.240.240; 2.W.240.244; 2.W.244.228;2.W.244.229; 2.W.244.230; 2.W.244.231; 2.W.244.236; 2.W.244.237; 2.W.244.238;2.W.244.239; 2.W.244.154; 2.W.244.157; 2.W.244.166; 2.W.244.169; 2.W.244.172;2.W.244.175; 2.W.244.240; 2.W.244.244;

2.Yのプロドラッグ
2.Y.228.228; 2.Y.228.229; 2.Y.228.230; 2.Y.228.231; 2.Y.228.236; 2.Y.228.237;2.Y.228.238; 2.Y.228.239; 2.Y.228.154; 2.Y.228.157; 2.Y.228.166; 2.Y.228.169;2.Y.228.172; 2.Y.228.175; 2.Y.228.240; 2.Y.228.244; 2.Y.229.228; 2.Y.229.229;2.Y.229.230; 2.Y.229.231; 2.Y.229.236; 2.Y.229.237; 2.Y.229.238; 2.Y.229.239;2.Y.229.154; 2.Y.229.157; 2.Y.229.166; 2.Y.229.169; 2.Y.229.172; 2.Y.229.175;2.Y.229.240; 2.Y.229.244; 2.Y.230.228; 2.Y.230.229; 2.Y.230.230; 2.Y.230.231;2.Y.230.236; 2.Y.230.237; 2.Y.230.238; 2.Y.230.239; 2.Y.230.154; 2.Y.230.157;2.Y.230.166; 2.Y.230.169; 2.Y.230.172; 2.Y.230.175; 2.Y.230.240; 2.Y.230.244;2.Y.231.228; 2.Y.231.229; 2.Y.231.230; 2.Y.231.231; 2.Y.231.236; 2.Y.231.237;2.Y.231.238; 2.Y.231.239; 2.Y.231.154; 2.Y.231.157; 2.Y.231.166; 2.Y.231.169;2.Y.231.172; 2.Y.231.175; 2.Y.231.240; 2.Y.231.244; 2.Y.236.228; 2.Y.236.229;2.Y.236.230; 2.Y.236.231; 2.Y.236.236; 2.Y.236.237; 2.Y.236.238; 2.Y.236.239;2.Y.236.154; 2.Y.236.157; 2.Y.236.166; 2.Y.236.169; 2.Y.236.172; 2.Y.236.175;2.Y.236.240; 2.Y.236.244; 2.Y.237.228; 2.Y.237.229; 2.Y.237.230; 2.Y.237.231;2.Y.237.236; 2.Y.237.237; 2.Y.237.238; 2.Y.237.239; 2.Y.237.154; 2.Y.237.157;2.Y.237.166; 2.Y.237.169; 2.Y.237.172; 2.Y.237.175; 2.Y.237.240; 2.Y.237.244;2.Y.238.228; 2.Y.238.229; 2.Y.238.230; 2.Y.238.231; 2.Y.238.236; 2.Y.238.237;2.Y.238.238; 2.Y.238.239; 2.Y.238.154; 2.Y.238.157; 2.Y.238.166; 2.Y.238.169;2.Y.238.172; 2.Y.238.175; 2.Y.238.240; 2.Y.238.244; 2.Y.239.228; 2.Y.239.229;2.Y.239.230; 2.Y.239.231; 2.Y.239.236; 2.Y.239.237; 2.Y.239.238; 2.Y.239.239;2.Y.239.154; 2.Y.239.157; 2.Y.239.166; 2.Y.239.169; 2.Y.239.172; 2.Y.239.175;2.Y.239.240; 2.Y.239.244; 2.Y.154.228; 2.Y.154.229; 2.Y.154.230; 2.Y.154.231;2.Y.154.236; 2.Y.154.237; 2.Y.154.238; 2.Y.154.239; 2.Y.154.154; 2.Y.154.157;2.Y.154.166; 2.Y.154.169; 2.Y.154.172; 2.Y.154.175; 2.Y.154.240; 2.Y.154.244;2.Y.157.228; 2.Y.157.229; 2.Y.157.230; 2.Y.157.231; 2.Y.157.236; 2.Y.157.237;2.Y.157.238; 2.Y.157.239; 2.Y.157.154; 2.Y.157.157; 2.Y.157.166; 2.Y.157.169;2.Y.157.172; 2.Y.157.175; 2.Y.157.240; 2.Y.157.244; 2.Y.166.228; 2.Y.166.229;2.Y.166.230; 2.Y.166.231; 2.Y.166.236; 2.Y.166.237; 2.Y.166.238; 2.Y.166.239;2.Y.166.154; 2.Y.166.157; 2.Y.166.166; 2.Y.166.169; 2.Y.166.172; 2.Y.166.175;2.Y.166.240; 2.Y.166.244; 2.Y.169.228; 2.Y.169.229; 2.Y.169.230; 2.Y.169.231;2.Y.169.236; 2.Y.169.237; 2.Y.169.238; 2.Y.169.239; 2.Y.169.154; 2.Y.169.157;2.Y.169.166; 2.Y.169.169; 2.Y.169.172; 2.Y.169.175; 2.Y.169.240; 2.Y.169.244;2.Y.172.228; 2.Y.172.229; 2.Y.172.230; 2.Y.172.231; 2.Y.172.236; 2.Y.172.237;2.Y.172.238; 2.Y.172.239; 2.Y.172.154; 2.Y.172.157; 2.Y.172.166; 2.Y.172.169;2.Y.172.172; 2.Y.172.175; 2.Y.172.240; 2.Y.172.244; 2.Y.175.228; 2.Y.175.229;2.Y.175.230; 2.Y.175.231; 2.Y.175.236; 2.Y.175.237; 2.Y.175.238; 2.Y.175.239;2.Y.175.154; 2.Y.175.157; 2.Y.175.166; 2.Y.175.169; 2.Y.175.172; 2.Y.175.175;2.Y.175.240; 2.Y.175.244; 2.Y.240.228; 2.Y.240.229; 2.Y.240.230; 2.Y.240.231;2.Y.240.236; 2.Y.240.237; 2.Y.240.238; 2.Y.240.239; 2.Y.240.154; 2.Y.240.157;2.Y.240.166; 2.Y.240.169; 2.Y.240.172; 2.Y.240.175; 2.Y.240.240; 2.Y.240.244;2.Y.244.228; 2.Y.244.229; 2.Y.244.230; 2.Y.244.231; 2.Y.244.236; 2.Y.244.237;2.Y.244.238; 2.Y.244.239; 2.Y.244.154; 2.Y.244.157; 2.Y.244.166; 2.Y.244.169;2.Y.244.172; 2.Y.244.175; 2.Y.244.240; 2.Y.244.244;

3.Bのプロドラッグ
3.B.228.228; 3.B.228.229; 3.B.228.230; 3.B.228.231; 3.B.228.236; 3.B.228.237;3.B.228.238; 3.B.228.239; 3.B.228.154; 3.B.228.157; 3.B.228.166; 3.B.228.169;3.B.228.172; 3.B.228.175; 3.B.228.240; 3.B.228.244; 3.B.229.228; 3.B.229.229;3.B.229.230; 3.B.229.231; 3.B.229.236; 3.B.229.237; 3.B.229.238; 3.B.229.239;3.B.229.154; 3.B.229.157; 3.B.229.166; 3.B.229.169; 3.B.229.172; 3.B.229.175;3.B.229.240; 3.B.229.244; 3.B.230.228; 3.B.230.229; 3.B.230.230; 3.B.230.231;3.B.230.236; 3.B.230.237; 3.B.230.238; 3.B.230.239; 3.B.230.154; 3.B.230.157;3.B.230.166; 3.B.230.169; 3.B.230.172; 3.B.230.175; 3.B.230.240; 3.B.230.244;3.B.231.228; 3.B.231.229; 3.B.231.230; 3.B.231.231; 3.B.231.236; 3.B.231.237;3.B.231.238; 3.B.231.239; 3.B.231.154; 3.B.231.157; 3.B.231.166; 3.B.231.169;3.B.231.172; 3.B.231.175; 3.B.231.240; 3.B.231.244; 3.B.236.228; 3.B.236.229;3.B.236.230; 3.B.236.231; 3.B.236.236; 3.B.236.237; 3.B.236.238; 3.B.236.239;3.B.236.154; 3.B.236.157; 3.B.236.166; 3.B.236.169; 3.B.236.172; 3.B.236.175;3.B.236.240; 3.B.236.244; 3.B.237.228; 3.B.237.229; 3.B.237.230; 3.B.237.231;3.B.237.236; 3.B.237.237; 3.B.237.238; 3.B.237.239; 3.B.237.154; 3.B.237.157;3.B.237.166; 3.B.237.169; 3.B.237.172; 3.B.237.175; 3.B.237.240; 3.B.237.244;3.B.238.228; 3.B.238.229; 3.B.238.230; 3.B.238.231; 3.B.238.236; 3.B.238.237;3.B.238.238; 3.B.238.239; 3.B.238.154; 3.B.238.157; 3.B.238.166; 3.B.238.169;3.B.238.172; 3.B.238.175; 3.B.238.240; 3.B.238.244; 3.B.239.228; 3.B.239.229;3.B.239.230; 3.B.239.231; 3.B.239.236; 3.B.239.237; 3.B.239.238; 3.B.239.239;3.B.239.154; 3.B.239.157; 3.B.239.166; 3.B.239.169; 3.B.239.172; 3.B.239.175;3.B.239.240; 3.B.239.244; 3.B.154.228; 3.B.154.229; 3.B.154.230; 3.B.154.231;3.B.154.236; 3.B.154.237; 3.B.154.238; 3.B.154.239; 3.B.154.154; 3.B.154.157;3.B.154.166; 3.B.154.169; 3.B.154.172; 3.B.154.175; 3.B.154.240; 3.B.154.244;3.B.157.228; 3.B.157.229; 3.B.157.230; 3.B.157.231; 3.B.157.236; 3.B.157.237;3.B.157.238; 3.B.157.239; 3.B.157.154; 3.B.157.157; 3.B.157.166; 3.B.157.169;3.B.157.172; 3.B.157.175; 3.B.157.240; 3.B.157.244; 3.B.166.228; 3.B.166.229;3.B.166.230; 3.B.166.231; 3.B.166.236; 3.B.166.237; 3.B.166.238; 3.B.166.239;3.B.166.154; 3.B.166.157; 3.B.166.166; 3.B.166.169; 3.B.166.172; 3.B.166.175;3.B.166.240; 3.B.166.244; 3.B.169.228; 3.B.169.229; 3.B.169.230; 3.B.169.231;3.B.169.236; 3.B.169.237; 3.B.169.238; 3.B.169.239; 3.B.169.154; 3.B.169.157;3.B.169.166; 3.B.169.169; 3.B.169.172; 3.B.169.175; 3.B.169.240; 3.B.169.244;3.B.172.228; 3.B.172.229; 3.B.172.230; 3.B.172.231; 3.B.172.236; 3.B.172.237;3.B.172.238; 3.B.172.239; 3.B.172.154; 3.B.172.157; 3.B.172.166; 3.B.172.169;3.B.172.172; 3.B.172.175; 3.B.172.240; 3.B.172.244; 3.B.175.228; 3.B.175.229;3.B.175.230; 3.B.175.231; 3.B.175.236; 3.B.175.237; 3.B.175.238; 3.B.175.239;3.B.175.154; 3.B.175.157; 3.B.175.166; 3.B.175.169; 3.B.175.172; 3.B.175.175;3.B.175.240; 3.B.175.244; 3.B.240.228; 3.B.240.229; 3.B.240.230; 3.B.240.231;3.B.240.236; 3.B.240.237; 3.B.240.238; 3.B.240.239; 3.B.240.154; 3.B.240.157;3.B.240.166; 3.B.240.169; 3.B.240.172; 3.B.240.175; 3.B.240.240; 3.B.240.244;3.B.244.228; 3.B.244.229; 3.B.244.230; 3.B.244.231; 3.B.244.236; 3.B.244.237;3.B.244.238; 3.B.244.239; 3.B.244.154; 3.B.244.157; 3.B.244.166; 3.B.244.169;3.B.244.172; 3.B.244.175; 3.B.244.240; 3.B.244.244;

3.Dのプロドラッグ
3.D.228.228; 3.D.228.229; 3.D.228.230; 3.D.228.231; 3.D.228.236; 3.D.228.237;3.D.228.238; 3.D.228.239; 3.D.228.154; 3.D.228.157; 3.D.228.166; 3.D.228.169;3.D.228.172; 3.D.228.175; 3.D.228.240; 3.D.228.244; 3.D.229.228; 3.D.229.229;3.D.229.230; 3.D.229.231; 3.D.229.236; 3.D.229.237; 3.D.229.238; 3.D.229.239;3.D.229.154; 3.D.229.157; 3.D.229.166; 3.D.229.169; 3.D.229.172; 3.D.229.175;3.D.229.240; 3.D.229.244; 3.D.230.228; 3.D.230.229; 3.D.230.230; 3.D.230.231;3.D.230.236; 3.D.230.237; 3.D.230.238; 3.D.230.239; 3.D.230.154; 3.D.230.157;3.D.230.166; 3.D.230.169; 3.D.230.172; 3.D.230.175; 3.D.230.240; 3.D.230.244;3.D.231.228; 3.D.231.229; 3.D.231.230; 3.D.231.231; 3.D.231.236; 3.D.231.237;3.D.231.238; 3.D.231.239; 3.D.231.154; 3.D.231.157; 3.D.231.166; 3.D.231.169;3.D.231.172; 3.D.231.175; 3.D.231.240; 3.D.231.244; 3.D.236.228; 3.D.236.229;3.D.236.230; 3.D.236.231; 3.D.236.236; 3.D.236.237; 3.D.236.238; 3.D.236.239;3.D.236.154; 3.D.236.157; 3.D.236.166; 3.D.236.169; 3.D.236.172; 3.D.236.175;3.D.236.240; 3.D.236.244; 3.D.237.228; 3.D.237.229; 3.D.237.230; 3.D.237.231;3.D.237.236; 3.D.237.237; 3.D.237.238; 3.D.237.239; 3.D.237.154; 3.D.237.157;3.D.237.166; 3.D.237.169; 3.D.237.172; 3.D.237.175; 3.D.237.240; 3.D.237.244;3.D.238.228; 3.D.238.229; 3.D.238.230; 3.D.238.231; 3.D.238.236; 3.D.238.237;3.D.238.238; 3.D.238.239; 3.D.238.154; 3.D.238.157; 3.D.238.166; 3.D.238.169; 3.D.238.172;3.D.238.175; 3.D.238.240; 3.D.238.244; 3.D.239.228; 3.D.239.229; 3.D.239.230;3.D.239.231; 3.D.239.236; 3.D.239.237; 3.D.239.238; 3.D.239.239; 3.D.239.154;3.D.239.157; 3.D.239.166; 3.D.239.169; 3.D.239.172; 3.D.239.175; 3.D.239.240;3.D.239.244; 3.D.154.228; 3.D.154.229; 3.D.154.230; 3.D.154.231; 3.D.154.236;3.D.154.237; 3.D.154.238; 3.D.154.239; 3.D.154.154; 3.D.154.157; 3.D.154.166;3.D.154.169; 3.D.154.172; 3.D.154.175; 3.D.154.240; 3.D.154.244; 3.D.157.228;3.D.157.229; 3.D.157.230; 3.D.157.231; 3.D.157.236; 3.D.157.237; 3.D.157.238;3.D.157.239; 3.D.157.154; 3.D.157.157; 3.D.157.166; 3.D.157.169; 3.D.157.172;3.D.157.175; 3.D.157.240; 3.D.157.244; 3.D.166.228; 3.D.166.229; 3.D.166.230;3.D.166.231; 3.D.166.236; 3.D.166.237; 3.D.166.238; 3.D.166.239; 3.D.166.154;3.D.166.157; 3.D.166.166; 3.D.166.169; 3.D.166.172; 3.D.166.175; 3.D.166.240;3.D.166.244; 3.D.169.228; 3.D.169.229; 3.D.169.230; 3.D.169.231; 3.D.169.236;3.D.169.237; 3.D.169.238; 3.D.169.239; 3.D.169.154; 3.D.169.157; 3.D.169.166;3.D.169.169; 3.D.169.172; 3.D.169.175; 3.D.169.240; 3.D.169.244; 3.D.172.228;3.D.172.229; 3.D.172.230; 3.D.172.231; 3.D.172.236; 3.D.172.237; 3.D.172.238;3.D.172.239; 3.D.172.154; 3.D.172.157; 3.D.172.166; 3.D.172.169; 3.D.172.172;3.D.172.175; 3.D.172.240; 3.D.172.244; 3.D.175.228; 3.D.175.229; 3.D.175.230;3.D.175.231; 3.D.175.236; 3.D.175.237; 3.D.175.238; 3.D.175.239; 3.D.175.154;3.D.175.157; 3.D.175.166; 3.D.175.169; 3.D.175.172; 3.D.175.175; 3.D.175.240;3.D.175.244; 3.D.240.228; 3.D.240.229; 3.D.240.230; 3.D.240.231; 3.D.240.236;3.D.240.237; 3.D.240.238; 3.D.240.239; 3.D.240.154; 3.D.240.157; 3.D.240.166;3.D.240.169; 3.D.240.172; 3.D.240.175; 3.D.240.240; 3.D.240.244; 3.D.244.228;3.D.244.229; 3.D.244.230; 3.D.244.231; 3.D.244.236; 3.D.244.237; 3.D.244.238;3.D.244.239; 3.D.244.154; 3.D.244.157; 3.D.244.166; 3.D.244.169; 3.D.244.172;3.D.244.175; 3.D.244.240; 3.D.244.244;

3.Eのプロドラッグ
3.E.228.228; 3.E.228.229; 3.E.228.230; 3.E.228.231; 3.E.228.236; 3.E.228.237;3.E.228.238; 3.E.228.239; 3.E.228.154; 3.E.228.157; 3.E.228.166; 3.E.228.169;3.E.228.172; 3.E.228.175; 3.E.228.240; 3.E.228.244; 3.E.229.228; 3.E.229.229;3.E.229.230; 3.E.229.231; 3.E.229.236; 3.E.229.237; 3.E.229.238; 3.E.229.239;3.E.229.154; 3.E.229.157; 3.E.229.166; 3.E.229.169; 3.E.229.172; 3.E.229.175;3.E.229.240; 3.E.229.244; 3.E.230.228; 3.E.230.229; 3.E.230.230; 3.E.230.231;3.E.230.236; 3.E.230.237; 3.E.230.238; 3.E.230.239; 3.E.230.154; 3.E.230.157;3.E.230.166; 3.E.230.169; 3.E.230.172; 3.E.230.175; 3.E.230.240; 3.E.230.244;3.E.231.228; 3.E.231.229; 3.E.231.230; 3.E.231.231; 3.E.231.236; 3.E.231.237;3.E.231.238; 3.E.231.239; 3.E.231.154; 3.E.231.157; 3.E.231.166; 3.E.231.169;3.E.231.172; 3.E.231.175; 3.E.231.240; 3.E.231.244; 3.E.236.228; 3.E.236.229;3.E.236.230; 3.E.236.231; 3.E.236.236; 3.E.236.237; 3.E.236.238; 3.E.236.239;3.E.236.154; 3.E.236.157; 3.E.236.166; 3.E.236.169; 3.E.236.172; 3.E.236.175;3.E.236.240; 3.E.236.244; 3.E.237.228; 3.E.237.229; 3.E.237.230; 3.E.237.231;3.E.237.236; 3.E.237.237; 3.E.237.238; 3.E.237.239; 3.E.237.154; 3.E.237.157;3.E.237.166; 3.E.237.169; 3.E.237.172; 3.E.237.175; 3.E.237.240; 3.E.237.244;3.E.238.228; 3.E.238.229; 3.E.238.230; 3.E.238.231; 3.E.238.236; 3.E.238.237;3.E.238.238; 3.E.238.239; 3.E.238.154; 3.E.238.157; 3.E.238.166; 3.E.238.169;3.E.238.172; 3.E.238.175; 3.E.238.240; 3.E.238.244; 3.E.239.228; 3.E.239.229;3.E.239.230; 3.E.239.231; 3.E.239.236; 3.E.239.237; 3.E.239.238; 3.E.239.239;3.E.239.154; 3.E.239.157; 3.E.239.166; 3.E.239.169; 3.E.239.172; 3.E.239.175;3.E.239.240; 3.E.239.244; 3.E.154.228; 3.E.154.229; 3.E.154.230; 3.E.154.231;3.E.154.236; 3.E.154.237; 3.E.154.238; 3.E.154.239; 3.E.154.154; 3.E.154.157;3.E.154.166; 3.E.154.169; 3.E.154.172; 3.E.154.175; 3.E.154.240; 3.E.154.244;3.E.157.228; 3.E.157.229; 3.E.157.230; 3.E.157.231; 3.E.157.236; 3.E.157.237;3.E.157.238; 3.E.157.239; 3.E.157.154; 3.E.157.157; 3.E.157.166; 3.E.157.169;3.E.157.172; 3.E.157.175; 3.E.157.240; 3.E.157.244; 3.E.166.228; 3.E.166.229;3.E.166.230; 3.E.166.231; 3.E.166.236; 3.E.166.237; 3.E.166.238; 3.E.166.239;3.E.166.154; 3.E.166.157; 3.E.166.166; 3.E.166.169; 3.E.166.172; 3.E.166.175;3.E.166.240; 3.E.166.244; 3.E.169.228; 3.E.169.229; 3.E.169.230; 3.E.169.231; 3.E.169.236;3.E.169.237; 3.E.169.238; 3.E.169.239; 3.E.169.154; 3.E.169.157; 3.E.169.166;3.E.169.169; 3.E.169.172; 3.E.169.175; 3.E.169.240; 3.E.169.244; 3.E.172.228;3.E.172.229; 3.E.172.230; 3.E.172.231; 3.E.172.236; 3.E.172.237; 3.E.172.238;3.E.172.239; 3.E.172.154; 3.E.172.157; 3.E.172.166; 3.E.172.169; 3.E.172.172;3.E.172.175; 3.E.172.240; 3.E.172.244; 3.E.175.228; 3.E.175.229; 3.E.175.230;3.E.175.231; 3.E.175.236; 3.E.175.237; 3.E.175.238; 3.E.175.239; 3.E.175.154;3.E.175.157; 3.E.175.166; 3.E.175.169; 3.E.175.172; 3.E.175.175; 3.E.175.240;3.E.175.244; 3.E.240.228; 3.E.240.229; 3.E.240.230; 3.E.240.231; 3.E.240.236;3.E.240.237; 3.E.240.238; 3.E.240.239; 3.E.240.154; 3.E.240.157; 3.E.240.166;3.E.240.169; 3.E.240.172; 3.E.240.175; 3.E.240.240; 3.E.240.244; 3.E.244.228;3.E.244.229; 3.E.244.230; 3.E.244.231; 3.E.244.236; 3.E.244.237; 3.E.244.238;3.E.244.239; 3.E.244.154; 3.E.244.157; 3.E.244.166; 3.E.244.169; 3.E.244.172;3.E.244.175; 3.E.244.240; 3.E.244.244;

3.Gのプロドラッグ
3.G.228.228; 3.G.228.229; 3.G.228.230; 3.G.228.231; 3.G.228.236; 3.G.228.237;3.G.228.238; 3.G.228.239; 3.G.228.154; 3.G.228.157; 3.G.228.166; 3.G.228.169;3.G.228.172; 3.G.228.175; 3.G.228.240; 3.G.228.244; 3.G.229.228; 3.G.229.229;3.G.229.230; 3.G.229.231; 3.G.229.236; 3.G.229.237; 3.G.229.238; 3.G.229.239;3.G.229.154; 3.G.229.157; 3.G.229.166; 3.G.229.169; 3.G.229.172; 3.G.229.175;3.G.229.240; 3.G.229.244; 3.G.230.228; 3.G.230.229; 3.G.230.230; 3.G.230.231;3.G.230.236; 3.G.230.237; 3.G.230.238; 3.G.230.239; 3.G.230.154; 3.G.230.157;3.G.230.166; 3.G.230.169; 3.G.230.172; 3.G.230.175; 3.G.230.240; 3.G.230.244;3.G.231.228; 3.G.231.229; 3.G.231.230; 3.G.231.231; 3.G.231.236; 3.G.231.237;3.G.231.238; 3.G.231.239; 3.G.231.154; 3.G.231.157; 3.G.231.166; 3.G.231.169;3.G.231.172; 3.G.231.175; 3.G.231.240; 3.G.231.244; 3.G.236.228; 3.G.236.229;3.G.236.230; 3.G.236.231; 3.G.236.236; 3.G.236.237; 3.G.236.238; 3.G.236.239;3.G.236.154; 3.G.236.157; 3.G.236.166; 3.G.236.169; 3.G.236.172; 3.G.236.175;3.G.236.240; 3.G.236.244; 3.G.237.228; 3.G.237.229; 3.G.237.230; 3.G.237.231;3.G.237.236; 3.G.237.237; 3.G.237.238; 3.G.237.239; 3.G.237.154; 3.G.237.157;3.G.237.166; 3.G.237.169; 3.G.237.172; 3.G.237.175; 3.G.237.240; 3.G.237.244;3.G.238.228; 3.G.238.229; 3.G.238.230; 3.G.238.231; 3.G.238.236; 3.G.238.237;3.G.238.238; 3.G.238.239; 3.G.238.154; 3.G.238.157; 3.G.238.166; 3.G.238.169;3.G.238.172; 3.G.238.175; 3.G.238.240; 3.G.238.244; 3.G.239.228; 3.G.239.229;3.G.239.230; 3.G.239.231; 3.G.239.236; 3.G.239.237; 3.G.239.238; 3.G.239.239;3.G.239.154; 3.G.239.157; 3.G.239.166; 3.G.239.169; 3.G.239.172; 3.G.239.175;3.G.239.240; 3.G.239.244; 3.G.154.228; 3.G.154.229; 3.G.154.230; 3.G.154.231;3.G.154.236; 3.G.154.237; 3.G.154.238; 3.G.154.239; 3.G.154.154; 3.G.154.157;3.G.154.166; 3.G.154.169; 3.G.154.172; 3.G.154.175; 3.G.154.240; 3.G.154.244;3.G.157.228; 3.G.157.229; 3.G.157.230; 3.G.157.231; 3.G.157.236; 3.G.157.237;3.G.157.238; 3.G.157.239; 3.G.157.154; 3.G.157.157; 3.G.157.166; 3.G.157.169;3.G.157.172; 3.G.157.175; 3.G.157.240; 3.G.157.244; 3.G.166.228; 3.G.166.229;3.G.166.230; 3.G.166.231; 3.G.166.236; 3.G.166.237; 3.G.166.238; 3.G.166.239;3.G.166.154; 3.G.166.157; 3.G.166.166; 3.G.166.169; 3.G.166.172; 3.G.166.175;3.G.166.240; 3.G.166.244; 3.G.169.228; 3.G.169.229; 3.G.169.230; 3.G.169.231;3.G.169.236; 3.G.169.237; 3.G.169.238; 3.G.169.239; 3.G.169.154; 3.G.169.157;3.G.169.166; 3.G.169.169; 3.G.169.172; 3.G.169.175; 3.G.169.240; 3.G.169.244;3.G.172.228; 3.G.172.229; 3.G.172.230; 3.G.172.231; 3.G.172.236; 3.G.172.237;3.G.172.238; 3.G.172.239; 3.G.172.154; 3.G.172.157; 3.G.172.166; 3.G.172.169;3.G.172.172; 3.G.172.175; 3.G.172.240; 3.G.172.244; 3.G.175.228; 3.G.175.229;3.G.175.230; 3.G.175.231; 3.G.175.236; 3.G.175.237; 3.G.175.238; 3.G.175.239;3.G.175.154; 3.G.175.157; 3.G.175.166; 3.G.175.169; 3.G.175.172; 3.G.175.175;3.G.175.240; 3.G.175.244; 3.G.240.228; 3.G.240.229; 3.G.240.230; 3.G.240.231;3.G.240.236; 3.G.240.237; 3.G.240.238; 3.G.240.239; 3.G.240.154; 3.G.240.157;3.G.240.166; 3.G.240.169; 3.G.240.172; 3.G.240.175; 3.G.240.240; 3.G.240.244;3.G.244.228; 3.G.244.229; 3.G.244.230; 3.G.244.231; 3.G.244.236; 3.G.244.237;3.G.244.238; 3.G.244.239; 3.G.244.154; 3.G.244.157; 3.G.244.166; 3.G.244.169;3.G.244.172; 3.G.244.175; 3.G.244.240; 3.G.244.244;

3.Iのプロドラッグ
3.I.228.228;3.I.228.229; 3.I.228.230; 3.I.228.231; 3.I.228.236; 3.I.228.237; 3.I.228.238;3.I.228.239; 3.I.228.154; 3.I.228.157; 3.I.228.166; 3.I.228.169; 3.I.228.172;3.I.228.175; 3.I.228.240; 3.I.228.244; 3.I.229.228; 3.I.229.229; 3.I.229.230;3.I.229.231; 3.I.229.236; 3.I.229.237; 3.I.229.238; 3.I.229.239; 3.I.229.154;3.I.229.157; 3.I.229.166; 3.I.229.169; 3.I.229.172; 3.I.229.175; 3.I.229.240;3.I.229.244; 3.I.230.228; 3.I.230.229; 3.I.230.230; 3.I.230.231; 3.I.230.236;3.I.230.237; 3.I.230.238; 3.I.230.239; 3.I.230.154; 3.I.230.157; 3.I.230.166;3.I.230.169; 3.I.230.172; 3.I.230.175; 3.I.230.240; 3.I.230.244; 3.I.231.228;3.I.231.229; 3.I.231.230; 3.I.231.231; 3.I.231.236; 3.I.231.237; 3.I.231.238;3.I.231.239; 3.I.231.154; 3.I.231.157; 3.I.231.166; 3.I.231.169; 3.I.231.172;3.I.231.175; 3.I.231.240; 3.I.231.244; 3.I.236.228; 3.I.236.229; 3.I.236.230;3.I.236.231; 3.I.236.236; 3.I.236.237; 3.I.236.238; 3.I.236.239; 3.I.236.154;3.I.236.157; 3.I.236.166; 3.I.236.169; 3.I.236.172; 3.I.236.175; 3.I.236.240;3.I.236.244; 3.I.237.228; 3.I.237.229; 3.I.237.230; 3.I.237.231; 3.I.237.236;3.I.237.237; 3.I.237.238; 3.I.237.239; 3.I.237.154; 3.I.237.157; 3.I.237.166;3.I.237.169; 3.I.237.172; 3.I.237.175; 3.I.237.240; 3.I.237.244; 3.I.238.228;3.I.238.229; 3.I.238.230; 3.I.238.231; 3.I.238.236; 3.I.238.237; 3.I.238.238;3.I.238.239; 3.I.238.154; 3.I.238.157; 3.I.238.166; 3.I.238.169; 3.I.238.172;3.I.238.175; 3.I.238.240; 3.I.238.244; 3.I.239.228; 3.I.239.229; 3.I.239.230;3.I.239.231; 3.I.239.236; 3.I.239.237; 3.I.239.238; 3.I.239.239; 3.I.239.154;3.I.239.157; 3.I.239.166; 3.I.239.169; 3.I.239.172; 3.I.239.175; 3.I.239.240;3.I.239.244; 3.I.154.228; 3.I.154.229; 3.I.154.230; 3.I.154.231; 3.I.154.236;3.I.154.237; 3.I.154.238; 3.I.154.239; 3.I.154.154; 3.I.154.157; 3.I.154.166;3.I.154.169; 3.I.154.172; 3.I.154.175; 3.I.154.240; 3.I.154.244; 3.I.157.228;3.I.157.229; 3.I.157.230; 3.I.157.231; 3.I.157.236; 3.I.157.237; 3.I.157.238;3.I.157.239; 3.I.157.154; 3.I.157.157; 3.I.157.166; 3.I.157.169; 3.I.157.172;3.I.157.175; 3.I.157.240; 3.I.157.244; 3.I.166.228; 3.I.166.229; 3.I.166.230;3.I.166.231; 3.I.166.236; 3.I.166.237; 3.I.166.238; 3.I.166.239; 3.I.166.154;3.I.166.157; 3.I.166.166; 3.I.166.169; 3.I.166.172; 3.I.166.175; 3.I.166.240;3.I.166.244; 3.I.169.228; 3.I.169.229; 3.I.169.230; 3.I.169.231; 3.I.169.236;3.I.169.237; 3.I.169.238; 3.I.169.239; 3.I.169.154; 3.I.169.157; 3.I.169.166;3.I.169.169; 3.I.169.172; 3.I.169.175; 3.I.169.240; 3.I.169.244; 3.I.172.228;3.I.172.229; 3.I.172.230; 3.I.172.231; 3.I.172.236; 3.I.172.237; 3.I.172.238;3.I.172.239; 3.I.172.154; 3.I.172.157; 3.I.172.166; 3.I.172.169; 3.I.172.172;3.I.172.175; 3.I.172.240; 3.I.172.244; 3.I.175.228; 3.I.175.229; 3.I.175.230;3.I.175.231; 3.I.175.236; 3.I.175.237; 3.I.175.238; 3.I.175.239; 3.I.175.154;3.I.175.157; 3.I.175.166; 3.I.175.169; 3.I.175.172; 3.I.175.175; 3.I.175.240;3.I.175.244; 3.I.240.228; 3.I.240.229; 3.I.240.230; 3.I.240.231; 3.I.240.236;3.I.240.237; 3.I.240.238; 3.I.240.239; 3.I.240.154; 3.I.240.157; 3.I.240.166;3.I.240.169; 3.I.240.172; 3.I.240.175; 3.I.240.240; 3.I.240.244; 3.I.244.228;3.I.244.229; 3.I.244.230; 3.I.244.231; 3.I.244.236; 3.I.244.237; 3.I.244.238;3.I.244.239; 3.I.244.154; 3.I.244.157; 3.I.244.166; 3.I.244.169; 3.I.244.172;3.I.244.175; 3.I.244.240; 3.I.244.244;

3.Jのプロドラッグ
3.J.228.228; 3.J.228.229; 3.J.228.230; 3.J.228.231; 3.J.228.236; 3.J.228.237;3.J.228.238; 3.J.228.239; 3.J.228.154; 3.J.228.157; 3.J.228.166; 3.J.228.169;3.J.228.172; 3.J.228.175; 3.J.228.240; 3.J.228.244; 3.J.229.228; 3.J.229.229;3.J.229.230; 3.J.229.231; 3.J.229.236; 3.J.229.237; 3.J.229.238; 3.J.229.239;3.J.229.154; 3.J.229.157; 3.J.229.166; 3.J.229.169; 3.J.229.172; 3.J.229.175;3.J.229.240; 3.J.229.244; 3.J.230.228; 3.J.230.229; 3.J.230.230; 3.J.230.231;3.J.230.236; 3.J.230.237; 3.J.230.238; 3.J.230.239; 3.J.230.154; 3.J.230.157;3.J.230.166; 3.J.230.169; 3.J.230.172; 3.J.230.175; 3.J.230.240; 3.J.230.244;3.J.231.228; 3.J.231.229; 3.J.231.230; 3.J.231.231; 3.J.231.236; 3.J.231.237;3.J.231.238; 3.J.231.239; 3.J.231.154; 3.J.231.157; 3.J.231.166; 3.J.231.169;3.J.231.172; 3.J.231.175; 3.J.231.240; 3.J.231.244; 3.J.236.228; 3.J.236.229;3.J.236.230; 3.J.236.231; 3.J.236.236; 3.J.236.237; 3.J.236.238; 3.J.236.239;3.J.236.154; 3.J.236.157; 3.J.236.166; 3.J.236.169; 3.J.236.172; 3.J.236.175;3.J.236.240; 3.J.236.244; 3.J.237.228; 3.J.237.229; 3.J.237.230; 3.J.237.231;3.J.237.236; 3.J.237.237; 3.J.237.238; 3.J.237.239; 3.J.237.154; 3.J.237.157;3.J.237.166; 3.J.237.169; 3.J.237.172; 3.J.237.175; 3.J.237.240; 3.J.237.244;3.J.238.228; 3.J.238.229; 3.J.238.230; 3.J.238.231; 3.J.238.236; 3.J.238.237;3.J.238.238; 3.J.238.239; 3.J.238.154; 3.J.238.157; 3.J.238.166; 3.J.238.169;3.J.238.172; 3.J.238.175; 3.J.238.240; 3.J.238.244; 3.J.239.228; 3.J.239.229;3.J.239.230; 3.J.239.231; 3.J.239.236; 3.J.239.237; 3.J.239.238; 3.J.239.239;3.J.239.154; 3.J.239.157; 3.J.239.166; 3.J.239.169; 3.J.239.172; 3.J.239.175;3.J.239.240; 3.J.239.244; 3.J.154.228; 3.J.154.229; 3.J.154.230; 3.J.154.231;3.J.154.236; 3.J.154.237; 3.J.154.238; 3.J.154.239; 3.J.154.154; 3.J.154.157;3.J.154.166; 3.J.154.169; 3.J.154.172; 3.J.154.175; 3.J.154.240; 3.J.154.244;3.J.157.228; 3.J.157.229; 3.J.157.230; 3.J.157.231; 3.J.157.236; 3.J.157.237;3.J.157.238; 3.J.157.239; 3.J.157.154; 3.J.157.157; 3.J.157.166; 3.J.157.169; 3.J.157.172;3.J.157.175; 3.J.157.240; 3.J.157.244; 3.J.166.228; 3.J.166.229; 3.J.166.230;3.J.166.231; 3.J.166.236; 3.J.166.237; 3.J.166.238; 3.J.166.239; 3.J.166.154;3.J.166.157; 3.J.166.166; 3.J.166.169; 3.J.166.172; 3.J.166.175; 3.J.166.240;3.J.166.244; 3.J.169.228; 3.J.169.229; 3.J.169.230; 3.J.169.231; 3.J.169.236;3.J.169.237; 3.J.169.238; 3.J.169.239; 3.J.169.154; 3.J.169.157; 3.J.169.166;3.J.169.169; 3.J.169.172; 3.J.169.175; 3.J.169.240; 3.J.169.244; 3.J.172.228;3.J.172.229; 3.J.172.230; 3.J.172.231; 3.J.172.236; 3.J.172.237; 3.J.172.238;3.J.172.239; 3.J.172.154; 3.J.172.157; 3.J.172.166; 3.J.172.169; 3.J.172.172;3.J.172.175; 3.J.172.240; 3.J.172.244; 3.J.175.228; 3.J.175.229; 3.J.175.230;3.J.175.231; 3.J.175.236; 3.J.175.237; 3.J.175.238; 3.J.175.239; 3.J.175.154;3.J.175.157; 3.J.175.166; 3.J.175.169; 3.J.175.172; 3.J.175.175; 3.J.175.240;3.J.175.244; 3.J.240.228; 3.J.240.229; 3.J.240.230; 3.J.240.231; 3.J.240.236;3.J.240.237; 3.J.240.238; 3.J.240.239; 3.J.240.154; 3.J.240.157; 3.J.240.166;3.J.240.169; 3.J.240.172; 3.J.240.175; 3.J.240.240; 3.J.240.244; 3.J.244.228;3.J.244.229; 3.J.244.230; 3.J.244.231; 3.J.244.236; 3.J.244.237; 3.J.244.238;3.J.244.239; 3.J.244.154; 3.J.244.157; 3.J.244.166; 3.J.244.169; 3.J.244.172;3.J.244.175; 3.J.244.240; 3.J.244.244;

3.Lのプロドラッグ
3.L.228.228; 3.L.228.229; 3.L.228.230; 3.L.228.231; 3.L.228.236; 3.L.228.237;3.L.228.238; 3.L.228.239; 3.L.228.154; 3.L.228.157; 3.L.228.166; 3.L.228.169;3.L.228.172; 3.L.228.175; 3.L.228.240; 3.L.228.244; 3.L.229.228; 3.L.229.229;3.L.229.230; 3.L.229.231; 3.L.229.236; 3.L.229.237; 3.L.229.238; 3.L.229.239;3.L.229.154; 3.L.229.157; 3.L.229.166; 3.L.229.169; 3.L.229.172; 3.L.229.175;3.L.229.240; 3.L.229.244; 3.L.230.228; 3.L.230.229; 3.L.230.230; 3.L.230.231;3.L.230.236; 3.L.230.237; 3.L.230.238; 3.L.230.239; 3.L.230.154; 3.L.230.157;3.L.230.166; 3.L.230.169; 3.L.230.172; 3.L.230.175; 3.L.230.240; 3.L.230.244;3.L.231.228; 3.L.231.229; 3.L.231.230; 3.L.231.231; 3.L.231.236; 3.L.231.237;3.L.231.238; 3.L.231.239; 3.L.231.154; 3.L.231.157; 3.L.231.166; 3.L.231.169;3.L.231.172; 3.L.231.175; 3.L.231.240; 3.L.231.244; 3.L.236.228; 3.L.236.229;3.L.236.230; 3.L.236.231; 3.L.236.236; 3.L.236.237; 3.L.236.238; 3.L.236.239;3.L.236.154; 3.L.236.157; 3.L.236.166; 3.L.236.169; 3.L.236.172; 3.L.236.175;3.L.236.240; 3.L.236.244; 3.L.237.228; 3.L.237.229; 3.L.237.230; 3.L.237.231;3.L.237.236; 3.L.237.237; 3.L.237.238; 3.L.237.239; 3.L.237.154; 3.L.237.157;3.L.237.166; 3.L.237.169; 3.L.237.172; 3.L.237.175; 3.L.237.240; 3.L.237.244;3.L.238.228; 3.L.238.229; 3.L.238.230; 3.L.238.231; 3.L.238.236; 3.L.238.237;3.L.238.238; 3.L.238.239; 3.L.238.154; 3.L.238.157; 3.L.238.166; 3.L.238.169;3.L.238.172; 3.L.238.175; 3.L.238.240; 3.L.238.244; 3.L.239.228; 3.L.239.229;3.L.239.230; 3.L.239.231; 3.L.239.236; 3.L.239.237; 3.L.239.238; 3.L.239.239;3.L.239.154; 3.L.239.157; 3.L.239.166; 3.L.239.169; 3.L.239.172; 3.L.239.175;3.L.239.240; 3.L.239.244; 3.L.154.228; 3.L.154.229; 3.L.154.230; 3.L.154.231;3.L.154.236; 3.L.154.237; 3.L.154.238; 3.L.154.239; 3.L.154.154; 3.L.154.157;3.L.154.166; 3.L.154.169; 3.L.154.172; 3.L.154.175; 3.L.154.240; 3.L.154.244;3.L.157.228; 3.L.157.229; 3.L.157.230; 3.L.157.231; 3.L.157.236; 3.L.157.237;3.L.157.238; 3.L.157.239; 3.L.157.154; 3.L.157.157; 3.L.157.166; 3.L.157.169;3.L.157.172; 3.L.157.175; 3.L.157.240; 3.L.157.244; 3.L.166.228; 3.L.166.229;3.L.166.230; 3.L.166.231; 3.L.166.236; 3.L.166.237; 3.L.166.238; 3.L.166.239;3.L.166.154; 3.L.166.157; 3.L.166.166; 3.L.166.169; 3.L.166.172; 3.L.166.175;3.L.166.240; 3.L.166.244; 3.L.169.228; 3.L.169.229; 3.L.169.230; 3.L.169.231;3.L.169.236; 3.L.169.237; 3.L.169.238; 3.L.169.239; 3.L.169.154; 3.L.169.157;3.L.169.166; 3.L.169.169; 3.L.169.172; 3.L.169.175; 3.L.169.240; 3.L.169.244;3.L.172.228; 3.L.172.229; 3.L.172.230; 3.L.172.231; 3.L.172.236; 3.L.172.237;3.L.172.238; 3.L.172.239; 3.L.172.154; 3.L.172.157; 3.L.172.166; 3.L.172.169;3.L.172.172; 3.L.172.175; 3.L.172.240; 3.L.172.244; 3.L.175.228; 3.L.175.229;3.L.175.230; 3.L.175.231; 3.L.175.236; 3.L.175.237; 3.L.175.238; 3.L.175.239;3.L.175.154; 3.L.175.157; 3.L.175.166; 3.L.175.169; 3.L.175.172; 3.L.175.175;3.L.175.240; 3.L.175.244; 3.L.240.228; 3.L.240.229; 3.L.240.230; 3.L.240.231;3.L.240.236; 3.L.240.237; 3.L.240.238; 3.L.240.239; 3.L.240.154; 3.L.240.157;3.L.240.166; 3.L.240.169; 3.L.240.172; 3.L.240.175; 3.L.240.240; 3.L.240.244;3.L.244.228; 3.L.244.229; 3.L.244.230; 3.L.244.231; 3.L.244.236; 3.L.244.237;3.L.244.238; 3.L.244.239; 3.L.244.154; 3.L.244.157; 3.L.244.166; 3.L.244.169;3.L.244.172; 3.L.244.175; 3.L.244.240; 3.L.244.244;

3.Oのプロドラッグ
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.157.169;3.O.157.172; 3.O.157.175; 3.O.157.240; 3.O.157.244; 3.O.166.228; 3.O.166.229;3.O.166.230; 3.O.166.231; 3.O.166.236; 3.O.166.237; 3.O.166.238; 3.O.166.239;3.O.166.154; 3.O.166.157; 3.O.166.166; 3.O.166.169; 3.O.166.172; 3.O.166.175;3.O.166.240; 3.O.166.244; 3.O.169.228; 3.O.169.229; 3.O.169.230; 3.O.169.231;3.O.169.236; 3.O.169.237; 3.O.169.238; 3.O.169.239; 3.O.169.154; 3.O.169.157;3.O.169.166; 3.O.169.169; 3.O.169.172; 3.O.169.175; 3.O.169.240; 3.O.169.244;3.O.172.228; 3.O.172.229; 3.O.172.230; 3.O.172.231; 3.O.172.236; 3.O.172.237;3.O.172.238; 3.O.172.239; 3.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.240.157;3.O.240.166; 3.O.240.169; 3.O.240.172; 3.O.240.175; 3.O.240.240; 3.O.240.244;3.O.244.228; 3.O.244.229; 3.O.244.230; 3.O.244.231; 3.O.244.236; 3.O.244.237;3.O.244.238; 3.O.244.239; 3.O.244.154; 3.O.244.157; 3.O.244.166; 3.O.244.169;3.O.244.172; 3.O.244.175; 3.O.244.240; 3.O.244.244;

3.Pのプロドラッグ
3.P.228.228; 3.P.228.229; 3.P.228.230; 3.P.228.231; 3.P.228.236; 3.P.228.237;3.P.228.238; 3.P.228.239; 3.P.228.154; 3.P.228.157; 3.P.228.166; 3.P.228.169;3.P.228.172; 3.P.228.175; 3.P.228.240; 3.P.228.244; 3.P.229.228; 3.P.229.229;3.P.229.230; 3.P.229.231; 3.P.229.236; 3.P.229.237; 3.P.229.238; 3.P.229.239;3.P.229.154; 3.P.229.157; 3.P.229.166; 3.P.229.169; 3.P.229.172; 3.P.229.175;3.P.229.240; 3.P.229.244; 3.P.230.228; 3.P.230.229; 3.P.230.230; 3.P.230.231;3.P.230.236; 3.P.230.237; 3.P.230.238; 3.P.230.239; 3.P.230.154; 3.P.230.157;3.P.230.166; 3.P.230.169; 3.P.230.172; 3.P.230.175; 3.P.230.240; 3.P.230.244;3.P.231.228; 3.P.231.229; 3.P.231.230; 3.P.231.231; 3.P.231.236; 3.P.231.237;3.P.231.238; 3.P.231.239; 3.P.231.154; 3.P.231.157; 3.P.231.166; 3.P.231.169;3.P.231.172; 3.P.231.175; 3.P.231.240; 3.P.231.244; 3.P.236.228; 3.P.236.229;3.P.236.230; 3.P.236.231; 3.P.236.236; 3.P.236.237; 3.P.236.238; 3.P.236.239;3.P.236.154; 3.P.236.157; 3.P.236.166; 3.P.236.169; 3.P.236.172; 3.P.236.175;3.P.236.240; 3.P.236.244; 3.P.237.228; 3.P.237.229; 3.P.237.230; 3.P.237.231;3.P.237.236; 3.P.237.237; 3.P.237.238; 3.P.237.239; 3.P.237.154; 3.P.237.157;3.P.237.166; 3.P.237.169; 3.P.237.172; 3.P.237.175; 3.P.237.240; 3.P.237.244;3.P.238.228; 3.P.238.229; 3.P.238.230; 3.P.238.231; 3.P.238.236; 3.P.238.237;3.P.238.238; 3.P.238.239; 3.P.238.154; 3.P.238.157; 3.P.238.166; 3.P.238.169;3.P.238.172; 3.P.238.175; 3.P.238.240; 3.P.238.244; 3.P.239.228; 3.P.239.229;3.P.239.230; 3.P.239.231; 3.P.239.236; 3.P.239.237; 3.P.239.238; 3.P.239.239;3.P.239.154; 3.P.239.157; 3.P.239.166; 3.P.239.169; 3.P.239.172; 3.P.239.175;3.P.239.240; 3.P.239.244; 3.P.154.228; 3.P.154.229; 3.P.154.230; 3.P.154.231; 3.P.154.236;3.P.154.237; 3.P.154.238; 3.P.154.239; 3.P.154.154; 3.P.154.157; 3.P.154.166;3.P.154.169; 3.P.154.172; 3.P.154.175; 3.P.154.240; 3.P.154.244; 3.P.157.228;3.P.157.229; 3.P.157.230; 3.P.157.231; 3.P.157.236; 3.P.157.237; 3.P.157.238;3.P.157.239; 3.P.157.154; 3.P.157.157; 3.P.157.166; 3.P.157.169; 3.P.157.172;3.P.157.175; 3.P.157.240; 3.P.157.244; 3.P.166.228; 3.P.166.229; 3.P.166.230;3.P.166.231; 3.P.166.236; 3.P.166.237; 3.P.166.238; 3.P.166.239; 3.P.166.154;3.P.166.157; 3.P.166.166; 3.P.166.169; 3.P.166.172; 3.P.166.175; 3.P.166.240;3.P.166.244; 3.P.169.228; 3.P.169.229; 3.P.169.230; 3.P.169.231; 3.P.169.236;3.P.169.237; 3.P.169.238; 3.P.169.239; 3.P.169.154; 3.P.169.157; 3.P.169.166;3.P.169.169; 3.P.169.172; 3.P.169.175; 3.P.169.240; 3.P.169.244; 3.P.172.228;3.P.172.229; 3.P.172.230; 3.P.172.231; 3.P.172.236; 3.P.172.237; 3.P.172.238;3.P.172.239; 3.P.172.154; 3.P.172.157; 3.P.172.166; 3.P.172.169; 3.P.172.172;3.P.172.175; 3.P.172.240; 3.P.172.244; 3.P.175.228; 3.P.175.229; 3.P.175.230;3.P.175.231; 3.P.175.236; 3.P.175.237; 3.P.175.238; 3.P.175.239; 3.P.175.154;3.P.175.157; 3.P.175.166; 3.P.175.169; 3.P.175.172; 3.P.175.175; 3.P.175.240;3.P.175.244; 3.P.240.228; 3.P.240.229; 3.P.240.230; 3.P.240.231; 3.P.240.236;3.P.240.237; 3.P.240.238; 3.P.240.239; 3.P.240.154; 3.P.240.157; 3.P.240.166;3.P.240.169; 3.P.240.172; 3.P.240.175; 3.P.240.240; 3.P.240.244; 3.P.244.228;3.P.244.229; 3.P.244.230; 3.P.244.231; 3.P.244.236; 3.P.244.237; 3.P.244.238;3.P.244.239; 3.P.244.154; 3.P.244.157; 3.P.244.166; 3.P.244.169; 3.P.244.172;3.P.244.175; 3.P.244.240; 3.P.244.244;

3.Uのプロドラッグ
3.U.228.228; 3.U.228.229; 3.U.228.230; 3.U.228.231; 3.U.228.236; 3.U.228.237;3.U.228.238; 3.U.228.239; 3.U.228.154; 3.U.228.157; 3.U.228.166; 3.U.228.169;3.U.228.172; 3.U.228.175; 3.U.228.240; 3.U.228.244; 3.U.229.228; 3.U.229.229;3.U.229.230; 3.U.229.231; 3.U.229.236; 3.U.229.237; 3.U.229.238; 3.U.229.239;3.U.229.154; 3.U.229.157; 3.U.229.166; 3.U.229.169; 3.U.229.172; 3.U.229.175;3.U.229.240; 3.U.229.244; 3.U.230.228; 3.U.230.229; 3.U.230.230; 3.U.230.231;3.U.230.236; 3.U.230.237; 3.U.230.238; 3.U.230.239; 3.U.230.154; 3.U.230.157;3.U.230.166; 3.U.230.169; 3.U.230.172; 3.U.230.175; 3.U.230.240; 3.U.230.244;3.U.231.228; 3.U.231.229; 3.U.231.230; 3.U.231.231; 3.U.231.236; 3.U.231.237;3.U.231.238; 3.U.231.239; 3.U.231.154; 3.U.231.157; 3.U.231.166; 3.U.231.169;3.U.231.172; 3.U.231.175; 3.U.231.240; 3.U.231.244; 3.U.236.228; 3.U.236.229;3.U.236.230; 3.U.236.231; 3.U.236.236; 3.U.236.237; 3.U.236.238; 3.U.236.239;3.U.236.154; 3.U.236.157; 3.U.236.166; 3.U.236.169; 3.U.236.172; 3.U.236.175;3.U.236.240; 3.U.236.244; 3.U.237.228; 3.U.237.229; 3.U.237.230; 3.U.237.231;3.U.237.236; 3.U.237.237; 3.U.237.238; 3.U.237.239; 3.U.237.154; 3.U.237.157;3.U.237.166; 3.U.237.169; 3.U.237.172; 3.U.237.175; 3.U.237.240; 3.U.237.244;3.U.238.228; 3.U.238.229; 3.U.238.230; 3.U.238.231; 3.U.238.236; 3.U.238.237;3.U.238.238; 3.U.238.239; 3.U.238.154; 3.U.238.157; 3.U.238.166; 3.U.238.169;3.U.238.172; 3.U.238.175; 3.U.238.240; 3.U.238.244; 3.U.239.228; 3.U.239.229;3.U.239.230; 3.U.239.231; 3.U.239.236; 3.U.239.237; 3.U.239.238; 3.U.239.239;3.U.239.154; 3.U.239.157; 3.U.239.166; 3.U.239.169; 3.U.239.172; 3.U.239.175;3.U.239.240; 3.U.239.244; 3.U.154.228; 3.U.154.229; 3.U.154.230; 3.U.154.231;3.U.154.236; 3.U.154.237; 3.U.154.238; 3.U.154.239; 3.U.154.154; 3.U.154.157;3.U.154.166; 3.U.154.169; 3.U.154.172; 3.U.154.175; 3.U.154.240; 3.U.154.244;3.U.157.228; 3.U.157.229; 3.U.157.230; 3.U.157.231; 3.U.157.236; 3.U.157.237;3.U.157.238; 3.U.157.239; 3.U.157.154; 3.U.157.157; 3.U.157.166; 3.U.157.169;3.U.157.172; 3.U.157.175; 3.U.157.240; 3.U.157.244; 3.U.166.228; 3.U.166.229;3.U.166.230; 3.U.166.231; 3.U.166.236; 3.U.166.237; 3.U.166.238; 3.U.166.239;3.U.166.154; 3.U.166.157; 3.U.166.166; 3.U.166.169; 3.U.166.172; 3.U.166.175;3.U.166.240; 3.U.166.244; 3.U.169.228; 3.U.169.229; 3.U.169.230; 3.U.169.231;3.U.169.236; 3.U.169.237; 3.U.169.238; 3.U.169.239; 3.U.169.154; 3.U.169.157;3.U.169.166; 3.U.169.169; 3.U.169.172; 3.U.169.175; 3.U.169.240; 3.U.169.244;3.U.172.228; 3.U.172.229; 3.U.172.230; 3.U.172.231; 3.U.172.236; 3.U.172.237;3.U.172.238; 3.U.172.239; 3.U.172.154; 3.U.172.157; 3.U.172.166; 3.U.172.169;3.U.172.172; 3.U.172.175; 3.U.172.240; 3.U.172.244; 3.U.175.228; 3.U.175.229;3.U.175.230; 3.U.175.231; 3.U.175.236; 3.U.175.237; 3.U.175.238; 3.U.175.239;3.U.175.154; 3.U.175.157; 3.U.175.166; 3.U.175.169; 3.U.175.172; 3.U.175.175;3.U.175.240; 3.U.175.244; 3.U.240.228; 3.U.240.229; 3.U.240.230; 3.U.240.231;3.U.240.236; 3.U.240.237; 3.U.240.238; 3.U.240.239; 3.U.240.154; 3.U.240.157;3.U.240.166; 3.U.240.169; 3.U.240.172; 3.U.240.175; 3.U.240.240; 3.U.240.244;3.U.244.228; 3.U.244.229; 3.U.244.230; 3.U.244.231; 3.U.244.236; 3.U.244.237;3.U.244.238; 3.U.244.239; 3.U.244.154; 3.U.244.157; 3.U.244.166; 3.U.244.169;3.U.244.172; 3.U.244.175; 3.U.244.240; 3.U.244.244;

3.Wのプロドラッグ
3.W.228.228; 3.W.228.229; 3.W.228.230; 3.W.228.231; 3.W.228.236; 3.W.228.237;3.W.228.238; 3.W.228.239; 3.W.228.154; 3.W.228.157; 3.W.228.166; 3.W.228.169;3.W.228.172; 3.W.228.175; 3.W.228.240; 3.W.228.244; 3.W.229.228; 3.W.229.229;3.W.229.230; 3.W.229.231; 3.W.229.236; 3.W.229.237; 3.W.229.238; 3.W.229.239;3.W.229.154; 3.W.229.157; 3.W.229.166; 3.W.229.169; 3.W.229.172; 3.W.229.175;3.W.229.240; 3.W.229.244; 3.W.230.228; 3.W.230.229; 3.W.230.230; 3.W.230.231;3.W.230.236; 3.W.230.237; 3.W.230.238; 3.W.230.239; 3.W.230.154; 3.W.230.157;3.W.230.166; 3.W.230.169; 3.W.230.172; 3.W.230.175; 3.W.230.240; 3.W.230.244;3.W.231.228; 3.W.231.229; 3.W.231.230; 3.W.231.231; 3.W.231.236; 3.W.231.237;3.W.231.238; 3.W.231.239; 3.W.231.154; 3.W.231.157; 3.W.231.166; 3.W.231.169;3.W.231.172; 3.W.231.175; 3.W.231.240; 3.W.231.244; 3.W.236.228; 3.W.236.229;3.W.236.230; 3.W.236.231; 3.W.236.236; 3.W.236.237; 3.W.236.238; 3.W.236.239;3.W.236.154; 3.W.236.157; 3.W.236.166; 3.W.236.169; 3.W.236.172; 3.W.236.175;3.W.236.240; 3.W.236.244; 3.W.237.228; 3.W.237.229; 3.W.237.230; 3.W.237.231;3.W.237.236; 3.W.237.237; 3.W.237.238; 3.W.237.239; 3.W.237.154; 3.W.237.157;3.W.237.166; 3.W.237.169; 3.W.237.172; 3.W.237.175; 3.W.237.240; 3.W.237.244;3.W.238.228; 3.W.238.229; 3.W.238.230; 3.W.238.231; 3.W.238.236; 3.W.238.237;3.W.238.238; 3.W.238.239; 3.W.238.154; 3.W.238.157; 3.W.238.166; 3.W.238.169;3.W.238.172; 3.W.238.175; 3.W.238.240; 3.W.238.244; 3.W.239.228; 3.W.239.229;3.W.239.230; 3.W.239.231; 3.W.239.236; 3.W.239.237; 3.W.239.238; 3.W.239.239;3.W.239.154; 3.W.239.157; 3.W.239.166; 3.W.239.169; 3.W.239.172; 3.W.239.175;3.W.239.240; 3.W.239.244; 3.W.154.228; 3.W.154.229; 3.W.154.230; 3.W.154.231;3.W.154.236; 3.W.154.237; 3.W.154.238; 3.W.154.239; 3.W.154.154; 3.W.154.157;3.W.154.166; 3.W.154.169; 3.W.154.172; 3.W.154.175; 3.W.154.240; 3.W.154.244;3.W.157.228; 3.W.157.229; 3.W.157.230; 3.W.157.231; 3.W.157.236; 3.W.157.237;3.W.157.238; 3.W.157.239; 3.W.157.154; 3.W.157.157; 3.W.157.166; 3.W.157.169;3.W.157.172; 3.W.157.175; 3.W.157.240; 3.W.157.244; 3.W.166.228; 3.W.166.229;3.W.166.230; 3.W.166.231; 3.W.166.236; 3.W.166.237; 3.W.166.238; 3.W.166.239;3.W.166.154; 3.W.166.157; 3.W.166.166; 3.W.166.169; 3.W.166.172; 3.W.166.175;3.W.166.240; 3.W.166.244; 3.W.169.228; 3.W.169.229; 3.W.169.230; 3.W.169.231;3.W.169.236; 3.W.169.237; 3.W.169.238; 3.W.169.239; 3.W.169.154; 3.W.169.157;3.W.169.166; 3.W.169.169; 3.W.169.172; 3.W.169.175; 3.W.169.240; 3.W.169.244;3.W.172.228; 3.W.172.229; 3.W.172.230; 3.W.172.231; 3.W.172.236; 3.W.172.237;3.W.172.238; 3.W.172.239; 3.W.172.154; 3.W.172.157; 3.W.172.166; 3.W.172.169;3.W.172.172; 3.W.172.175; 3.W.172.240; 3.W.172.244; 3.W.175.228; 3.W.175.229;3.W.175.230; 3.W.175.231; 3.W.175.236; 3.W.175.237; 3.W.175.238; 3.W.175.239;3.W.175.154; 3.W.175.157; 3.W.175.166; 3.W.175.169; 3.W.175.172; 3.W.175.175;3.W.175.240; 3.W.175.244; 3.W.240.228; 3.W.240.229; 3.W.240.230; 3.W.240.231;3.W.240.236; 3.W.240.237; 3.W.240.238; 3.W.240.239; 3.W.240.154; 3.W.240.157;3.W.240.166; 3.W.240.169; 3.W.240.172; 3.W.240.175; 3.W.240.240; 3.W.240.244;3.W.244.228; 3.W.244.229; 3.W.244.230; 3.W.244.231; 3.W.244.236; 3.W.244.237;3.W.244.238; 3.W.244.239; 3.W.244.154; 3.W.244.157; 3.W.244.166; 3.W.244.169;3.W.244.172; 3.W.244.175; 3.W.244.240; 3.W.244.244;

3.Yのプロドラッグ
3.Y.228.228; 3.Y.228.229; 3.Y.228.230; 3.Y.228.231; 3.Y.228.236; 3.Y.228.237;3.Y.228.238; 3.Y.228.239; 3.Y.228.154; 3.Y.228.157; 3.Y.228.166; 3.Y.228.169;3.Y.228.172; 3.Y.228.175; 3.Y.228.240; 3.Y.228.244; 3.Y.229.228; 3.Y.229.229;3.Y.229.230; 3.Y.229.231; 3.Y.229.236; 3.Y.229.237; 3.Y.229.238; 3.Y.229.239;3.Y.229.154; 3.Y.229.157; 3.Y.229.166; 3.Y.229.169; 3.Y.229.172; 3.Y.229.175;3.Y.229.240; 3.Y.229.244; 3.Y.230.228; 3.Y.230.229; 3.Y.230.230; 3.Y.230.231;3.Y.230.236; 3.Y.230.237; 3.Y.230.238; 3.Y.230.239; 3.Y.230.154; 3.Y.230.157;3.Y.230.166; 3.Y.230.169; 3.Y.230.172; 3.Y.230.175; 3.Y.230.240; 3.Y.230.244;3.Y.231.228; 3.Y.231.229; 3.Y.231.230; 3.Y.231.231; 3.Y.231.236; 3.Y.231.237;3.Y.231.238; 3.Y.231.239; 3.Y.231.154; 3.Y.231.157; 3.Y.231.166; 3.Y.231.169;3.Y.231.172; 3.Y.231.175; 3.Y.231.240; 3.Y.231.244; 3.Y.236.228; 3.Y.236.229;3.Y.236.230; 3.Y.236.231; 3.Y.236.236; 3.Y.236.237; 3.Y.236.238; 3.Y.236.239;3.Y.236.154; 3.Y.236.157; 3.Y.236.166; 3.Y.236.169; 3.Y.236.172; 3.Y.236.175;3.Y.236.240; 3.Y.236.244; 3.Y.237.228; 3.Y.237.229; 3.Y.237.230; 3.Y.237.231;3.Y.237.236; 3.Y.237.237; 3.Y.237.238; 3.Y.237.239; 3.Y.237.154; 3.Y.237.157;3.Y.237.166; 3.Y.237.169; 3.Y.237.172; 3.Y.237.175; 3.Y.237.240; 3.Y.237.244;3.Y.238.228; 3.Y.238.229; 3.Y.238.230; 3.Y.238.231; 3.Y.238.236; 3.Y.238.237;3.Y.238.238; 3.Y.238.239; 3.Y.238.154; 3.Y.238.157; 3.Y.238.166; 3.Y.238.169; 3.Y.238.172;3.Y.238.175; 3.Y.238.240; 3.Y.238.244; 3.Y.239.228; 3.Y.239.229; 3.Y.239.230;3.Y.239.231; 3.Y.239.236; 3.Y.239.237; 3.Y.239.238; 3.Y.239.239; 3.Y.239.154;3.Y.239.157; 3.Y.239.166; 3.Y.239.169; 3.Y.239.172; 3.Y.239.175; 3.Y.239.240;3.Y.239.244; 3.Y.154.228; 3.Y.154.229; 3.Y.154.230; 3.Y.154.231; 3.Y.154.236;3.Y.154.237; 3.Y.154.238; 3.Y.154.239; 3.Y.154.154; 3.Y.154.157; 3.Y.154.166;3.Y.154.169; 3.Y.154.172; 3.Y.154.175; 3.Y.154.240; 3.Y.154.244; 3.Y.157.228;3.Y.157.229; 3.Y.157.230; 3.Y.157.231; 3.Y.157.236; 3.Y.157.237; 3.Y.157.238;3.Y.157.239; 3.Y.157.154; 3.Y.157.157; 3.Y.157.166; 3.Y.157.169; 3.Y.157.172;3.Y.157.175; 3.Y.157.240; 3.Y.157.244; 3.Y.166.228; 3.Y.166.229; 3.Y.166.230;3.Y.166.231; 3.Y.166.236; 3.Y.166.237; 3.Y.166.238; 3.Y.166.239; 3.Y.166.154;3.Y.166.157; 3.Y.166.166; 3.Y.166.169; 3.Y.166.172; 3.Y.166.175; 3.Y.166.240;3.Y.166.244; 3.Y.169.228; 3.Y.169.229; 3.Y.169.230; 3.Y.169.231; 3.Y.169.236;3.Y.169.237; 3.Y.169.238; 3.Y.169.239; 3.Y.169.154; 3.Y.169.157; 3.Y.169.166;3.Y.169.169; 3.Y.169.172; 3.Y.169.175; 3.Y.169.240; 3.Y.169.244; 3.Y.172.228;3.Y.172.229; 3.Y.172.230; 3.Y.172.231; 3.Y.172.236; 3.Y.172.237; 3.Y.172.238;3.Y.172.239; 3.Y.172.154; 3.Y.172.157; 3.Y.172.166; 3.Y.172.169; 3.Y.172.172;3.Y.172.175; 3.Y.172.240; 3.Y.172.244; 3.Y.175.228; 3.Y.175.229; 3.Y.175.230;3.Y.175.231; 3.Y.175.236; 3.Y.175.237; 3.Y.175.238; 3.Y.175.239; 3.Y.175.154;3.Y.175.157; 3.Y.175.166; 3.Y.175.169; 3.Y.175.172; 3.Y.175.175; 3.Y.175.240;3.Y.175.244; 3.Y.240.228; 3.Y.240.229; 3.Y.240.230; 3.Y.240.231; 3.Y.240.236;3.Y.240.237; 3.Y.240.238; 3.Y.240.239; 3.Y.240.154; 3.Y.240.157; 3.Y.240.166;3.Y.240.169; 3.Y.240.172; 3.Y.240.175; 3.Y.240.240; 3.Y.240.244; 3.Y.244.228;3.Y.244.229; 3.Y.244.230; 3.Y.244.231; 3.Y.244.236; 3.Y.244.237; 3.Y.244.238;3.Y.244.239; 3.Y.244.154; 3.Y.244.157; 3.Y.244.166; 3.Y.244.169; 3.Y.244.172;3.Y.244.175; 3.Y.244.240; 3.Y.244.244;

4.Bのプロドラッグ
4.B.228.228; 4.B.228.229; 4.B.228.230; 4.B.228.231; 4.B.228.236; 4.B.228.237;4.B.228.238; 4.B.228.239; 4.B.228.154; 4.B.228.157; 4.B.228.166; 4.B.228.169;4.B.228.172; 4.B.228.175; 4.B.228.240; 4.B.228.244; 4.B.229.228; 4.B.229.229;4.B.229.230; 4.B.229.231; 4.B.229.236; 4.B.229.237; 4.B.229.238; 4.B.229.239;4.B.229.154; 4.B.229.157; 4.B.229.166; 4.B.229.169; 4.B.229.172; 4.B.229.175;4.B.229.240; 4.B.229.244; 4.B.230.228; 4.B.230.229; 4.B.230.230; 4.B.230.231;4.B.230.236; 4.B.230.237; 4.B.230.238; 4.B.230.239; 4.B.230.154; 4.B.230.157;4.B.230.166; 4.B.230.169; 4.B.230.172; 4.B.230.175; 4.B.230.240; 4.B.230.244;4.B.231.228; 4.B.231.229; 4.B.231.230; 4.B.231.231; 4.B.231.236; 4.B.231.237;4.B.231.238; 4.B.231.239; 4.B.231.154; 4.B.231.157; 4.B.231.166; 4.B.231.169;4.B.231.172; 4.B.231.175; 4.B.231.240; 4.B.231.244; 4.B.236.228; 4.B.236.229;4.B.236.230; 4.B.236.231; 4.B.236.236; 4.B.236.237; 4.B.236.238; 4.B.236.239;4.B.236.154; 4.B.236.157; 4.B.236.166; 4.B.236.169; 4.B.236.172; 4.B.236.175;4.B.236.240; 4.B.236.244; 4.B.237.228; 4.B.237.229; 4.B.237.230; 4.B.237.231;4.B.237.236; 4.B.237.237; 4.B.237.238; 4.B.237.239; 4.B.237.154; 4.B.237.157;4.B.237.166; 4.B.237.169; 4.B.237.172; 4.B.237.175; 4.B.237.240; 4.B.237.244;4.B.238.228; 4.B.238.229; 4.B.238.230; 4.B.238.231; 4.B.238.236; 4.B.238.237;4.B.238.238; 4.B.238.239; 4.B.238.154; 4.B.238.157; 4.B.238.166; 4.B.238.169;4.B.238.172; 4.B.238.175; 4.B.238.240; 4.B.238.244; 4.B.239.228; 4.B.239.229;4.B.239.230; 4.B.239.231; 4.B.239.236; 4.B.239.237; 4.B.239.238; 4.B.239.239;4.B.239.154; 4.B.239.157; 4.B.239.166; 4.B.239.169; 4.B.239.172; 4.B.239.175;4.B.239.240; 4.B.239.244; 4.B.154.228; 4.B.154.229; 4.B.154.230; 4.B.154.231;4.B.154.236; 4.B.154.237; 4.B.154.238; 4.B.154.239; 4.B.154.154; 4.B.154.157;4.B.154.166; 4.B.154.169; 4.B.154.172; 4.B.154.175; 4.B.154.240; 4.B.154.244;4.B.157.228; 4.B.157.229; 4.B.157.230; 4.B.157.231; 4.B.157.236; 4.B.157.237;4.B.157.238; 4.B.157.239; 4.B.157.154; 4.B.157.157; 4.B.157.166; 4.B.157.169;4.B.157.172; 4.B.157.175; 4.B.157.240; 4.B.157.244; 4.B.166.228; 4.B.166.229;4.B.166.230; 4.B.166.231; 4.B.166.236; 4.B.166.237; 4.B.166.238; 4.B.166.239;4.B.166.154; 4.B.166.157; 4.B.166.166; 4.B.166.169; 4.B.166.172; 4.B.166.175;4.B.166.240; 4.B.166.244; 4.B.169.228; 4.B.169.229; 4.B.169.230; 4.B.169.231; 4.B.169.236;4.B.169.237; 4.B.169.238; 4.B.169.239; 4.B.169.154; 4.B.169.157; 4.B.169.166;4.B.169.169; 4.B.169.172; 4.B.169.175; 4.B.169.240; 4.B.169.244; 4.B.172.228;4.B.172.229; 4.B.172.230; 4.B.172.231; 4.B.172.236; 4.B.172.237; 4.B.172.238;4.B.172.239; 4.B.172.154; 4.B.172.157; 4.B.172.166; 4.B.172.169; 4.B.172.172;4.B.172.175; 4.B.172.240; 4.B.172.244; 4.B.175.228; 4.B.175.229; 4.B.175.230;4.B.175.231; 4.B.175.236; 4.B.175.237; 4.B.175.238; 4.B.175.239; 4.B.175.154;4.B.175.157; 4.B.175.166; 4.B.175.169; 4.B.175.172; 4.B.175.175; 4.B.175.240;4.B.175.244; 4.B.240.228; 4.B.240.229; 4.B.240.230; 4.B.240.231; 4.B.240.236;4.B.240.237; 4.B.240.238; 4.B.240.239; 4.B.240.154; 4.B.240.157; 4.B.240.166;4.B.240.169; 4.B.240.172; 4.B.240.175; 4.B.240.240; 4.B.240.244; 4.B.244.228;4.B.244.229; 4.B.244.230; 4.B.244.231; 4.B.244.236; 4.B.244.237; 4.B.244.238;4.B.244.239; 4.B.244.154; 4.B.244.157; 4.B.244.166; 4.B.244.169; 4.B.244.172;4.B.244.175; 4.B.244.240; 4.B.244.244;

4.Dのプロドラッグ
4.D.228.228; 4.D.228.229; 4.D.228.230; 4.D.228.231; 4.D.228.236; 4.D.228.237;4.D.228.238; 4.D.228.239; 4.D.228.154; 4.D.228.157; 4.D.228.166; 4.D.228.169;4.D.228.172; 4.D.228.175; 4.D.228.240; 4.D.228.244; 4.D.229.228; 4.D.229.229;4.D.229.230; 4.D.229.231; 4.D.229.236; 4.D.229.237; 4.D.229.238; 4.D.229.239;4.D.229.154; 4.D.229.157; 4.D.229.166; 4.D.229.169; 4.D.229.172; 4.D.229.175;4.D.229.240; 4.D.229.244; 4.D.230.228; 4.D.230.229; 4.D.230.230; 4.D.230.231;4.D.230.236; 4.D.230.237; 4.D.230.238; 4.D.230.239; 4.D.230.154; 4.D.230.157;4.D.230.166; 4.D.230.169; 4.D.230.172; 4.D.230.175; 4.D.230.240; 4.D.230.244;4.D.231.228; 4.D.231.229; 4.D.231.230; 4.D.231.231; 4.D.231.236; 4.D.231.237;4.D.231.238; 4.D.231.239; 4.D.231.154; 4.D.231.157; 4.D.231.166; 4.D.231.169;4.D.231.172; 4.D.231.175; 4.D.231.240; 4.D.231.244; 4.D.236.228; 4.D.236.229;4.D.236.230; 4.D.236.231; 4.D.236.236; 4.D.236.237; 4.D.236.238; 4.D.236.239;4.D.236.154; 4.D.236.157; 4.D.236.166; 4.D.236.169; 4.D.236.172; 4.D.236.175;4.D.236.240; 4.D.236.244; 4.D.237.228; 4.D.237.229; 4.D.237.230; 4.D.237.231;4.D.237.236; 4.D.237.237; 4.D.237.238; 4.D.237.239; 4.D.237.154; 4.D.237.157;4.D.237.166; 4.D.237.169; 4.D.237.172; 4.D.237.175; 4.D.237.240; 4.D.237.244;4.D.238.228; 4.D.238.229; 4.D.238.230; 4.D.238.231; 4.D.238.236; 4.D.238.237;4.D.238.238; 4.D.238.239; 4.D.238.154; 4.D.238.157; 4.D.238.166; 4.D.238.169;4.D.238.172; 4.D.238.175; 4.D.238.240; 4.D.238.244; 4.D.239.228; 4.D.239.229;4.D.239.230; 4.D.239.231; 4.D.239.236; 4.D.239.237; 4.D.239.238; 4.D.239.239;4.D.239.154; 4.D.239.157; 4.D.239.166; 4.D.239.169; 4.D.239.172; 4.D.239.175;4.D.239.240; 4.D.239.244; 4.D.154.228; 4.D.154.229; 4.D.154.230; 4.D.154.231;4.D.154.236; 4.D.154.237; 4.D.154.238; 4.D.154.239; 4.D.154.154; 4.D.154.157;4.D.154.166; 4.D.154.169; 4.D.154.172; 4.D.154.175; 4.D.154.240; 4.D.154.244;4.D.157.228; 4.D.157.229; 4.D.157.230; 4.D.157.231; 4.D.157.236; 4.D.157.237;4.D.157.238; 4.D.157.239; 4.D.157.154; 4.D.157.157; 4.D.157.166; 4.D.157.169;4.D.157.172; 4.D.157.175; 4.D.157.240; 4.D.157.244; 4.D.166.228; 4.D.166.229;4.D.166.230; 4.D.166.231; 4.D.166.236; 4.D.166.237; 4.D.166.238; 4.D.166.239;4.D.166.154; 4.D.166.157; 4.D.166.166; 4.D.166.169; 4.D.166.172; 4.D.166.175;4.D.166.240; 4.D.166.244; 4.D.169.228; 4.D.169.229; 4.D.169.230; 4.D.169.231;4.D.169.236; 4.D.169.237; 4.D.169.238; 4.D.169.239; 4.D.169.154; 4.D.169.157;4.D.169.166; 4.D.169.169; 4.D.169.172; 4.D.169.175; 4.D.169.240; 4.D.169.244;4.D.172.228; 4.D.172.229; 4.D.172.230; 4.D.172.231; 4.D.172.236; 4.D.172.237;4.D.172.238; 4.D.172.239; 4.D.172.154; 4.D.172.157; 4.D.172.166; 4.D.172.169;4.D.172.172; 4.D.172.175; 4.D.172.240; 4.D.172.244; 4.D.175.228; 4.D.175.229;4.D.175.230; 4.D.175.231; 4.D.175.236; 4.D.175.237; 4.D.175.238; 4.D.175.239;4.D.175.154; 4.D.175.157; 4.D.175.166; 4.D.175.169; 4.D.175.172; 4.D.175.175;4.D.175.240; 4.D.175.244; 4.D.240.228; 4.D.240.229; 4.D.240.230; 4.D.240.231;4.D.240.236; 4.D.240.237; 4.D.240.238; 4.D.240.239; 4.D.240.154; 4.D.240.157;4.D.240.166; 4.D.240.169; 4.D.240.172; 4.D.240.175; 4.D.240.240; 4.D.240.244;4.D.244.228; 4.D.244.229; 4.D.244.230; 4.D.244.231; 4.D.244.236; 4.D.244.237;4.D.244.238; 4.D.244.239; 4.D.244.154; 4.D.244.157; 4.D.244.166; 4.D.244.169;4.D.244.172; 4.D.244.175; 4.D.244.240; 4.D.244.244;

4.Eのプロドラッグ
4.E.228.228;4.E.228.229; 4.E.228.230; 4.E.228.231; 4.E.228.236; 4.E.228.237; 4.E.228.238;4.E.228.239; 4.E.228.154; 4.E.228.157; 4.E.228.166; 4.E.228.169; 4.E.228.172;4.E.228.175; 4.E.228.240; 4.E.228.244; 4.E.229.228; 4.E.229.229; 4.E.229.230;4.E.229.231; 4.E.229.236; 4.E.229.237; 4.E.229.238; 4.E.229.239; 4.E.229.154;4.E.229.157; 4.E.229.166; 4.E.229.169; 4.E.229.172; 4.E.229.175; 4.E.229.240;4.E.229.244; 4.E.230.228; 4.E.230.229; 4.E.230.230; 4.E.230.231; 4.E.230.236;4.E.230.237; 4.E.230.238; 4.E.230.239; 4.E.230.154; 4.E.230.157; 4.E.230.166;4.E.230.169; 4.E.230.172; 4.E.230.175; 4.E.230.240; 4.E.230.244; 4.E.231.228;4.E.231.229; 4.E.231.230; 4.E.231.231; 4.E.231.236; 4.E.231.237; 4.E.231.238;4.E.231.239; 4.E.231.154; 4.E.231.157; 4.E.231.166; 4.E.231.169; 4.E.231.172;4.E.231.175; 4.E.231.240; 4.E.231.244; 4.E.236.228; 4.E.236.229; 4.E.236.230;4.E.236.231; 4.E.236.236; 4.E.236.237; 4.E.236.238; 4.E.236.239; 4.E.236.154;4.E.236.157; 4.E.236.166; 4.E.236.169; 4.E.236.172; 4.E.236.175; 4.E.236.240;4.E.236.244; 4.E.237.228; 4.E.237.229; 4.E.237.230; 4.E.237.231; 4.E.237.236;4.E.237.237; 4.E.237.238; 4.E.237.239; 4.E.237.154; 4.E.237.157; 4.E.237.166;4.E.237.169; 4.E.237.172; 4.E.237.175; 4.E.237.240; 4.E.237.244; 4.E.238.228;4.E.238.229; 4.E.238.230; 4.E.238.231; 4.E.238.236; 4.E.238.237; 4.E.238.238;4.E.238.239; 4.E.238.154; 4.E.238.157; 4.E.238.166; 4.E.238.169; 4.E.238.172;4.E.238.175; 4.E.238.240; 4.E.238.244; 4.E.239.228; 4.E.239.229; 4.E.239.230;4.E.239.231; 4.E.239.236; 4.E.239.237; 4.E.239.238; 4.E.239.239; 4.E.239.154;4.E.239.157; 4.E.239.166; 4.E.239.169; 4.E.239.172; 4.E.239.175; 4.E.239.240;4.E.239.244; 4.E.154.228; 4.E.154.229; 4.E.154.230; 4.E.154.231; 4.E.154.236;4.E.154.237; 4.E.154.238; 4.E.154.239; 4.E.154.154; 4.E.154.157; 4.E.154.166;4.E.154.169; 4.E.154.172; 4.E.154.175; 4.E.154.240; 4.E.154.244; 4.E.157.228;4.E.157.229; 4.E.157.230; 4.E.157.231; 4.E.157.236; 4.E.157.237; 4.E.157.238;4.E.157.239; 4.E.157.154; 4.E.157.157; 4.E.157.166; 4.E.157.169; 4.E.157.172;4.E.157.175; 4.E.157.240; 4.E.157.244; 4.E.166.228; 4.E.166.229; 4.E.166.230;4.E.166.231; 4.E.166.236; 4.E.166.237; 4.E.166.238; 4.E.166.239; 4.E.166.154;4.E.166.157; 4.E.166.166; 4.E.166.169; 4.E.166.172; 4.E.166.175; 4.E.166.240;4.E.166.244; 4.E.169.228; 4.E.169.229; 4.E.169.230; 4.E.169.231; 4.E.169.236;4.E.169.237; 4.E.169.238; 4.E.169.239; 4.E.169.154; 4.E.169.157; 4.E.169.166;4.E.169.169; 4.E.169.172; 4.E.169.175; 4.E.169.240; 4.E.169.244; 4.E.172.228;4.E.172.229; 4.E.172.230; 4.E.172.231; 4.E.172.236; 4.E.172.237; 4.E.172.238;4.E.172.239; 4.E.172.154; 4.E.172.157; 4.E.172.166; 4.E.172.169; 4.E.172.172;4.E.172.175; 4.E.172.240; 4.E.172.244; 4.E.175.228; 4.E.175.229; 4.E.175.230;4.E.175.231; 4.E.175.236; 4.E.175.237; 4.E.175.238; 4.E.175.239; 4.E.175.154;4.E.175.157; 4.E.175.166; 4.E.175.169; 4.E.175.172; 4.E.175.175; 4.E.175.240;4.E.175.244; 4.E.240.228; 4.E.240.229; 4.E.240.230; 4.E.240.231; 4.E.240.236;4.E.240.237; 4.E.240.238; 4.E.240.239; 4.E.240.154; 4.E.240.157; 4.E.240.166;4.E.240.169; 4.E.240.172; 4.E.240.175; 4.E.240.240; 4.E.240.244; 4.E.244.228;4.E.244.229; 4.E.244.230; 4.E.244.231; 4.E.244.236; 4.E.244.237; 4.E.244.238;4.E.244.239; 4.E.244.154; 4.E.244.157; 4.E.244.166; 4.E.244.169; 4.E.244.172;4.E.244.175; 4.E.244.240; 4.E.244.244;

4.Gのプロドラッグ
4.G.228.228; 4.G.228.229; 4.G.228.230; 4.G.228.231; 4.G.228.236; 4.G.228.237;4.G.228.238; 4.G.228.239; 4.G.228.154; 4.G.228.157; 4.G.228.166; 4.G.228.169;4.G.228.172; 4.G.228.175; 4.G.228.240; 4.G.228.244; 4.G.229.228; 4.G.229.229;4.G.229.230; 4.G.229.231; 4.G.229.236; 4.G.229.237; 4.G.229.238; 4.G.229.239;4.G.229.154; 4.G.229.157; 4.G.229.166; 4.G.229.169; 4.G.229.172; 4.G.229.175;4.G.229.240; 4.G.229.244; 4.G.230.228; 4.G.230.229; 4.G.230.230; 4.G.230.231;4.G.230.236; 4.G.230.237; 4.G.230.238; 4.G.230.239; 4.G.230.154; 4.G.230.157;4.G.230.166; 4.G.230.169; 4.G.230.172; 4.G.230.175; 4.G.230.240; 4.G.230.244;4.G.231.228; 4.G.231.229; 4.G.231.230; 4.G.231.231; 4.G.231.236; 4.G.231.237;4.G.231.238; 4.G.231.239; 4.G.231.154; 4.G.231.157; 4.G.231.166; 4.G.231.169;4.G.231.172; 4.G.231.175; 4.G.231.240; 4.G.231.244; 4.G.236.228; 4.G.236.229;4.G.236.230; 4.G.236.231; 4.G.236.236; 4.G.236.237; 4.G.236.238; 4.G.236.239;4.G.236.154; 4.G.236.157; 4.G.236.166; 4.G.236.169; 4.G.236.172; 4.G.236.175;4.G.236.240; 4.G.236.244; 4.G.237.228; 4.G.237.229; 4.G.237.230; 4.G.237.231;4.G.237.236; 4.G.237.237; 4.G.237.238; 4.G.237.239; 4.G.237.154; 4.G.237.157;4.G.237.166; 4.G.237.169; 4.G.237.172; 4.G.237.175; 4.G.237.240; 4.G.237.244;4.G.238.228; 4.G.238.229; 4.G.238.230; 4.G.238.231; 4.G.238.236; 4.G.238.237;4.G.238.238; 4.G.238.239; 4.G.238.154; 4.G.238.157; 4.G.238.166; 4.G.238.169;4.G.238.172; 4.G.238.175; 4.G.238.240; 4.G.238.244; 4.G.239.228; 4.G.239.229;4.G.239.230; 4.G.239.231; 4.G.239.236; 4.G.239.237; 4.G.239.238; 4.G.239.239;4.G.239.154; 4.G.239.157; 4.G.239.166; 4.G.239.169; 4.G.239.172; 4.G.239.175;4.G.239.240; 4.G.239.244; 4.G.154.228; 4.G.154.229; 4.G.154.230; 4.G.154.231;4.G.154.236; 4.G.154.237; 4.G.154.238; 4.G.154.239; 4.G.154.154; 4.G.154.157;4.G.154.166; 4.G.154.169; 4.G.154.172; 4.G.154.175; 4.G.154.240; 4.G.154.244;4.G.157.228; 4.G.157.229; 4.G.157.230; 4.G.157.231; 4.G.157.236; 4.G.157.237;4.G.157.238; 4.G.157.239; 4.G.157.154; 4.G.157.157; 4.G.157.166; 4.G.157.169; 4.G.157.172;4.G.157.175; 4.G.157.240; 4.G.157.244; 4.G.166.228; 4.G.166.229; 4.G.166.230;4.G.166.231; 4.G.166.236; 4.G.166.237; 4.G.166.238; 4.G.166.239; 4.G.166.154;4.G.166.157; 4.G.166.166; 4.G.166.169; 4.G.166.172; 4.G.166.175; 4.G.166.240;4.G.166.244; 4.G.169.228; 4.G.169.229; 4.G.169.230; 4.G.169.231; 4.G.169.236;4.G.169.237; 4.G.169.238; 4.G.169.239; 4.G.169.154; 4.G.169.157; 4.G.169.166;4.G.169.169; 4.G.169.172; 4.G.169.175; 4.G.169.240; 4.G.169.244; 4.G.172.228;4.G.172.229; 4.G.172.230; 4.G.172.231; 4.G.172.236; 4.G.172.237; 4.G.172.238;4.G.172.239; 4.G.172.154; 4.G.172.157; 4.G.172.166; 4.G.172.169; 4.G.172.172;4.G.172.175; 4.G.172.240; 4.G.172.244; 4.G.175.228; 4.G.175.229; 4.G.175.230;4.G.175.231; 4.G.175.236; 4.G.175.237; 4.G.175.238; 4.G.175.239; 4.G.175.154;4.G.175.157; 4.G.175.166; 4.G.175.169; 4.G.175.172; 4.G.175.175; 4.G.175.240;4.G.175.244; 4.G.240.228; 4.G.240.229; 4.G.240.230; 4.G.240.231; 4.G.240.236;4.G.240.237; 4.G.240.238; 4.G.240.239; 4.G.240.154; 4.G.240.157; 4.G.240.166;4.G.240.169; 4.G.240.172; 4.G.240.175; 4.G.240.240; 4.G.240.244; 4.G.244.228;4.G.244.229; 4.G.244.230; 4.G.244.231; 4.G.244.236; 4.G.244.237; 4.G.244.238;4.G.244.239; 4.G.244.154; 4.G.244.157; 4.G.244.166; 4.G.244.169; 4.G.244.172;4.G.244.175; 4.G.244.240; 4.G.244.244;

4.Iのプロドラッグ
4.I.228.228; 4.I.228.229; 4.I.228.230; 4.I.228.231; 4.I.228.236; 4.I.228.237;4.I.228.238; 4.I.228.239; 4.I.228.154; 4.I.228.157; 4.I.228.166; 4.I.228.169;4.I.228.172; 4.I.228.175; 4.I.228.240; 4.I.228.244; 4.I.229.228; 4.I.229.229;4.I.229.230; 4.I.229.231; 4.I.229.236; 4.I.229.237; 4.I.229.238; 4.I.229.239;4.I.229.154; 4.I.229.157; 4.I.229.166; 4.I.229.169; 4.I.229.172; 4.I.229.175;4.I.229.240; 4.I.229.244; 4.I.230.228; 4.I.230.229; 4.I.230.230; 4.I.230.231;4.I.230.236; 4.I.230.237; 4.I.230.238; 4.I.230.239; 4.I.230.154; 4.I.230.157;4.I.230.166; 4.I.230.169; 4.I.230.172; 4.I.230.175; 4.I.230.240; 4.I.230.244;4.I.231.228; 4.I.231.229; 4.I.231.230; 4.I.231.231; 4.I.231.236; 4.I.231.237;4.I.231.238; 4.I.231.239; 4.I.231.154; 4.I.231.157; 4.I.231.166; 4.I.231.169;4.I.231.172; 4.I.231.175; 4.I.231.240; 4.I.231.244; 4.I.236.228; 4.I.236.229;4.I.236.230; 4.I.236.231; 4.I.236.236; 4.I.236.237; 4.I.236.238; 4.I.236.239;4.I.236.154; 4.I.236.157; 4.I.236.166; 4.I.236.169; 4.I.236.172; 4.I.236.175;4.I.236.240; 4.I.236.244; 4.I.237.228; 4.I.237.229; 4.I.237.230; 4.I.237.231;4.I.237.236; 4.I.237.237; 4.I.237.238; 4.I.237.239; 4.I.237.154; 4.I.237.157;4.I.237.166; 4.I.237.169; 4.I.237.172; 4.I.237.175; 4.I.237.240; 4.I.237.244;4.I.238.228; 4.I.238.229; 4.I.238.230; 4.I.238.231; 4.I.238.236; 4.I.238.237;4.I.238.238; 4.I.238.239; 4.I.238.154; 4.I.238.157; 4.I.238.166; 4.I.238.169;4.I.238.172; 4.I.238.175; 4.I.238.240; 4.I.238.244; 4.I.239.228; 4.I.239.229;4.I.239.230; 4.I.239.231; 4.I.239.236; 4.I.239.237; 4.I.239.238; 4.I.239.239;4.I.239.154; 4.I.239.157; 4.I.239.166; 4.I.239.169; 4.I.239.172; 4.I.239.175;4.I.239.240; 4.I.239.244; 4.I.154.228; 4.I.154.229; 4.I.154.230; 4.I.154.231;4.I.154.236; 4.I.154.237; 4.I.154.238; 4.I.154.239; 4.I.154.154; 4.I.154.157;4.I.154.166; 4.I.154.169; 4.I.154.172; 4.I.154.175; 4.I.154.240; 4.I.154.244;4.I.157.228; 4.I.157.229; 4.I.157.230; 4.I.157.231; 4.I.157.236; 4.I.157.237;4.I.157.238; 4.I.157.239; 4.I.157.154; 4.I.157.157; 4.I.157.166; 4.I.157.169;4.I.157.172; 4.I.157.175; 4.I.157.240; 4.I.157.244; 4.I.166.228; 4.I.166.229;4.I.166.230; 4.I.166.231; 4.I.166.236; 4.I.166.237; 4.I.166.238; 4.I.166.239;4.I.166.154; 4.I.166.157; 4.I.166.166; 4.I.166.169; 4.I.166.172; 4.I.166.175;4.I.166.240; 4.I.166.244; 4.I.169.228; 4.I.169.229; 4.I.169.230; 4.I.169.231;4.I.169.236; 4.I.169.237; 4.I.169.238; 4.I.169.239; 4.I.169.154; 4.I.169.157;4.I.169.166; 4.I.169.169; 4.I.169.172; 4.I.169.175; 4.I.169.240; 4.I.169.244;4.I.172.228; 4.I.172.229; 4.I.172.230; 4.I.172.231; 4.I.172.236; 4.I.172.237;4.I.172.238; 4.I.172.239; 4.I.172.154; 4.I.172.157; 4.I.172.166; 4.I.172.169;4.I.172.172; 4.I.172.175; 4.I.172.240; 4.I.172.244; 4.I.175.228; 4.I.175.229;4.I.175.230; 4.I.175.231; 4.I.175.236; 4.I.175.237; 4.I.175.238; 4.I.175.239;4.I.175.154; 4.I.175.157; 4.I.175.166; 4.I.175.169; 4.I.175.172; 4.I.175.175;4.I.175.240; 4.I.175.244; 4.I.240.228; 4.I.240.229; 4.I.240.230; 4.I.240.231;4.I.240.236; 4.I.240.237; 4.I.240.238; 4.I.240.239; 4.I.240.154; 4.I.240.157;4.I.240.166; 4.I.240.169; 4.I.240.172; 4.I.240.175; 4.I.240.240; 4.I.240.244;4.I.244.228; 4.I.244.229; 4.I.244.230; 4.I.244.231; 4.I.244.236; 4.I.244.237;4.I.244.238; 4.I.244.239; 4.I.244.154; 4.I.244.157; 4.I.244.166; 4.I.244.169;4.I.244.172; 4.I.244.175; 4.I.244.240; 4.I.244.244;

4.Jのプロドラッグ
4.J.228.228; 4.J.228.229; 4.J.228.230; 4.J.228.231; 4.J.228.236; 4.J.228.237;4.J.228.238; 4.J.228.239; 4.J.228.154; 4.J.228.157; 4.J.228.166; 4.J.228.169;4.J.228.172; 4.J.228.175; 4.J.228.240; 4.J.228.244; 4.J.229.228; 4.J.229.229;4.J.229.230; 4.J.229.231; 4.J.229.236; 4.J.229.237; 4.J.229.238; 4.J.229.239;4.J.229.154; 4.J.229.157; 4.J.229.166; 4.J.229.169; 4.J.229.172; 4.J.229.175;4.J.229.240; 4.J.229.244; 4.J.230.228; 4.J.230.229; 4.J.230.230; 4.J.230.231;4.J.230.236; 4.J.230.237; 4.J.230.238; 4.J.230.239; 4.J.230.154; 4.J.230.157;4.J.230.166; 4.J.230.169; 4.J.230.172; 4.J.230.175; 4.J.230.240; 4.J.230.244;4.J.231.228; 4.J.231.229; 4.J.231.230; 4.J.231.231; 4.J.231.236; 4.J.231.237;4.J.231.238; 4.J.231.239; 4.J.231.154; 4.J.231.157; 4.J.231.166; 4.J.231.169;4.J.231.172; 4.J.231.175; 4.J.231.240; 4.J.231.244; 4.J.236.228; 4.J.236.229;4.J.236.230; 4.J.236.231; 4.J.236.236; 4.J.236.237; 4.J.236.238; 4.J.236.239;4.J.236.154; 4.J.236.157; 4.J.236.166; 4.J.236.169; 4.J.236.172; 4.J.236.175;4.J.236.240; 4.J.236.244; 4.J.237.228; 4.J.237.229; 4.J.237.230; 4.J.237.231;4.J.237.236; 4.J.237.237; 4.J.237.238; 4.J.237.239; 4.J.237.154; 4.J.237.157;4.J.237.166; 4.J.237.169; 4.J.237.172; 4.J.237.175; 4.J.237.240; 4.J.237.244;4.J.238.228; 4.J.238.229; 4.J.238.230; 4.J.238.231; 4.J.238.236; 4.J.238.237;4.J.238.238; 4.J.238.239; 4.J.238.154; 4.J.238.157; 4.J.238.166; 4.J.238.169;4.J.238.172; 4.J.238.175; 4.J.238.240; 4.J.238.244; 4.J.239.228; 4.J.239.229;4.J.239.230; 4.J.239.231; 4.J.239.236; 4.J.239.237; 4.J.239.238; 4.J.239.239;4.J.239.154; 4.J.239.157; 4.J.239.166; 4.J.239.169; 4.J.239.172; 4.J.239.175;4.J.239.240; 4.J.239.244; 4.J.154.228; 4.J.154.229; 4.J.154.230; 4.J.154.231;4.J.154.236; 4.J.154.237; 4.J.154.238; 4.J.154.239; 4.J.154.154; 4.J.154.157;4.J.154.166; 4.J.154.169; 4.J.154.172; 4.J.154.175; 4.J.154.240; 4.J.154.244;4.J.157.228; 4.J.157.229; 4.J.157.230; 4.J.157.231; 4.J.157.236; 4.J.157.237;4.J.157.238; 4.J.157.239; 4.J.157.154; 4.J.157.157; 4.J.157.166; 4.J.157.169;4.J.157.172; 4.J.157.175; 4.J.157.240; 4.J.157.244; 4.J.166.228; 4.J.166.229;4.J.166.230; 4.J.166.231; 4.J.166.236; 4.J.166.237; 4.J.166.238; 4.J.166.239;4.J.166.154; 4.J.166.157; 4.J.166.166; 4.J.166.169; 4.J.166.172; 4.J.166.175;4.J.166.240; 4.J.166.244; 4.J.169.228; 4.J.169.229; 4.J.169.230; 4.J.169.231;4.J.169.236; 4.J.169.237; 4.J.169.238; 4.J.169.239; 4.J.169.154; 4.J.169.157;4.J.169.166; 4.J.169.169; 4.J.169.172; 4.J.169.175; 4.J.169.240; 4.J.169.244;4.J.172.228; 4.J.172.229; 4.J.172.230; 4.J.172.231; 4.J.172.236; 4.J.172.237;4.J.172.238; 4.J.172.239; 4.J.172.154; 4.J.172.157; 4.J.172.166; 4.J.172.169;4.J.172.172; 4.J.172.175; 4.J.172.240; 4.J.172.244; 4.J.175.228; 4.J.175.229;4.J.175.230; 4.J.175.231; 4.J.175.236; 4.J.175.237; 4.J.175.238; 4.J.175.239;4.J.175.154; 4.J.175.157; 4.J.175.166; 4.J.175.169; 4.J.175.172; 4.J.175.175;4.J.175.240; 4.J.175.244; 4.J.240.228; 4.J.240.229; 4.J.240.230; 4.J.240.231;4.J.240.236; 4.J.240.237; 4.J.240.238; 4.J.240.239; 4.J.240.154; 4.J.240.157;4.J.240.166; 4.J.240.169; 4.J.240.172; 4.J.240.175; 4.J.240.240; 4.J.240.244;4.J.244.228; 4.J.244.229; 4.J.244.230; 4.J.244.231; 4.J.244.236; 4.J.244.237;4.J.244.238; 4.J.244.239; 4.J.244.154; 4.J.244.157; 4.J.244.166; 4.J.244.169;4.J.244.172; 4.J.244.175; 4.J.244.240; 4.J.244.244;

4.Lのプロドラッグ
4.L.228.228; 4.L.228.229; 4.L.228.230; 4.L.228.231; 4.L.228.236; 4.L.228.237;4.L.228.238; 4.L.228.239; 4.L.228.154; 4.L.228.157; 4.L.228.166; 4.L.228.169;4.L.228.172; 4.L.228.175; 4.L.228.240; 4.L.228.244; 4.L.229.228; 4.L.229.229;4.L.229.230; 4.L.229.231; 4.L.229.236; 4.L.229.237; 4.L.229.238; 4.L.229.239;4.L.229.154; 4.L.229.157; 4.L.229.166; 4.L.229.169; 4.L.229.172; 4.L.229.175;4.L.229.240; 4.L.229.244; 4.L.230.228; 4.L.230.229; 4.L.230.230; 4.L.230.231;4.L.230.236; 4.L.230.237; 4.L.230.238; 4.L.230.239; 4.L.230.154; 4.L.230.157;4.L.230.166; 4.L.230.169; 4.L.230.172; 4.L.230.175; 4.L.230.240; 4.L.230.244;4.L.231.228; 4.L.231.229; 4.L.231.230; 4.L.231.231; 4.L.231.236; 4.L.231.237;4.L.231.238; 4.L.231.239; 4.L.231.154; 4.L.231.157; 4.L.231.166; 4.L.231.169;4.L.231.172; 4.L.231.175; 4.L.231.240; 4.L.231.244; 4.L.236.228; 4.L.236.229;4.L.236.230; 4.L.236.231; 4.L.236.236; 4.L.236.237; 4.L.236.238; 4.L.236.239;4.L.236.154; 4.L.236.157; 4.L.236.166; 4.L.236.169; 4.L.236.172; 4.L.236.175;4.L.236.240; 4.L.236.244; 4.L.237.228; 4.L.237.229; 4.L.237.230; 4.L.237.231;4.L.237.236; 4.L.237.237; 4.L.237.238; 4.L.237.239; 4.L.237.154; 4.L.237.157;4.L.237.166; 4.L.237.169; 4.L.237.172; 4.L.237.175; 4.L.237.240; 4.L.237.244;4.L.238.228; 4.L.238.229; 4.L.238.230; 4.L.238.231; 4.L.238.236; 4.L.238.237;4.L.238.238; 4.L.238.239; 4.L.238.154; 4.L.238.157; 4.L.238.166; 4.L.238.169;4.L.238.172; 4.L.238.175; 4.L.238.240; 4.L.238.244; 4.L.239.228; 4.L.239.229;4.L.239.230; 4.L.239.231; 4.L.239.236; 4.L.239.237; 4.L.239.238; 4.L.239.239;4.L.239.154; 4.L.239.157; 4.L.239.166; 4.L.239.169; 4.L.239.172; 4.L.239.175;4.L.239.240; 4.L.239.244; 4.L.154.228; 4.L.154.229; 4.L.154.230; 4.L.154.231; 4.L.154.236;4.L.154.237; 4.L.154.238; 4.L.154.239; 4.L.154.154; 4.L.154.157; 4.L.154.166;4.L.154.169; 4.L.154.172; 4.L.154.175; 4.L.154.240; 4.L.154.244; 4.L.157.228;4.L.157.229; 4.L.157.230; 4.L.157.231; 4.L.157.236; 4.L.157.237; 4.L.157.238;4.L.157.239; 4.L.157.154; 4.L.157.157; 4.L.157.166; 4.L.157.169; 4.L.157.172;4.L.157.175; 4.L.157.240; 4.L.157.244; 4.L.166.228; 4.L.166.229; 4.L.166.230;4.L.166.231; 4.L.166.236; 4.L.166.237; 4.L.166.238; 4.L.166.239; 4.L.166.154;4.L.166.157; 4.L.166.166; 4.L.166.169; 4.L.166.172; 4.L.166.175; 4.L.166.240;4.L.166.244; 4.L.169.228; 4.L.169.229; 4.L.169.230; 4.L.169.231; 4.L.169.236;4.L.169.237; 4.L.169.238; 4.L.169.239; 4.L.169.154; 4.L.169.157; 4.L.169.166;4.L.169.169; 4.L.169.172; 4.L.169.175; 4.L.169.240; 4.L.169.244; 4.L.172.228;4.L.172.229; 4.L.172.230; 4.L.172.231; 4.L.172.236; 4.L.172.237; 4.L.172.238;4.L.172.239; 4.L.172.154; 4.L.172.157; 4.L.172.166; 4.L.172.169; 4.L.172.172;4.L.172.175; 4.L.172.240; 4.L.172.244; 4.L.175.228; 4.L.175.229; 4.L.175.230;4.L.175.231; 4.L.175.236; 4.L.175.237; 4.L.175.238; 4.L.175.239; 4.L.175.154;4.L.175.157; 4.L.175.166; 4.L.175.169; 4.L.175.172; 4.L.175.175; 4.L.175.240;4.L.175.244; 4.L.240.228; 4.L.240.229; 4.L.240.230; 4.L.240.231; 4.L.240.236;4.L.240.237; 4.L.240.238; 4.L.240.239; 4.L.240.154; 4.L.240.157; 4.L.240.166;4.L.240.169; 4.L.240.172; 4.L.240.175; 4.L.240.240; 4.L.240.244; 4.L.244.228;4.L.244.229; 4.L.244.230; 4.L.244.231; 4.L.244.236; 4.L.244.237; 4.L.244.238;4.L.244.239; 4.L.244.154; 4.L.244.157; 4.L.244.166; 4.L.244.169; 4.L.244.172;4.L.244.175; 4.L.244.240; 4.L.244.244;

4.Oのプロドラッグ
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.157.169;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.169.228; 4.O.169.229; 4.O.169.230; 4.O.169.231;4.O.169.236; 4.O.169.237; 4.O.169.238; 4.O.169.239; 4.O.169.154; 4.O.169.157; 4.O.169.166;4.O.169.169; 4.O.169.172; 4.O.169.175; 4.O.169.240; 4.O.169.244; 4.O.172.228;4.O.172.229; 4.O.172.230; 4.O.172.231; 4.O.172.236; 4.O.172.237; 4.O.172.238;4.O.172.239; 4.O.172.154; 4.O.172.157; 4.O.172.166; 4.O.172.169; 4.O.172.172;4.O.172.175; 4.O.172.240; 4.O.172.244; 4.O.175.228; 4.O.175.229; 4.O.175.230;4.O.175.231; 4.O.175.236; 4.O.175.237; 4.O.175.238; 4.O.175.239; 4.O.175.154;4.O.175.157; 4.O.175.166; 4.O.175.169; 4.O.175.172; 4.O.175.175; 4.O.175.240;4.O.175.244; 4.O.240.228; 4.O.240.229; 4.O.240.230; 4.O.240.231; 4.O.240.236;4.O.240.237; 4.O.240.238; 4.O.240.239; 4.O.240.154; 4.O.240.157; 4.O.240.166;4.O.240.169; 4.O.240.172; 4.O.240.175; 4.O.240.240; 4.O.240.244; 4.O.244.228;4.O.244.229; 4.O.244.230; 4.O.244.231; 4.O.244.236; 4.O.244.237; 4.O.244.238;4.O.244.239; 4.O.244.154; 4.O.244.157; 4.O.244.166; 4.O.244.169; 4.O.244.172;4.O.244.175; 4.O.244.240; 4.O.244.244;

4.Pのプロドラッグ
4.P.228.228; 4.P.228.229; 4.P.228.230; 4.P.228.231; 4.P.228.236; 4.P.228.237;4.P.228.238; 4.P.228.239; 4.P.228.154; 4.P.228.157; 4.P.228.166; 4.P.228.169;4.P.228.172; 4.P.228.175; 4.P.228.240; 4.P.228.244; 4.P.229.228; 4.P.229.229;4.P.229.230; 4.P.229.231; 4.P.229.236; 4.P.229.237; 4.P.229.238; 4.P.229.239;4.P.229.154; 4.P.229.157; 4.P.229.166; 4.P.229.169; 4.P.229.172; 4.P.229.175;4.P.229.240; 4.P.229.244; 4.P.230.228; 4.P.230.229; 4.P.230.230; 4.P.230.231;4.P.230.236; 4.P.230.237; 4.P.230.238; 4.P.230.239; 4.P.230.154; 4.P.230.157;4.P.230.166; 4.P.230.169; 4.P.230.172; 4.P.230.175; 4.P.230.240; 4.P.230.244;4.P.231.228; 4.P.231.229; 4.P.231.230; 4.P.231.231; 4.P.231.236; 4.P.231.237;4.P.231.238; 4.P.231.239; 4.P.231.154; 4.P.231.157; 4.P.231.166; 4.P.231.169;4.P.231.172; 4.P.231.175; 4.P.231.240; 4.P.231.244; 4.P.236.228; 4.P.236.229;4.P.236.230; 4.P.236.231; 4.P.236.236; 4.P.236.237; 4.P.236.238; 4.P.236.239;4.P.236.154; 4.P.236.157; 4.P.236.166; 4.P.236.169; 4.P.236.172; 4.P.236.175;4.P.236.240; 4.P.236.244; 4.P.237.228; 4.P.237.229; 4.P.237.230; 4.P.237.231;4.P.237.236; 4.P.237.237; 4.P.237.238; 4.P.237.239; 4.P.237.154; 4.P.237.157;4.P.237.166; 4.P.237.169; 4.P.237.172; 4.P.237.175; 4.P.237.240; 4.P.237.244;4.P.238.228; 4.P.238.229; 4.P.238.230; 4.P.238.231; 4.P.238.236; 4.P.238.237;4.P.238.238; 4.P.238.239; 4.P.238.154; 4.P.238.157; 4.P.238.166; 4.P.238.169;4.P.238.172; 4.P.238.175; 4.P.238.240; 4.P.238.244; 4.P.239.228; 4.P.239.229;4.P.239.230; 4.P.239.231; 4.P.239.236; 4.P.239.237; 4.P.239.238; 4.P.239.239;4.P.239.154; 4.P.239.157; 4.P.239.166; 4.P.239.169; 4.P.239.172; 4.P.239.175;4.P.239.240; 4.P.239.244; 4.P.154.228; 4.P.154.229; 4.P.154.230; 4.P.154.231;4.P.154.236; 4.P.154.237; 4.P.154.238; 4.P.154.239; 4.P.154.154; 4.P.154.157;4.P.154.166; 4.P.154.169; 4.P.154.172; 4.P.154.175; 4.P.154.240; 4.P.154.244;4.P.157.228; 4.P.157.229; 4.P.157.230; 4.P.157.231; 4.P.157.236; 4.P.157.237;4.P.157.238; 4.P.157.239; 4.P.157.154; 4.P.157.157; 4.P.157.166; 4.P.157.169;4.P.157.172; 4.P.157.175; 4.P.157.240; 4.P.157.244; 4.P.166.228; 4.P.166.229;4.P.166.230; 4.P.166.231; 4.P.166.236; 4.P.166.237; 4.P.166.238; 4.P.166.239;4.P.166.154; 4.P.166.157; 4.P.166.166; 4.P.166.169; 4.P.166.172; 4.P.166.175;4.P.166.240; 4.P.166.244; 4.P.169.228; 4.P.169.229; 4.P.169.230; 4.P.169.231;4.P.169.236; 4.P.169.237; 4.P.169.238; 4.P.169.239; 4.P.169.154; 4.P.169.157;4.P.169.166; 4.P.169.169; 4.P.169.172; 4.P.169.175; 4.P.169.240; 4.P.169.244;4.P.172.228; 4.P.172.229; 4.P.172.230; 4.P.172.231; 4.P.172.236; 4.P.172.237;4.P.172.238; 4.P.172.239; 4.P.172.154; 4.P.172.157; 4.P.172.166; 4.P.172.169;4.P.172.172; 4.P.172.175; 4.P.172.240; 4.P.172.244; 4.P.175.228; 4.P.175.229;4.P.175.230; 4.P.175.231; 4.P.175.236; 4.P.175.237; 4.P.175.238; 4.P.175.239;4.P.175.154; 4.P.175.157; 4.P.175.166; 4.P.175.169; 4.P.175.172; 4.P.175.175;4.P.175.240; 4.P.175.244; 4.P.240.228; 4.P.240.229; 4.P.240.230; 4.P.240.231;4.P.240.236; 4.P.240.237; 4.P.240.238; 4.P.240.239; 4.P.240.154; 4.P.240.157;4.P.240.166; 4.P.240.169; 4.P.240.172; 4.P.240.175; 4.P.240.240; 4.P.240.244;4.P.244.228; 4.P.244.229; 4.P.244.230; 4.P.244.231; 4.P.244.236; 4.P.244.237;4.P.244.238; 4.P.244.239; 4.P.244.154; 4.P.244.157; 4.P.244.166; 4.P.244.169;4.P.244.172; 4.P.244.175; 4.P.244.240; 4.P.244.244;

4.Uのプロドラッグ
4.U.228.228; 4.U.228.229; 4.U.228.230; 4.U.228.231; 4.U.228.236; 4.U.228.237;4.U.228.238; 4.U.228.239; 4.U.228.154; 4.U.228.157; 4.U.228.166; 4.U.228.169;4.U.228.172; 4.U.228.175; 4.U.228.240; 4.U.228.244; 4.U.229.228; 4.U.229.229;4.U.229.230; 4.U.229.231; 4.U.229.236; 4.U.229.237; 4.U.229.238; 4.U.229.239;4.U.229.154; 4.U.229.157; 4.U.229.166; 4.U.229.169; 4.U.229.172; 4.U.229.175;4.U.229.240; 4.U.229.244; 4.U.230.228; 4.U.230.229; 4.U.230.230; 4.U.230.231;4.U.230.236; 4.U.230.237; 4.U.230.238; 4.U.230.239; 4.U.230.154; 4.U.230.157;4.U.230.166; 4.U.230.169; 4.U.230.172; 4.U.230.175; 4.U.230.240; 4.U.230.244;4.U.231.228; 4.U.231.229; 4.U.231.230; 4.U.231.231; 4.U.231.236; 4.U.231.237;4.U.231.238; 4.U.231.239; 4.U.231.154; 4.U.231.157; 4.U.231.166; 4.U.231.169;4.U.231.172; 4.U.231.175; 4.U.231.240; 4.U.231.244; 4.U.236.228; 4.U.236.229;4.U.236.230; 4.U.236.231; 4.U.236.236; 4.U.236.237; 4.U.236.238; 4.U.236.239;4.U.236.154; 4.U.236.157; 4.U.236.166; 4.U.236.169; 4.U.236.172; 4.U.236.175;4.U.236.240; 4.U.236.244; 4.U.237.228; 4.U.237.229; 4.U.237.230; 4.U.237.231;4.U.237.236; 4.U.237.237; 4.U.237.238; 4.U.237.239; 4.U.237.154; 4.U.237.157;4.U.237.166; 4.U.237.169; 4.U.237.172; 4.U.237.175; 4.U.237.240; 4.U.237.244;4.U.238.228; 4.U.238.229; 4.U.238.230; 4.U.238.231; 4.U.238.236; 4.U.238.237;4.U.238.238; 4.U.238.239; 4.U.238.154; 4.U.238.157; 4.U.238.166; 4.U.238.169;4.U.238.172; 4.U.238.175; 4.U.238.240; 4.U.238.244; 4.U.239.228; 4.U.239.229;4.U.239.230; 4.U.239.231; 4.U.239.236; 4.U.239.237; 4.U.239.238; 4.U.239.239;4.U.239.154; 4.U.239.157; 4.U.239.166; 4.U.239.169; 4.U.239.172; 4.U.239.175;4.U.239.240; 4.U.239.244; 4.U.154.228; 4.U.154.229; 4.U.154.230; 4.U.154.231;4.U.154.236; 4.U.154.237; 4.U.154.238; 4.U.154.239; 4.U.154.154; 4.U.154.157;4.U.154.166; 4.U.154.169; 4.U.154.172; 4.U.154.175; 4.U.154.240; 4.U.154.244;4.U.157.228; 4.U.157.229; 4.U.157.230; 4.U.157.231; 4.U.157.236; 4.U.157.237;4.U.157.238; 4.U.157.239; 4.U.157.154; 4.U.157.157; 4.U.157.166; 4.U.157.169;4.U.157.172; 4.U.157.175; 4.U.157.240; 4.U.157.244; 4.U.166.228; 4.U.166.229;4.U.166.230; 4.U.166.231; 4.U.166.236; 4.U.166.237; 4.U.166.238; 4.U.166.239;4.U.166.154; 4.U.166.157; 4.U.166.166; 4.U.166.169; 4.U.166.172; 4.U.166.175;4.U.166.240; 4.U.166.244; 4.U.169.228; 4.U.169.229; 4.U.169.230; 4.U.169.231; 4.U.169.236;4.U.169.237; 4.U.169.238; 4.U.169.239; 4.U.169.154; 4.U.169.157; 4.U.169.166;4.U.169.169; 4.U.169.172; 4.U.169.175; 4.U.169.240; 4.U.169.244; 4.U.172.228;4.U.172.229; 4.U.172.230; 4.U.172.231; 4.U.172.236; 4.U.172.237; 4.U.172.238;4.U.172.239; 4.U.172.154; 4.U.172.157; 4.U.172.166; 4.U.172.169; 4.U.172.172;4.U.172.175; 4.U.172.240; 4.U.172.244; 4.U.175.228; 4.U.175.229; 4.U.175.230;4.U.175.231; 4.U.175.236; 4.U.175.237; 4.U.175.238; 4.U.175.239; 4.U.175.154;4.U.175.157; 4.U.175.166; 4.U.175.169; 4.U.175.172; 4.U.175.175; 4.U.175.240;4.U.175.244; 4.U.240.228; 4.U.240.229; 4.U.240.230; 4.U.240.231; 4.U.240.236;4.U.240.237; 4.U.240.238; 4.U.240.239; 4.U.240.154; 4.U.240.157; 4.U.240.166;4.U.240.169; 4.U.240.172; 4.U.240.175; 4.U.240.240; 4.U.240.244; 4.U.244.228;4.U.244.229; 4.U.244.230; 4.U.244.231; 4.U.244.236; 4.U.244.237; 4.U.244.238;4.U.244.239; 4.U.244.154; 4.U.244.157; 4.U.244.166; 4.U.244.169; 4.U.244.172;4.U.244.175; 4.U.244.240; 4.U.244.244;

4.Wのプロドラッグ
4.W.228.228; 4.W.228.229; 4.W.228.230; 4.W.228.231; 4.W.228.236; 4.W.228.237;4.W.228.238; 4.W.228.239; 4.W.228.154; 4.W.228.157; 4.W.228.166; 4.W.228.169;4.W.228.172; 4.W.228.175; 4.W.228.240; 4.W.228.244; 4.W.229.228; 4.W.229.229;4.W.229.230; 4.W.229.231; 4.W.229.236; 4.W.229.237; 4.W.229.238; 4.W.229.239;4.W.229.154; 4.W.229.157; 4.W.229.166; 4.W.229.169; 4.W.229.172; 4.W.229.175;4.W.229.240; 4.W.229.244; 4.W.230.228; 4.W.230.229; 4.W.230.230; 4.W.230.231;4.W.230.236; 4.W.230.237; 4.W.230.238; 4.W.230.239; 4.W.230.154; 4.W.230.157;4.W.230.166; 4.W.230.169; 4.W.230.172; 4.W.230.175; 4.W.230.240; 4.W.230.244;4.W.231.228; 4.W.231.229; 4.W.231.230; 4.W.231.231; 4.W.231.236; 4.W.231.237;4.W.231.238; 4.W.231.239; 4.W.231.154; 4.W.231.157; 4.W.231.166; 4.W.231.169;4.W.231.172; 4.W.231.175; 4.W.231.240; 4.W.231.244; 4.W.236.228; 4.W.236.229;4.W.236.230; 4.W.236.231; 4.W.236.236; 4.W.236.237; 4.W.236.238; 4.W.236.239;4.W.236.154; 4.W.236.157; 4.W.236.166; 4.W.236.169; 4.W.236.172; 4.W.236.175;4.W.236.240; 4.W.236.244; 4.W.237.228; 4.W.237.229; 4.W.237.230; 4.W.237.231;4.W.237.236; 4.W.237.237; 4.W.237.238; 4.W.237.239; 4.W.237.154; 4.W.237.157;4.W.237.166; 4.W.237.169; 4.W.237.172; 4.W.237.175; 4.W.237.240; 4.W.237.244;4.W.238.228; 4.W.238.229; 4.W.238.230; 4.W.238.231; 4.W.238.236; 4.W.238.237;4.W.238.238; 4.W.238.239; 4.W.238.154; 4.W.238.157; 4.W.238.166; 4.W.238.169;4.W.238.172; 4.W.238.175; 4.W.238.240; 4.W.238.244; 4.W.239.228; 4.W.239.229;4.W.239.230; 4.W.239.231; 4.W.239.236; 4.W.239.237; 4.W.239.238; 4.W.239.239;4.W.239.154; 4.W.239.157; 4.W.239.166; 4.W.239.169; 4.W.239.172; 4.W.239.175;4.W.239.240; 4.W.239.244; 4.W.154.228; 4.W.154.229; 4.W.154.230; 4.W.154.231;4.W.154.236; 4.W.154.237; 4.W.154.238; 4.W.154.239; 4.W.154.154; 4.W.154.157;4.W.154.166; 4.W.154.169; 4.W.154.172; 4.W.154.175; 4.W.154.240; 4.W.154.244;4.W.157.228; 4.W.157.229; 4.W.157.230; 4.W.157.231; 4.W.157.236; 4.W.157.237;4.W.157.238; 4.W.157.239; 4.W.157.154; 4.W.157.157; 4.W.157.166; 4.W.157.169;4.W.157.172; 4.W.157.175; 4.W.157.240; 4.W.157.244; 4.W.166.228; 4.W.166.229;4.W.166.230; 4.W.166.231; 4.W.166.236; 4.W.166.237; 4.W.166.238; 4.W.166.239;4.W.166.154; 4.W.166.157; 4.W.166.166; 4.W.166.169; 4.W.166.172; 4.W.166.175;4.W.166.240; 4.W.166.244; 4.W.169.228; 4.W.169.229; 4.W.169.230; 4.W.169.231;4.W.169.236; 4.W.169.237; 4.W.169.238; 4.W.169.239; 4.W.169.154; 4.W.169.157;4.W.169.166; 4.W.169.169; 4.W.169.172; 4.W.169.175; 4.W.169.240; 4.W.169.244;4.W.172.228; 4.W.172.229; 4.W.172.230; 4.W.172.231; 4.W.172.236; 4.W.172.237;4.W.172.238; 4.W.172.239; 4.W.172.154; 4.W.172.157; 4.W.172.166; 4.W.172.169;4.W.172.172; 4.W.172.175; 4.W.172.240; 4.W.172.244; 4.W.175.228; 4.W.175.229;4.W.175.230; 4.W.175.231; 4.W.175.236; 4.W.175.237; 4.W.175.238; 4.W.175.239;4.W.175.154; 4.W.175.157; 4.W.175.166; 4.W.175.169; 4.W.175.172; 4.W.175.175;4.W.175.240; 4.W.175.244; 4.W.240.228; 4.W.240.229; 4.W.240.230; 4.W.240.231;4.W.240.236; 4.W.240.237; 4.W.240.238; 4.W.240.239; 4.W.240.154; 4.W.240.157;4.W.240.166; 4.W.240.169; 4.W.240.172; 4.W.240.175; 4.W.240.240; 4.W.240.244;4.W.244.228; 4.W.244.229; 4.W.244.230; 4.W.244.231; 4.W.244.236; 4.W.244.237;4.W.244.238; 4.W.244.239; 4.W.244.154; 4.W.244.157; 4.W.244.166; 4.W.244.169;4.W.244.172; 4.W.244.175; 4.W.244.240; 4.W.244.244;

4.Yのプロドラッグ
4.Y.228.228;4.Y.228.229; 4.Y.228.230; 4.Y.228.231; 4.Y.228.236; 4.Y.228.237; 4.Y.228.238;4.Y.228.239; 4.Y.228.154; 4.Y.228.157; 4.Y.228.166; 4.Y.228.169; 4.Y.228.172;4.Y.228.175; 4.Y.228.240; 4.Y.228.244; 4.Y.229.228; 4.Y.229.229; 4.Y.229.230;4.Y.229.231; 4.Y.229.236; 4.Y.229.237; 4.Y.229.238; 4.Y.229.239; 4.Y.229.154;4.Y.229.157; 4.Y.229.166; 4.Y.229.169; 4.Y.229.172; 4.Y.229.175; 4.Y.229.240;4.Y.229.244; 4.Y.230.228; 4.Y.230.229; 4.Y.230.230; 4.Y.230.231; 4.Y.230.236;4.Y.230.237; 4.Y.230.238; 4.Y.230.239; 4.Y.230.154; 4.Y.230.157; 4.Y.230.166;4.Y.230.169; 4.Y.230.172; 4.Y.230.175; 4.Y.230.240; 4.Y.230.244; 4.Y.231.228;4.Y.231.229; 4.Y.231.230; 4.Y.231.231; 4.Y.231.236; 4.Y.231.237; 4.Y.231.238;4.Y.231.239; 4.Y.231.154; 4.Y.231.157; 4.Y.231.166; 4.Y.231.169; 4.Y.231.172;4.Y.231.175; 4.Y.231.240; 4.Y.231.244; 4.Y.236.228; 4.Y.236.229; 4.Y.236.230;4.Y.236.231; 4.Y.236.236; 4.Y.236.237; 4.Y.236.238; 4.Y.236.239; 4.Y.236.154;4.Y.236.157; 4.Y.236.166; 4.Y.236.169; 4.Y.236.172; 4.Y.236.175; 4.Y.236.240;4.Y.236.244; 4.Y.237.228; 4.Y.237.229; 4.Y.237.230; 4.Y.237.231; 4.Y.237.236;4.Y.237.237; 4.Y.237.238; 4.Y.237.239; 4.Y.237.154; 4.Y.237.157; 4.Y.237.166;4.Y.237.169; 4.Y.237.172; 4.Y.237.175; 4.Y.237.240; 4.Y.237.244; 4.Y.238.228;4.Y.238.229; 4.Y.238.230; 4.Y.238.231; 4.Y.238.236; 4.Y.238.237; 4.Y.238.238;4.Y.238.239; 4.Y.238.154; 4.Y.238.157; 4.Y.238.166; 4.Y.238.169; 4.Y.238.172;4.Y.238.175; 4.Y.238.240; 4.Y.238.244; 4.Y.239.228; 4.Y.239.229; 4.Y.239.230;4.Y.239.231; 4.Y.239.236; 4.Y.239.237; 4.Y.239.238; 4.Y.239.239; 4.Y.239.154;4.Y.239.157; 4.Y.239.166; 4.Y.239.169; 4.Y.239.172; 4.Y.239.175; 4.Y.239.240;4.Y.239.244; 4.Y.154.228; 4.Y.154.229; 4.Y.154.230; 4.Y.154.231; 4.Y.154.236;4.Y.154.237; 4.Y.154.238; 4.Y.154.239; 4.Y.154.154; 4.Y.154.157; 4.Y.154.166;4.Y.154.169; 4.Y.154.172; 4.Y.154.175; 4.Y.154.240; 4.Y.154.244; 4.Y.157.228;4.Y.157.229; 4.Y.157.230; 4.Y.157.231; 4.Y.157.236; 4.Y.157.237; 4.Y.157.238;4.Y.157.239; 4.Y.157.154; 4.Y.157.157; 4.Y.157.166; 4.Y.157.169; 4.Y.157.172;4.Y.157.175; 4.Y.157.240; 4.Y.157.244; 4.Y.166.228; 4.Y.166.229; 4.Y.166.230;4.Y.166.231; 4.Y.166.236; 4.Y.166.237; 4.Y.166.238; 4.Y.166.239; 4.Y.166.154;4.Y.166.157; 4.Y.166.166; 4.Y.166.169; 4.Y.166.172; 4.Y.166.175; 4.Y.166.240;4.Y.166.244; 4.Y.169.228; 4.Y.169.229; 4.Y.169.230; 4.Y.169.231; 4.Y.169.236;4.Y.169.237; 4.Y.169.238; 4.Y.169.239; 4.Y.169.154; 4.Y.169.157; 4.Y.169.166;4.Y.169.169; 4.Y.169.172; 4.Y.169.175; 4.Y.169.240; 4.Y.169.244; 4.Y.172.228;4.Y.172.229; 4.Y.172.230; 4.Y.172.231; 4.Y.172.236; 4.Y.172.237; 4.Y.172.238;4.Y.172.239; 4.Y.172.154; 4.Y.172.157; 4.Y.172.166; 4.Y.172.169; 4.Y.172.172;4.Y.172.175; 4.Y.172.240; 4.Y.172.244; 4.Y.175.228; 4.Y.175.229; 4.Y.175.230;4.Y.175.231; 4.Y.175.236; 4.Y.175.237; 4.Y.175.238; 4.Y.175.239; 4.Y.175.154;4.Y.175.157; 4.Y.175.166; 4.Y.175.169; 4.Y.175.172; 4.Y.175.175; 4.Y.175.240;4.Y.175.244; 4.Y.240.228; 4.Y.240.229; 4.Y.240.230; 4.Y.240.231; 4.Y.240.236;4.Y.240.237; 4.Y.240.238; 4.Y.240.239; 4.Y.240.154; 4.Y.240.157; 4.Y.240.166;4.Y.240.169; 4.Y.240.172; 4.Y.240.175; 4.Y.240.240; 4.Y.240.244; 4.Y.244.228;4.Y.244.229; 4.Y.244.230; 4.Y.244.231; 4.Y.244.236; 4.Y.244.237; 4.Y.244.238;4.Y.244.239; 4.Y.244.154; 4.Y.244.157; 4.Y.244.166; 4.Y.244.169; 4.Y.244.172;4.Y.244.175; 4.Y.244.240; 4.Y.244.244;

5.Bのプロドラッグ
5.B.228.228; 5.B.228.229; 5.B.228.230; 5.B.228.231; 5.B.228.236; 5.B.228.237;5.B.228.238; 5.B.228.239; 5.B.228.154; 5.B.228.157; 5.B.228.166; 5.B.228.169;5.B.228.172; 5.B.228.175; 5.B.228.240; 5.B.228.244; 5.B.229.228; 5.B.229.229;5.B.229.230; 5.B.229.231; 5.B.229.236; 5.B.229.237; 5.B.229.238; 5.B.229.239;5.B.229.154; 5.B.229.157; 5.B.229.166; 5.B.229.169; 5.B.229.172; 5.B.229.175;5.B.229.240; 5.B.229.244; 5.B.230.228; 5.B.230.229; 5.B.230.230; 5.B.230.231;5.B.230.236; 5.B.230.237; 5.B.230.238; 5.B.230.239; 5.B.230.154; 5.B.230.157;5.B.230.166; 5.B.230.169; 5.B.230.172; 5.B.230.175; 5.B.230.240; 5.B.230.244;5.B.231.228; 5.B.231.229; 5.B.231.230; 5.B.231.231; 5.B.231.236; 5.B.231.237;5.B.231.238; 5.B.231.239; 5.B.231.154; 5.B.231.157; 5.B.231.166; 5.B.231.169;5.B.231.172; 5.B.231.175; 5.B.231.240; 5.B.231.244; 5.B.236.228; 5.B.236.229;5.B.236.230; 5.B.236.231; 5.B.236.236; 5.B.236.237; 5.B.236.238; 5.B.236.239;5.B.236.154; 5.B.236.157; 5.B.236.166; 5.B.236.169; 5.B.236.172; 5.B.236.175;5.B.236.240; 5.B.236.244; 5.B.237.228; 5.B.237.229; 5.B.237.230; 5.B.237.231;5.B.237.236; 5.B.237.237; 5.B.237.238; 5.B.237.239; 5.B.237.154; 5.B.237.157;5.B.237.166; 5.B.237.169; 5.B.237.172; 5.B.237.175; 5.B.237.240; 5.B.237.244;5.B.238.228; 5.B.238.229; 5.B.238.230; 5.B.238.231; 5.B.238.236; 5.B.238.237;5.B.238.238; 5.B.238.239; 5.B.238.154; 5.B.238.157; 5.B.238.166; 5.B.238.169;5.B.238.172; 5.B.238.175; 5.B.238.240; 5.B.238.244; 5.B.239.228; 5.B.239.229;5.B.239.230; 5.B.239.231; 5.B.239.236; 5.B.239.237; 5.B.239.238; 5.B.239.239;5.B.239.154; 5.B.239.157; 5.B.239.166; 5.B.239.169; 5.B.239.172; 5.B.239.175;5.B.239.240; 5.B.239.244; 5.B.154.228; 5.B.154.229; 5.B.154.230; 5.B.154.231;5.B.154.236; 5.B.154.237; 5.B.154.238; 5.B.154.239; 5.B.154.154; 5.B.154.157;5.B.154.166; 5.B.154.169; 5.B.154.172; 5.B.154.175; 5.B.154.240; 5.B.154.244;5.B.157.228; 5.B.157.229; 5.B.157.230; 5.B.157.231; 5.B.157.236; 5.B.157.237;5.B.157.238; 5.B.157.239; 5.B.157.154; 5.B.157.157; 5.B.157.166; 5.B.157.169; 5.B.157.172;5.B.157.175; 5.B.157.240; 5.B.157.244; 5.B.166.228; 5.B.166.229; 5.B.166.230;5.B.166.231; 5.B.166.236; 5.B.166.237; 5.B.166.238; 5.B.166.239; 5.B.166.154;5.B.166.157; 5.B.166.166; 5.B.166.169; 5.B.166.172; 5.B.166.175; 5.B.166.240;5.B.166.244; 5.B.169.228; 5.B.169.229; 5.B.169.230; 5.B.169.231; 5.B.169.236;5.B.169.237; 5.B.169.238; 5.B.169.239; 5.B.169.154; 5.B.169.157; 5.B.169.166;5.B.169.169; 5.B.169.172; 5.B.169.175; 5.B.169.240; 5.B.169.244; 5.B.172.228;5.B.172.229; 5.B.172.230; 5.B.172.231; 5.B.172.236; 5.B.172.237; 5.B.172.238;5.B.172.239; 5.B.172.154; 5.B.172.157; 5.B.172.166; 5.B.172.169; 5.B.172.172;5.B.172.175; 5.B.172.240; 5.B.172.244; 5.B.175.228; 5.B.175.229; 5.B.175.230;5.B.175.231; 5.B.175.236; 5.B.175.237; 5.B.175.238; 5.B.175.239; 5.B.175.154;5.B.175.157; 5.B.175.166; 5.B.175.169; 5.B.175.172; 5.B.175.175; 5.B.175.240;5.B.175.244; 5.B.240.228; 5.B.240.229; 5.B.240.230; 5.B.240.231; 5.B.240.236;5.B.240.237; 5.B.240.238; 5.B.240.239; 5.B.240.154; 5.B.240.157; 5.B.240.166; 5.B.240.169;5.B.240.172; 5.B.240.175; 5.B.240.240; 5.B.240.244; 5.B.244.228; 5.B.244.229;5.B.244.230; 5.B.244.231; 5.B.244.236; 5.B.244.237; 5.B.244.238; 5.B.244.239;5.B.244.154; 5.B.244.157; 5.B.244.166; 5.B.244.169; 5.B.244.172; 5.B.244.175;5.B.244.240; 5.B.244.244;

5.Dのプロドラッグ
5.D.228.228; 5.D.228.229; 5.D.228.230; 5.D.228.231; 5.D.228.236; 5.D.228.237;5.D.228.238; 5.D.228.239; 5.D.228.154; 5.D.228.157; 5.D.228.166; 5.D.228.169;5.D.228.172; 5.D.228.175; 5.D.228.240; 5.D.228.244; 5.D.229.228; 5.D.229.229;5.D.229.230; 5.D.229.231; 5.D.229.236; 5.D.229.237; 5.D.229.238; 5.D.229.239;5.D.229.154; 5.D.229.157; 5.D.229.166; 5.D.229.169; 5.D.229.172; 5.D.229.175;5.D.229.240; 5.D.229.244; 5.D.230.228; 5.D.230.229; 5.D.230.230; 5.D.230.231;5.D.230.236; 5.D.230.237; 5.D.230.238; 5.D.230.239; 5.D.230.154; 5.D.230.157;5.D.230.166; 5.D.230.169; 5.D.230.172; 5.D.230.175; 5.D.230.240; 5.D.230.244;5.D.231.228; 5.D.231.229; 5.D.231.230; 5.D.231.231; 5.D.231.236; 5.D.231.237;5.D.231.238; 5.D.231.239; 5.D.231.154; 5.D.231.157; 5.D.231.166; 5.D.231.169;5.D.231.172; 5.D.231.175; 5.D.231.240; 5.D.231.244; 5.D.236.228; 5.D.236.229;5.D.236.230; 5.D.236.231; 5.D.236.236; 5.D.236.237; 5.D.236.238; 5.D.236.239;5.D.236.154; 5.D.236.157; 5.D.236.166; 5.D.236.169; 5.D.236.172; 5.D.236.175;5.D.236.240; 5.D.236.244; 5.D.237.228; 5.D.237.229; 5.D.237.230; 5.D.237.231;5.D.237.236; 5.D.237.237; 5.D.237.238; 5.D.237.239; 5.D.237.154; 5.D.237.157;5.D.237.166; 5.D.237.169; 5.D.237.172; 5.D.237.175; 5.D.237.240; 5.D.237.244;5.D.238.228; 5.D.238.229; 5.D.238.230; 5.D.238.231; 5.D.238.236; 5.D.238.237;5.D.238.238; 5.D.238.239; 5.D.238.154; 5.D.238.157; 5.D.238.166; 5.D.238.169;5.D.238.172; 5.D.238.175; 5.D.238.240; 5.D.238.244; 5.D.239.228; 5.D.239.229;5.D.239.230; 5.D.239.231; 5.D.239.236; 5.D.239.237; 5.D.239.238; 5.D.239.239;5.D.239.154; 5.D.239.157; 5.D.239.166; 5.D.239.169; 5.D.239.172; 5.D.239.175;5.D.239.240; 5.D.239.244; 5.D.154.228; 5.D.154.229; 5.D.154.230; 5.D.154.231;5.D.154.236; 5.D.154.237; 5.D.154.238; 5.D.154.239; 5.D.154.154; 5.D.154.157;5.D.154.166; 5.D.154.169; 5.D.154.172; 5.D.154.175; 5.D.154.240; 5.D.154.244;5.D.157.228; 5.D.157.229; 5.D.157.230; 5.D.157.231; 5.D.157.236; 5.D.157.237;5.D.157.238; 5.D.157.239; 5.D.157.154; 5.D.157.157; 5.D.157.166; 5.D.157.169;5.D.157.172; 5.D.157.175; 5.D.157.240; 5.D.157.244; 5.D.166.228; 5.D.166.229;5.D.166.230; 5.D.166.231; 5.D.166.236; 5.D.166.237; 5.D.166.238; 5.D.166.239;5.D.166.154; 5.D.166.157; 5.D.166.166; 5.D.166.169; 5.D.166.172; 5.D.166.175;5.D.166.240; 5.D.166.244; 5.D.169.228; 5.D.169.229; 5.D.169.230; 5.D.169.231;5.D.169.236; 5.D.169.237; 5.D.169.238; 5.D.169.239; 5.D.169.154; 5.D.169.157;5.D.169.166; 5.D.169.169; 5.D.169.172; 5.D.169.175; 5.D.169.240; 5.D.169.244;5.D.172.228; 5.D.172.229; 5.D.172.230; 5.D.172.231; 5.D.172.236; 5.D.172.237;5.D.172.238; 5.D.172.239; 5.D.172.154; 5.D.172.157; 5.D.172.166; 5.D.172.169;5.D.172.172; 5.D.172.175; 5.D.172.240; 5.D.172.244; 5.D.175.228; 5.D.175.229;5.D.175.230; 5.D.175.231; 5.D.175.236; 5.D.175.237; 5.D.175.238; 5.D.175.239;5.D.175.154; 5.D.175.157; 5.D.175.166; 5.D.175.169; 5.D.175.172; 5.D.175.175;5.D.175.240; 5.D.175.244; 5.D.240.228; 5.D.240.229; 5.D.240.230; 5.D.240.231;5.D.240.236; 5.D.240.237; 5.D.240.238; 5.D.240.239; 5.D.240.154; 5.D.240.157;5.D.240.166; 5.D.240.169; 5.D.240.172; 5.D.240.175; 5.D.240.240; 5.D.240.244;5.D.244.228; 5.D.244.229; 5.D.244.230; 5.D.244.231; 5.D.244.236; 5.D.244.237;5.D.244.238; 5.D.244.239; 5.D.244.154; 5.D.244.157; 5.D.244.166; 5.D.244.169;5.D.244.172; 5.D.244.175; 5.D.244.240; 5.D.244.244;

5.Eのプロドラッグ
5.E.228.228; 5.E.228.229; 5.E.228.230; 5.E.228.231; 5.E.228.236; 5.E.228.237;5.E.228.238; 5.E.228.239; 5.E.228.154; 5.E.228.157; 5.E.228.166; 5.E.228.169;5.E.228.172; 5.E.228.175; 5.E.228.240; 5.E.228.244; 5.E.229.228; 5.E.229.229;5.E.229.230; 5.E.229.231; 5.E.229.236; 5.E.229.237; 5.E.229.238; 5.E.229.239;5.E.229.154; 5.E.229.157; 5.E.229.166; 5.E.229.169; 5.E.229.172; 5.E.229.175;5.E.229.240; 5.E.229.244; 5.E.230.228; 5.E.230.229; 5.E.230.230; 5.E.230.231;5.E.230.236; 5.E.230.237; 5.E.230.238; 5.E.230.239; 5.E.230.154; 5.E.230.157;5.E.230.166; 5.E.230.169; 5.E.230.172; 5.E.230.175; 5.E.230.240; 5.E.230.244;5.E.231.228; 5.E.231.229; 5.E.231.230; 5.E.231.231; 5.E.231.236; 5.E.231.237;5.E.231.238; 5.E.231.239; 5.E.231.154; 5.E.231.157; 5.E.231.166; 5.E.231.169;5.E.231.172; 5.E.231.175; 5.E.231.240; 5.E.231.244; 5.E.236.228; 5.E.236.229;5.E.236.230; 5.E.236.231; 5.E.236.236; 5.E.236.237; 5.E.236.238; 5.E.236.239;5.E.236.154; 5.E.236.157; 5.E.236.166; 5.E.236.169; 5.E.236.172; 5.E.236.175;5.E.236.240; 5.E.236.244; 5.E.237.228; 5.E.237.229; 5.E.237.230; 5.E.237.231;5.E.237.236; 5.E.237.237; 5.E.237.238; 5.E.237.239; 5.E.237.154; 5.E.237.157;5.E.237.166; 5.E.237.169; 5.E.237.172; 5.E.237.175; 5.E.237.240; 5.E.237.244;5.E.238.228; 5.E.238.229; 5.E.238.230; 5.E.238.231; 5.E.238.236; 5.E.238.237;5.E.238.238; 5.E.238.239; 5.E.238.154; 5.E.238.157; 5.E.238.166; 5.E.238.169;5.E.238.172; 5.E.238.175; 5.E.238.240; 5.E.238.244; 5.E.239.228; 5.E.239.229;5.E.239.230; 5.E.239.231; 5.E.239.236; 5.E.239.237; 5.E.239.238; 5.E.239.239;5.E.239.154; 5.E.239.157; 5.E.239.166; 5.E.239.169; 5.E.239.172; 5.E.239.175;5.E.239.240; 5.E.239.244; 5.E.154.228; 5.E.154.229; 5.E.154.230; 5.E.154.231;5.E.154.236; 5.E.154.237; 5.E.154.238; 5.E.154.239; 5.E.154.154; 5.E.154.157;5.E.154.166; 5.E.154.169; 5.E.154.172; 5.E.154.175; 5.E.154.240; 5.E.154.244;5.E.157.228; 5.E.157.229; 5.E.157.230; 5.E.157.231; 5.E.157.236; 5.E.157.237;5.E.157.238; 5.E.157.239; 5.E.157.154; 5.E.157.157; 5.E.157.166; 5.E.157.169;5.E.157.172; 5.E.157.175; 5.E.157.240; 5.E.157.244; 5.E.166.228; 5.E.166.229;5.E.166.230; 5.E.166.231; 5.E.166.236; 5.E.166.237; 5.E.166.238; 5.E.166.239;5.E.166.154; 5.E.166.157; 5.E.166.166; 5.E.166.169; 5.E.166.172; 5.E.166.175;5.E.166.240; 5.E.166.244; 5.E.169.228; 5.E.169.229; 5.E.169.230; 5.E.169.231;5.E.169.236; 5.E.169.237; 5.E.169.238; 5.E.169.239; 5.E.169.154; 5.E.169.157;5.E.169.166; 5.E.169.169; 5.E.169.172; 5.E.169.175; 5.E.169.240; 5.E.169.244;5.E.172.228; 5.E.172.229; 5.E.172.230; 5.E.172.231; 5.E.172.236; 5.E.172.237;5.E.172.238; 5.E.172.239; 5.E.172.154; 5.E.172.157; 5.E.172.166; 5.E.172.169;5.E.172.172; 5.E.172.175; 5.E.172.240; 5.E.172.244; 5.E.175.228; 5.E.175.229;5.E.175.230; 5.E.175.231; 5.E.175.236; 5.E.175.237; 5.E.175.238; 5.E.175.239;5.E.175.154; 5.E.175.157; 5.E.175.166; 5.E.175.169; 5.E.175.172; 5.E.175.175;5.E.175.240; 5.E.175.244; 5.E.240.228; 5.E.240.229; 5.E.240.230; 5.E.240.231;5.E.240.236; 5.E.240.237; 5.E.240.238; 5.E.240.239; 5.E.240.154; 5.E.240.157;5.E.240.166; 5.E.240.169; 5.E.240.172; 5.E.240.175; 5.E.240.240; 5.E.240.244;5.E.244.228; 5.E.244.229; 5.E.244.230; 5.E.244.231; 5.E.244.236; 5.E.244.237;5.E.244.238; 5.E.244.239; 5.E.244.154; 5.E.244.157; 5.E.244.166; 5.E.244.169;5.E.244.172; 5.E.244.175; 5.E.244.240; 5.E.244.244;

5.Gのプロドラッグ
5.G.228.228; 5.G.228.229; 5.G.228.230; 5.G.228.231; 5.G.228.236; 5.G.228.237;5.G.228.238; 5.G.228.239; 5.G.228.154; 5.G.228.157; 5.G.228.166; 5.G.228.169;5.G.228.172; 5.G.228.175; 5.G.228.240; 5.G.228.244; 5.G.229.228; 5.G.229.229;5.G.229.230; 5.G.229.231; 5.G.229.236; 5.G.229.237; 5.G.229.238; 5.G.229.239;5.G.229.154; 5.G.229.157; 5.G.229.166; 5.G.229.169; 5.G.229.172; 5.G.229.175;5.G.229.240; 5.G.229.244; 5.G.230.228; 5.G.230.229; 5.G.230.230; 5.G.230.231;5.G.230.236; 5.G.230.237; 5.G.230.238; 5.G.230.239; 5.G.230.154; 5.G.230.157;5.G.230.166; 5.G.230.169; 5.G.230.172; 5.G.230.175; 5.G.230.240; 5.G.230.244;5.G.231.228; 5.G.231.229; 5.G.231.230; 5.G.231.231; 5.G.231.236; 5.G.231.237;5.G.231.238; 5.G.231.239; 5.G.231.154; 5.G.231.157; 5.G.231.166; 5.G.231.169;5.G.231.172; 5.G.231.175; 5.G.231.240; 5.G.231.244; 5.G.236.228; 5.G.236.229;5.G.236.230; 5.G.236.231; 5.G.236.236; 5.G.236.237; 5.G.236.238; 5.G.236.239;5.G.236.154; 5.G.236.157; 5.G.236.166; 5.G.236.169; 5.G.236.172; 5.G.236.175;5.G.236.240; 5.G.236.244; 5.G.237.228; 5.G.237.229; 5.G.237.230; 5.G.237.231;5.G.237.236; 5.G.237.237; 5.G.237.238; 5.G.237.239; 5.G.237.154; 5.G.237.157;5.G.237.166; 5.G.237.169; 5.G.237.172; 5.G.237.175; 5.G.237.240; 5.G.237.244;5.G.238.228; 5.G.238.229; 5.G.238.230; 5.G.238.231; 5.G.238.236; 5.G.238.237;5.G.238.238; 5.G.238.239; 5.G.238.154; 5.G.238.157; 5.G.238.166; 5.G.238.169;5.G.238.172; 5.G.238.175; 5.G.238.240; 5.G.238.244; 5.G.239.228; 5.G.239.229;5.G.239.230; 5.G.239.231; 5.G.239.236; 5.G.239.237; 5.G.239.238; 5.G.239.239;5.G.239.154; 5.G.239.157; 5.G.239.166; 5.G.239.169; 5.G.239.172; 5.G.239.175;5.G.239.240; 5.G.239.244; 5.G.154.228; 5.G.154.229; 5.G.154.230; 5.G.154.231; 5.G.154.236;5.G.154.237; 5.G.154.238; 5.G.154.239; 5.G.154.154; 5.G.154.157; 5.G.154.166;5.G.154.169; 5.G.154.172; 5.G.154.175; 5.G.154.240; 5.G.154.244; 5.G.157.228;5.G.157.229; 5.G.157.230; 5.G.157.231; 5.G.157.236; 5.G.157.237; 5.G.157.238;5.G.157.239; 5.G.157.154; 5.G.157.157; 5.G.157.166; 5.G.157.169; 5.G.157.172;5.G.157.175; 5.G.157.240; 5.G.157.244; 5.G.166.228; 5.G.166.229; 5.G.166.230;5.G.166.231; 5.G.166.236; 5.G.166.237; 5.G.166.238; 5.G.166.239; 5.G.166.154;5.G.166.157; 5.G.166.166; 5.G.166.169; 5.G.166.172; 5.G.166.175; 5.G.166.240;5.G.166.244; 5.G.169.228; 5.G.169.229; 5.G.169.230; 5.G.169.231; 5.G.169.236;5.G.169.237; 5.G.169.238; 5.G.169.239; 5.G.169.154; 5.G.169.157; 5.G.169.166;5.G.169.169; 5.G.169.172; 5.G.169.175; 5.G.169.240; 5.G.169.244; 5.G.172.228;5.G.172.229; 5.G.172.230; 5.G.172.231; 5.G.172.236; 5.G.172.237; 5.G.172.238;5.G.172.239; 5.G.172.154; 5.G.172.157; 5.G.172.166; 5.G.172.169; 5.G.172.172;5.G.172.175; 5.G.172.240; 5.G.172.244; 5.G.175.228; 5.G.175.229; 5.G.175.230;5.G.175.231; 5.G.175.236; 5.G.175.237; 5.G.175.238; 5.G.175.239; 5.G.175.154;5.G.175.157; 5.G.175.166; 5.G.175.169; 5.G.175.172; 5.G.175.175; 5.G.175.240;5.G.175.244; 5.G.240.228; 5.G.240.229; 5.G.240.230; 5.G.240.231; 5.G.240.236;5.G.240.237; 5.G.240.238; 5.G.240.239; 5.G.240.154; 5.G.240.157; 5.G.240.166;5.G.240.169; 5.G.240.172; 5.G.240.175; 5.G.240.240; 5.G.240.244; 5.G.244.228;5.G.244.229; 5.G.244.230; 5.G.244.231; 5.G.244.236; 5.G.244.237; 5.G.244.238;5.G.244.239; 5.G.244.154; 5.G.244.157; 5.G.244.166; 5.G.244.169; 5.G.244.172;5.G.244.175; 5.G.244.240; 5.G.244.244;

5.Iのプロドラッグ
5.I.228.228; 5.I.228.229; 5.I.228.230; 5.I.228.231; 5.I.228.236; 5.I.228.237;5.I.228.238; 5.I.228.239; 5.I.228.154; 5.I.228.157; 5.I.228.166; 5.I.228.169;5.I.228.172; 5.I.228.175; 5.I.228.240; 5.I.228.244; 5.I.229.228; 5.I.229.229;5.I.229.230; 5.I.229.231; 5.I.229.236; 5.I.229.237; 5.I.229.238; 5.I.229.239;5.I.229.154; 5.I.229.157; 5.I.229.166; 5.I.229.169; 5.I.229.172; 5.I.229.175;5.I.229.240; 5.I.229.244; 5.I.230.228; 5.I.230.229; 5.I.230.230; 5.I.230.231;5.I.230.236; 5.I.230.237; 5.I.230.238; 5.I.230.239; 5.I.230.154; 5.I.230.157;5.I.230.166; 5.I.230.169; 5.I.230.172; 5.I.230.175; 5.I.230.240; 5.I.230.244;5.I.231.228; 5.I.231.229; 5.I.231.230; 5.I.231.231; 5.I.231.236; 5.I.231.237;5.I.231.238; 5.I.231.239; 5.I.231.154; 5.I.231.157; 5.I.231.166; 5.I.231.169;5.I.231.172; 5.I.231.175; 5.I.231.240; 5.I.231.244; 5.I.236.228; 5.I.236.229;5.I.236.230; 5.I.236.231; 5.I.236.236; 5.I.236.237; 5.I.236.238; 5.I.236.239;5.I.236.154; 5.I.236.157; 5.I.236.166; 5.I.236.169; 5.I.236.172; 5.I.236.175;5.I.236.240; 5.I.236.244; 5.I.237.228; 5.I.237.229; 5.I.237.230; 5.I.237.231;5.I.237.236; 5.I.237.237; 5.I.237.238; 5.I.237.239; 5.I.237.154; 5.I.237.157;5.I.237.166; 5.I.237.169; 5.I.237.172; 5.I.237.175; 5.I.237.240; 5.I.237.244;5.I.238.228; 5.I.238.229; 5.I.238.230; 5.I.238.231; 5.I.238.236; 5.I.238.237;5.I.238.238; 5.I.238.239; 5.I.238.154; 5.I.238.157; 5.I.238.166; 5.I.238.169;5.I.238.172; 5.I.238.175; 5.I.238.240; 5.I.238.244; 5.I.239.228; 5.I.239.229;5.I.239.230; 5.I.239.231; 5.I.239.236; 5.I.239.237; 5.I.239.238; 5.I.239.239;5.I.239.154; 5.I.239.157; 5.I.239.166; 5.I.239.169; 5.I.239.172; 5.I.239.175;5.I.239.240; 5.I.239.244; 5.I.154.228; 5.I.154.229; 5.I.154.230; 5.I.154.231;5.I.154.236; 5.I.154.237; 5.I.154.238; 5.I.154.239; 5.I.154.154; 5.I.154.157;5.I.154.166; 5.I.154.169; 5.I.154.172; 5.I.154.175; 5.I.154.240; 5.I.154.244;5.I.157.228; 5.I.157.229; 5.I.157.230; 5.I.157.231; 5.I.157.236; 5.I.157.237;5.I.157.238; 5.I.157.239; 5.I.157.154; 5.I.157.157; 5.I.157.166; 5.I.157.169;5.I.157.172; 5.I.157.175; 5.I.157.240; 5.I.157.244; 5.I.166.228; 5.I.166.229;5.I.166.230; 5.I.166.231; 5.I.166.236; 5.I.166.237; 5.I.166.238; 5.I.166.239;5.I.166.154; 5.I.166.157; 5.I.166.166; 5.I.166.169; 5.I.166.172; 5.I.166.175;5.I.166.240; 5.I.166.244; 5.I.169.228; 5.I.169.229; 5.I.169.230; 5.I.169.231;5.I.169.236; 5.I.169.237; 5.I.169.238; 5.I.169.239; 5.I.169.154; 5.I.169.157;5.I.169.166; 5.I.169.169; 5.I.169.172; 5.I.169.175; 5.I.169.240; 5.I.169.244;5.I.172.228; 5.I.172.229; 5.I.172.230; 5.I.172.231; 5.I.172.236; 5.I.172.237;5.I.172.238; 5.I.172.239; 5.I.172.154; 5.I.172.157; 5.I.172.166; 5.I.172.169;5.I.172.172; 5.I.172.175; 5.I.172.240; 5.I.172.244; 5.I.175.228; 5.I.175.229;5.I.175.230; 5.I.175.231; 5.I.175.236; 5.I.175.237; 5.I.175.238; 5.I.175.239;5.I.175.154; 5.I.175.157; 5.I.175.166; 5.I.175.169; 5.I.175.172; 5.I.175.175;5.I.175.240; 5.I.175.244; 5.I.240.228; 5.I.240.229; 5.I.240.230; 5.I.240.231;5.I.240.236; 5.I.240.237; 5.I.240.238; 5.I.240.239; 5.I.240.154; 5.I.240.157;5.I.240.166; 5.I.240.169; 5.I.240.172; 5.I.240.175; 5.I.240.240; 5.I.240.244;5.I.244.228; 5.I.244.229; 5.I.244.230; 5.I.244.231; 5.I.244.236; 5.I.244.237;5.I.244.238; 5.I.244.239; 5.I.244.154; 5.I.244.157; 5.I.244.166; 5.I.244.169;5.I.244.172; 5.I.244.175; 5.I.244.240; 5.I.244.244;

5.Jのプロドラッグ
5.J.228.228; 5.J.228.229; 5.J.228.230; 5.J.228.231; 5.J.228.236; 5.J.228.237;5.J.228.238; 5.J.228.239; 5.J.228.154; 5.J.228.157; 5.J.228.166; 5.J.228.169;5.J.228.172; 5.J.228.175; 5.J.228.240; 5.J.228.244; 5.J.229.228; 5.J.229.229;5.J.229.230; 5.J.229.231; 5.J.229.236; 5.J.229.237; 5.J.229.238; 5.J.229.239;5.J.229.154; 5.J.229.157; 5.J.229.166; 5.J.229.169; 5.J.229.172; 5.J.229.175;5.J.229.240; 5.J.229.244; 5.J.230.228; 5.J.230.229; 5.J.230.230; 5.J.230.231;5.J.230.236; 5.J.230.237; 5.J.230.238; 5.J.230.239; 5.J.230.154; 5.J.230.157;5.J.230.166; 5.J.230.169; 5.J.230.172; 5.J.230.175; 5.J.230.240; 5.J.230.244;5.J.231.228; 5.J.231.229; 5.J.231.230; 5.J.231.231; 5.J.231.236; 5.J.231.237;5.J.231.238; 5.J.231.239; 5.J.231.154; 5.J.231.157; 5.J.231.166; 5.J.231.169;5.J.231.172; 5.J.231.175; 5.J.231.240; 5.J.231.244; 5.J.236.228; 5.J.236.229;5.J.236.230; 5.J.236.231; 5.J.236.236; 5.J.236.237; 5.J.236.238; 5.J.236.239;5.J.236.154; 5.J.236.157; 5.J.236.166; 5.J.236.169; 5.J.236.172; 5.J.236.175;5.J.236.240; 5.J.236.244; 5.J.237.228; 5.J.237.229; 5.J.237.230; 5.J.237.231;5.J.237.236; 5.J.237.237; 5.J.237.238; 5.J.237.239; 5.J.237.154; 5.J.237.157;5.J.237.166; 5.J.237.169; 5.J.237.172; 5.J.237.175; 5.J.237.240; 5.J.237.244;5.J.238.228; 5.J.238.229; 5.J.238.230; 5.J.238.231; 5.J.238.236; 5.J.238.237;5.J.238.238; 5.J.238.239; 5.J.238.154; 5.J.238.157; 5.J.238.166; 5.J.238.169;5.J.238.172; 5.J.238.175; 5.J.238.240; 5.J.238.244; 5.J.239.228; 5.J.239.229;5.J.239.230; 5.J.239.231; 5.J.239.236; 5.J.239.237; 5.J.239.238; 5.J.239.239;5.J.239.154; 5.J.239.157; 5.J.239.166; 5.J.239.169; 5.J.239.172; 5.J.239.175;5.J.239.240; 5.J.239.244; 5.J.154.228; 5.J.154.229; 5.J.154.230; 5.J.154.231;5.J.154.236; 5.J.154.237; 5.J.154.238; 5.J.154.239; 5.J.154.154; 5.J.154.157;5.J.154.166; 5.J.154.169; 5.J.154.172; 5.J.154.175; 5.J.154.240; 5.J.154.244;5.J.157.228; 5.J.157.229; 5.J.157.230; 5.J.157.231; 5.J.157.236; 5.J.157.237;5.J.157.238; 5.J.157.239; 5.J.157.154; 5.J.157.157; 5.J.157.166; 5.J.157.169;5.J.157.172; 5.J.157.175; 5.J.157.240; 5.J.157.244; 5.J.166.228; 5.J.166.229;5.J.166.230; 5.J.166.231; 5.J.166.236; 5.J.166.237; 5.J.166.238; 5.J.166.239;5.J.166.154; 5.J.166.157; 5.J.166.166; 5.J.166.169; 5.J.166.172; 5.J.166.175;5.J.166.240; 5.J.166.244; 5.J.169.228; 5.J.169.229; 5.J.169.230; 5.J.169.231;5.J.169.236; 5.J.169.237; 5.J.169.238; 5.J.169.239; 5.J.169.154; 5.J.169.157;5.J.169.166; 5.J.169.169; 5.J.169.172; 5.J.169.175; 5.J.169.240; 5.J.169.244;5.J.172.228; 5.J.172.229; 5.J.172.230; 5.J.172.231; 5.J.172.236; 5.J.172.237;5.J.172.238; 5.J.172.239; 5.J.172.154; 5.J.172.157; 5.J.172.166; 5.J.172.169;5.J.172.172; 5.J.172.175; 5.J.172.240; 5.J.172.244; 5.J.175.228; 5.J.175.229;5.J.175.230; 5.J.175.231; 5.J.175.236; 5.J.175.237; 5.J.175.238; 5.J.175.239;5.J.175.154; 5.J.175.157; 5.J.175.166; 5.J.175.169; 5.J.175.172; 5.J.175.175;5.J.175.240; 5.J.175.244; 5.J.240.228; 5.J.240.229; 5.J.240.230; 5.J.240.231;5.J.240.236; 5.J.240.237; 5.J.240.238; 5.J.240.239; 5.J.240.154; 5.J.240.157;5.J.240.166; 5.J.240.169; 5.J.240.172; 5.J.240.175; 5.J.240.240; 5.J.240.244;5.J.244.228; 5.J.244.229; 5.J.244.230; 5.J.244.231; 5.J.244.236; 5.J.244.237;5.J.244.238; 5.J.244.239; 5.J.244.154; 5.J.244.157; 5.J.244.166; 5.J.244.169;5.J.244.172; 5.J.244.175; 5.J.244.240; 5.J.244.244;

5.Lのプロドラッグ
5.L.228.228; 5.L.228.229; 5.L.228.230; 5.L.228.231; 5.L.228.236; 5.L.228.237;5.L.228.238; 5.L.228.239; 5.L.228.154; 5.L.228.157; 5.L.228.166; 5.L.228.169;5.L.228.172; 5.L.228.175; 5.L.228.240; 5.L.228.244; 5.L.229.228; 5.L.229.229;5.L.229.230; 5.L.229.231; 5.L.229.236; 5.L.229.237; 5.L.229.238; 5.L.229.239;5.L.229.154; 5.L.229.157; 5.L.229.166; 5.L.229.169; 5.L.229.172; 5.L.229.175;5.L.229.240; 5.L.229.244; 5.L.230.228; 5.L.230.229; 5.L.230.230; 5.L.230.231;5.L.230.236; 5.L.230.237; 5.L.230.238; 5.L.230.239; 5.L.230.154; 5.L.230.157;5.L.230.166; 5.L.230.169; 5.L.230.172; 5.L.230.175; 5.L.230.240; 5.L.230.244;5.L.231.228; 5.L.231.229; 5.L.231.230; 5.L.231.231; 5.L.231.236; 5.L.231.237;5.L.231.238; 5.L.231.239; 5.L.231.154; 5.L.231.157; 5.L.231.166; 5.L.231.169;5.L.231.172; 5.L.231.175; 5.L.231.240; 5.L.231.244; 5.L.236.228; 5.L.236.229;5.L.236.230; 5.L.236.231; 5.L.236.236; 5.L.236.237; 5.L.236.238; 5.L.236.239;5.L.236.154; 5.L.236.157; 5.L.236.166; 5.L.236.169; 5.L.236.172; 5.L.236.175;5.L.236.240; 5.L.236.244; 5.L.237.228; 5.L.237.229; 5.L.237.230; 5.L.237.231;5.L.237.236; 5.L.237.237; 5.L.237.238; 5.L.237.239; 5.L.237.154; 5.L.237.157;5.L.237.166; 5.L.237.169; 5.L.237.172; 5.L.237.175; 5.L.237.240; 5.L.237.244;5.L.238.228; 5.L.238.229; 5.L.238.230; 5.L.238.231; 5.L.238.236; 5.L.238.237;5.L.238.238; 5.L.238.239; 5.L.238.154; 5.L.238.157; 5.L.238.166; 5.L.238.169; 5.L.238.172;5.L.238.175; 5.L.238.240; 5.L.238.244; 5.L.239.228; 5.L.239.229; 5.L.239.230;5.L.239.231; 5.L.239.236; 5.L.239.237; 5.L.239.238; 5.L.239.239; 5.L.239.154;5.L.239.157; 5.L.239.166; 5.L.239.169; 5.L.239.172; 5.L.239.175; 5.L.239.240;5.L.239.244; 5.L.154.228; 5.L.154.229; 5.L.154.230; 5.L.154.231; 5.L.154.236;5.L.154.237; 5.L.154.238; 5.L.154.239; 5.L.154.154; 5.L.154.157; 5.L.154.166;5.L.154.169; 5.L.154.172; 5.L.154.175; 5.L.154.240; 5.L.154.244; 5.L.157.228;5.L.157.229; 5.L.157.230; 5.L.157.231; 5.L.157.236; 5.L.157.237; 5.L.157.238;5.L.157.239; 5.L.157.154; 5.L.157.157; 5.L.157.166; 5.L.157.169; 5.L.157.172;5.L.157.175; 5.L.157.240; 5.L.157.244; 5.L.166.228; 5.L.166.229; 5.L.166.230;5.L.166.231; 5.L.166.236; 5.L.166.237; 5.L.166.238; 5.L.166.239; 5.L.166.154;5.L.166.157; 5.L.166.166; 5.L.166.169; 5.L.166.172; 5.L.166.175; 5.L.166.240;5.L.166.244; 5.L.169.228; 5.L.169.229; 5.L.169.230; 5.L.169.231; 5.L.169.236;5.L.169.237; 5.L.169.238; 5.L.169.239; 5.L.169.154; 5.L.169.157; 5.L.169.166;5.L.169.169; 5.L.169.172; 5.L.169.175; 5.L.169.240; 5.L.169.244; 5.L.172.228;5.L.172.229; 5.L.172.230; 5.L.172.231; 5.L.172.236; 5.L.172.237; 5.L.172.238;5.L.172.239; 5.L.172.154; 5.L.172.157; 5.L.172.166; 5.L.172.169; 5.L.172.172;5.L.172.175; 5.L.172.240; 5.L.172.244; 5.L.175.228; 5.L.175.229; 5.L.175.230;5.L.175.231; 5.L.175.236; 5.L.175.237; 5.L.175.238; 5.L.175.239; 5.L.175.154;5.L.175.157; 5.L.175.166; 5.L.175.169; 5.L.175.172; 5.L.175.175; 5.L.175.240;5.L.175.244; 5.L.240.228; 5.L.240.229; 5.L.240.230; 5.L.240.231; 5.L.240.236;5.L.240.237; 5.L.240.238; 5.L.240.239; 5.L.240.154; 5.L.240.157; 5.L.240.166;5.L.240.169; 5.L.240.172; 5.L.240.175; 5.L.240.240; 5.L.240.244; 5.L.244.228;5.L.244.229; 5.L.244.230; 5.L.244.231; 5.L.244.236; 5.L.244.237; 5.L.244.238;5.L.244.239; 5.L.244.154; 5.L.244.157; 5.L.244.166; 5.L.244.169; 5.L.244.172;5.L.244.175; 5.L.244.240; 5.L.244.244;

5.Oのプロドラッグ
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.157.169;5.O.157.172; 5.O.157.175; 5.O.157.240; 5.O.157.244; 5.O.166.228; 5.O.166.229;5.O.166.230; 5.O.166.231; 5.O.166.236; 5.O.166.237; 5.O.166.238; 5.O.166.239;5.O.166.154; 5.O.166.157; 5.O.166.166; 5.O.166.169; 5.O.166.172; 5.O.166.175;5.O.166.240; 5.O.166.244; 5.O.169.228; 5.O.169.229; 5.O.169.230; 5.O.169.231; 5.O.169.236;5.O.169.237; 5.O.169.238; 5.O.169.239; 5.O.169.154; 5.O.169.157; 5.O.169.166;5.O.169.169; 5.O.169.172; 5.O.169.175; 5.O.169.240; 5.O.169.244; 5.O.172.228;5.O.172.229; 5.O.172.230; 5.O.172.231; 5.O.172.236; 5.O.172.237; 5.O.172.238;5.O.172.239; 5.O.172.154; 5.O.172.157; 5.O.172.166; 5.O.172.169; 5.O.172.172;5.O.172.175; 5.O.172.240; 5.O.172.244; 5.O.175.228; 5.O.175.229; 5.O.175.230;5.O.175.231; 5.O.175.236; 5.O.175.237; 5.O.175.238; 5.O.175.239; 5.O.175.154;5.O.175.157; 5.O.175.166; 5.O.175.169; 5.O.175.172; 5.O.175.175; 5.O.175.240;5.O.175.244; 5.O.240.228; 5.O.240.229; 5.O.240.230; 5.O.240.231; 5.O.240.236;5.O.240.237; 5.O.240.238; 5.O.240.239; 5.O.240.154; 5.O.240.157; 5.O.240.166;5.O.240.169; 5.O.240.172; 5.O.240.175; 5.O.240.240; 5.O.240.244; 5.O.244.228;5.O.244.229; 5.O.244.230; 5.O.244.231; 5.O.244.236; 5.O.244.237; 5.O.244.238;5.O.244.239; 5.O.244.154; 5.O.244.157; 5.O.244.166; 5.O.244.169; 5.O.244.172;5.O.244.175; 5.O.244.240; 5.O.244.244;

5.Pのプロドラッグ
5.P.228.228; 5.P.228.229; 5.P.228.230; 5.P.228.231; 5.P.228.236; 5.P.228.237;5.P.228.238; 5.P.228.239; 5.P.228.154; 5.P.228.157; 5.P.228.166; 5.P.228.169;5.P.228.172; 5.P.228.175; 5.P.228.240; 5.P.228.244; 5.P.229.228; 5.P.229.229;5.P.229.230; 5.P.229.231; 5.P.229.236; 5.P.229.237; 5.P.229.238; 5.P.229.239;5.P.229.154; 5.P.229.157; 5.P.229.166; 5.P.229.169; 5.P.229.172; 5.P.229.175;5.P.229.240; 5.P.229.244; 5.P.230.228; 5.P.230.229; 5.P.230.230; 5.P.230.231;5.P.230.236; 5.P.230.237; 5.P.230.238; 5.P.230.239; 5.P.230.154; 5.P.230.157;5.P.230.166; 5.P.230.169; 5.P.230.172; 5.P.230.175; 5.P.230.240; 5.P.230.244;5.P.231.228; 5.P.231.229; 5.P.231.230; 5.P.231.231; 5.P.231.236; 5.P.231.237;5.P.231.238; 5.P.231.239; 5.P.231.154; 5.P.231.157; 5.P.231.166; 5.P.231.169;5.P.231.172; 5.P.231.175; 5.P.231.240; 5.P.231.244; 5.P.236.228; 5.P.236.229;5.P.236.230; 5.P.236.231; 5.P.236.236; 5.P.236.237; 5.P.236.238; 5.P.236.239;5.P.236.154; 5.P.236.157; 5.P.236.166; 5.P.236.169; 5.P.236.172; 5.P.236.175;5.P.236.240; 5.P.236.244; 5.P.237.228; 5.P.237.229; 5.P.237.230; 5.P.237.231;5.P.237.236; 5.P.237.237; 5.P.237.238; 5.P.237.239; 5.P.237.154; 5.P.237.157;5.P.237.166; 5.P.237.169; 5.P.237.172; 5.P.237.175; 5.P.237.240; 5.P.237.244;5.P.238.228; 5.P.238.229; 5.P.238.230; 5.P.238.231; 5.P.238.236; 5.P.238.237;5.P.238.238; 5.P.238.239; 5.P.238.154; 5.P.238.157; 5.P.238.166; 5.P.238.169;5.P.238.172; 5.P.238.175; 5.P.238.240; 5.P.238.244; 5.P.239.228; 5.P.239.229;5.P.239.230; 5.P.239.231; 5.P.239.236; 5.P.239.237; 5.P.239.238; 5.P.239.239;5.P.239.154; 5.P.239.157; 5.P.239.166; 5.P.239.169; 5.P.239.172; 5.P.239.175;5.P.239.240; 5.P.239.244; 5.P.154.228; 5.P.154.229; 5.P.154.230; 5.P.154.231;5.P.154.236; 5.P.154.237; 5.P.154.238; 5.P.154.239; 5.P.154.154; 5.P.154.157;5.P.154.166; 5.P.154.169; 5.P.154.172; 5.P.154.175; 5.P.154.240; 5.P.154.244;5.P.157.228; 5.P.157.229; 5.P.157.230; 5.P.157.231; 5.P.157.236; 5.P.157.237;5.P.157.238; 5.P.157.239; 5.P.157.154; 5.P.157.157; 5.P.157.166; 5.P.157.169;5.P.157.172; 5.P.157.175; 5.P.157.240; 5.P.157.244; 5.P.166.228; 5.P.166.229;5.P.166.230; 5.P.166.231; 5.P.166.236; 5.P.166.237; 5.P.166.238; 5.P.166.239;5.P.166.154; 5.P.166.157; 5.P.166.166; 5.P.166.169; 5.P.166.172; 5.P.166.175;5.P.166.240; 5.P.166.244; 5.P.169.228; 5.P.169.229; 5.P.169.230; 5.P.169.231;5.P.169.236; 5.P.169.237; 5.P.169.238; 5.P.169.239; 5.P.169.154; 5.P.169.157;5.P.169.166; 5.P.169.169; 5.P.169.172; 5.P.169.175; 5.P.169.240; 5.P.169.244;5.P.172.228; 5.P.172.229; 5.P.172.230; 5.P.172.231; 5.P.172.236; 5.P.172.237;5.P.172.238; 5.P.172.239; 5.P.172.154; 5.P.172.157; 5.P.172.166; 5.P.172.169;5.P.172.172; 5.P.172.175; 5.P.172.240; 5.P.172.244; 5.P.175.228; 5.P.175.229;5.P.175.230; 5.P.175.231; 5.P.175.236; 5.P.175.237; 5.P.175.238; 5.P.175.239;5.P.175.154; 5.P.175.157; 5.P.175.166; 5.P.175.169; 5.P.175.172; 5.P.175.175;5.P.175.240; 5.P.175.244; 5.P.240.228; 5.P.240.229; 5.P.240.230; 5.P.240.231;5.P.240.236; 5.P.240.237; 5.P.240.238; 5.P.240.239; 5.P.240.154; 5.P.240.157;5.P.240.166; 5.P.240.169; 5.P.240.172; 5.P.240.175; 5.P.240.240; 5.P.240.244;5.P.244.228; 5.P.244.229; 5.P.244.230; 5.P.244.231; 5.P.244.236; 5.P.244.237;5.P.244.238; 5.P.244.239; 5.P.244.154; 5.P.244.157; 5.P.244.166; 5.P.244.169;5.P.244.172; 5.P.244.175; 5.P.244.240; 5.P.244.244;

5.Uのプロドラッグ
5.U.228.228;5.U.228.229; 5.U.228.230; 5.U.228.231; 5.U.228.236; 5.U.228.237; 5.U.228.238;5.U.228.239; 5.U.228.154; 5.U.228.157; 5.U.228.166; 5.U.228.169; 5.U.228.172;5.U.228.175; 5.U.228.240; 5.U.228.244; 5.U.229.228; 5.U.229.229; 5.U.229.230;5.U.229.231; 5.U.229.236; 5.U.229.237; 5.U.229.238; 5.U.229.239; 5.U.229.154;5.U.229.157; 5.U.229.166; 5.U.229.169; 5.U.229.172; 5.U.229.175; 5.U.229.240;5.U.229.244; 5.U.230.228; 5.U.230.229; 5.U.230.230; 5.U.230.231; 5.U.230.236;5.U.230.237; 5.U.230.238; 5.U.230.239; 5.U.230.154; 5.U.230.157; 5.U.230.166;5.U.230.169; 5.U.230.172; 5.U.230.175; 5.U.230.240; 5.U.230.244; 5.U.231.228;5.U.231.229; 5.U.231.230; 5.U.231.231; 5.U.231.236; 5.U.231.237; 5.U.231.238;5.U.231.239; 5.U.231.154; 5.U.231.157; 5.U.231.166; 5.U.231.169; 5.U.231.172;5.U.231.175; 5.U.231.240; 5.U.231.244; 5.U.236.228; 5.U.236.229; 5.U.236.230;5.U.236.231; 5.U.236.236; 5.U.236.237; 5.U.236.238; 5.U.236.239; 5.U.236.154;5.U.236.157; 5.U.236.166; 5.U.236.169; 5.U.236.172; 5.U.236.175; 5.U.236.240;5.U.236.244; 5.U.237.228; 5.U.237.229; 5.U.237.230; 5.U.237.231; 5.U.237.236;5.U.237.237; 5.U.237.238; 5.U.237.239; 5.U.237.154; 5.U.237.157; 5.U.237.166;5.U.237.169; 5.U.237.172; 5.U.237.175; 5.U.237.240; 5.U.237.244; 5.U.238.228;5.U.238.229; 5.U.238.230; 5.U.238.231; 5.U.238.236; 5.U.238.237; 5.U.238.238;5.U.238.239; 5.U.238.154; 5.U.238.157; 5.U.238.166; 5.U.238.169; 5.U.238.172;5.U.238.175; 5.U.238.240; 5.U.238.244; 5.U.239.228; 5.U.239.229; 5.U.239.230;5.U.239.231; 5.U.239.236; 5.U.239.237; 5.U.239.238; 5.U.239.239; 5.U.239.154;5.U.239.157; 5.U.239.166; 5.U.239.169; 5.U.239.172; 5.U.239.175; 5.U.239.240;5.U.239.244; 5.U.154.228; 5.U.154.229; 5.U.154.230; 5.U.154.231; 5.U.154.236;5.U.154.237; 5.U.154.238; 5.U.154.239; 5.U.154.154; 5.U.154.157; 5.U.154.166;5.U.154.169; 5.U.154.172; 5.U.154.175; 5.U.154.240; 5.U.154.244; 5.U.157.228;5.U.157.229; 5.U.157.230; 5.U.157.231; 5.U.157.236; 5.U.157.237; 5.U.157.238;5.U.157.239; 5.U.157.154; 5.U.157.157; 5.U.157.166; 5.U.157.169; 5.U.157.172;5.U.157.175; 5.U.157.240; 5.U.157.244; 5.U.166.228; 5.U.166.229; 5.U.166.230;5.U.166.231; 5.U.166.236; 5.U.166.237; 5.U.166.238; 5.U.166.239; 5.U.166.154;5.U.166.157; 5.U.166.166; 5.U.166.169; 5.U.166.172; 5.U.166.175; 5.U.166.240;5.U.166.244; 5.U.169.228; 5.U.169.229; 5.U.169.230; 5.U.169.231; 5.U.169.236;5.U.169.237; 5.U.169.238; 5.U.169.239; 5.U.169.154; 5.U.169.157; 5.U.169.166;5.U.169.169; 5.U.169.172; 5.U.169.175; 5.U.169.240; 5.U.169.244; 5.U.172.228;5.U.172.229; 5.U.172.230; 5.U.172.231; 5.U.172.236; 5.U.172.237; 5.U.172.238;5.U.172.239; 5.U.172.154; 5.U.172.157; 5.U.172.166; 5.U.172.169; 5.U.172.172;5.U.172.175; 5.U.172.240; 5.U.172.244; 5.U.175.228; 5.U.175.229; 5.U.175.230;5.U.175.231; 5.U.175.236; 5.U.175.237; 5.U.175.238; 5.U.175.239; 5.U.175.154;5.U.175.157; 5.U.175.166; 5.U.175.169; 5.U.175.172; 5.U.175.175; 5.U.175.240;5.U.175.244; 5.U.240.228; 5.U.240.229; 5.U.240.230; 5.U.240.231; 5.U.240.236;5.U.240.237; 5.U.240.238; 5.U.240.239; 5.U.240.154; 5.U.240.157; 5.U.240.166;5.U.240.169; 5.U.240.172; 5.U.240.175; 5.U.240.240; 5.U.240.244; 5.U.244.228;5.U.244.229; 5.U.244.230; 5.U.244.231; 5.U.244.236; 5.U.244.237; 5.U.244.238;5.U.244.239; 5.U.244.154; 5.U.244.157; 5.U.244.166; 5.U.244.169; 5.U.244.172;5.U.244.175; 5.U.244.240; 5.U.244.244;

5.Wのプロドラッグ
5.W.228.228;5.W.228.229; 5.W.228.230; 5.W.228.231; 5.W.228.236; 5.W.228.237; 5.W.228.238;5.W.228.239; 5.W.228.154; 5.W.228.157; 5.W.228.166; 5.W.228.169; 5.W.228.172;5.W.228.175; 5.W.228.240; 5.W.228.244; 5.W.229.228; 5.W.229.229; 5.W.229.230;5.W.229.231; 5.W.229.236; 5.W.229.237; 5.W.229.238; 5.W.229.239; 5.W.229.154;5.W.229.157; 5.W.229.166; 5.W.229.169; 5.W.229.172; 5.W.229.175; 5.W.229.240;5.W.229.244; 5.W.230.228; 5.W.230.229; 5.W.230.230; 5.W.230.231; 5.W.230.236;5.W.230.237; 5.W.230.238; 5.W.230.239; 5.W.230.154; 5.W.230.157; 5.W.230.166;5.W.230.169; 5.W.230.172; 5.W.230.175; 5.W.230.240; 5.W.230.244; 5.W.231.228;5.W.231.229; 5.W.231.230; 5.W.231.231; 5.W.231.236; 5.W.231.237; 5.W.231.238;5.W.231.239; 5.W.231.154; 5.W.231.157; 5.W.231.166; 5.W.231.169; 5.W.231.172;5.W.231.175; 5.W.231.240; 5.W.231.244; 5.W.236.228; 5.W.236.229; 5.W.236.230;5.W.236.231; 5.W.236.236; 5.W.236.237; 5.W.236.238; 5.W.236.239; 5.W.236.154;5.W.236.157; 5.W.236.166; 5.W.236.169; 5.W.236.172; 5.W.236.175; 5.W.236.240;5.W.236.244; 5.W.237.228; 5.W.237.229; 5.W.237.230; 5.W.237.231; 5.W.237.236;5.W.237.237; 5.W.237.238; 5.W.237.239; 5.W.237.154; 5.W.237.157; 5.W.237.166;5.W.237.169; 5.W.237.172; 5.W.237.175; 5.W.237.240; 5.W.237.244; 5.W.238.228; 5.W.238.229;5.W.238.230; 5.W.238.231; 5.W.238.236; 5.W.238.237; 5.W.238.238; 5.W.238.239;5.W.238.154; 5.W.238.157; 5.W.238.166; 5.W.238.169; 5.W.238.172; 5.W.238.175;5.W.238.240; 5.W.238.244; 5.W.239.228; 5.W.239.229; 5.W.239.230; 5.W.239.231;5.W.239.236; 5.W.239.237; 5.W.239.238; 5.W.239.239; 5.W.239.154; 5.W.239.157;5.W.239.166; 5.W.239.169; 5.W.239.172; 5.W.239.175; 5.W.239.240; 5.W.239.244;5.W.154.228; 5.W.154.229; 5.W.154.230; 5.W.154.231; 5.W.154.236; 5.W.154.237;5.W.154.238; 5.W.154.239; 5.W.154.154; 5.W.154.157; 5.W.154.166; 5.W.154.169;5.W.154.172; 5.W.154.175; 5.W.154.240; 5.W.154.244; 5.W.157.228; 5.W.157.229;5.W.157.230; 5.W.157.231; 5.W.157.236; 5.W.157.237; 5.W.157.238; 5.W.157.239;5.W.157.154; 5.W.157.157; 5.W.157.166; 5.W.157.169; 5.W.157.172; 5.W.157.175;5.W.157.240; 5.W.157.244; 5.W.166.228; 5.W.166.229; 5.W.166.230; 5.W.166.231;5.W.166.236; 5.W.166.237; 5.W.166.238; 5.W.166.239; 5.W.166.154; 5.W.166.157;5.W.166.166; 5.W.166.169; 5.W.166.172; 5.W.166.175; 5.W.166.240; 5.W.166.244;5.W.169.228; 5.W.169.229; 5.W.169.230; 5.W.169.231; 5.W.169.236; 5.W.169.237;5.W.169.238; 5.W.169.239; 5.W.169.154; 5.W.169.157; 5.W.169.166; 5.W.169.169;5.W.169.172; 5.W.169.175; 5.W.169.240; 5.W.169.244; 5.W.172.228; 5.W.172.229;5.W.172.230; 5.W.172.231; 5.W.172.236; 5.W.172.237; 5.W.172.238; 5.W.172.239;5.W.172.154; 5.W.172.157; 5.W.172.166; 5.W.172.169; 5.W.172.172; 5.W.172.175;5.W.172.240; 5.W.172.244; 5.W.175.228; 5.W.175.229; 5.W.175.230; 5.W.175.231;5.W.175.236; 5.W.175.237; 5.W.175.238; 5.W.175.239; 5.W.175.154; 5.W.175.157;5.W.175.166; 5.W.175.169; 5.W.175.172; 5.W.175.175; 5.W.175.240; 5.W.175.244;5.W.240.228; 5.W.240.229; 5.W.240.230; 5.W.240.231; 5.W.240.236; 5.W.240.237;5.W.240.238; 5.W.240.239; 5.W.240.154; 5.W.240.157; 5.W.240.166; 5.W.240.169;5.W.240.172; 5.W.240.175; 5.W.240.240; 5.W.240.244; 5.W.244.228; 5.W.244.229;5.W.244.230; 5.W.244.231; 5.W.244.236; 5.W.244.237; 5.W.244.238; 5.W.244.239;5.W.244.154; 5.W.244.157; 5.W.244.166; 5.W.244.169; 5.W.244.172; 5.W.244.175;5.W.244.240; 5.W.244.244;

5.Yのプロドラッグ
5.Y.228.228; 5.Y.228.229; 5.Y.228.230; 5.Y.228.231; 5.Y.228.236; 5.Y.228.237;5.Y.228.238; 5.Y.228.239; 5.Y.228.154; 5.Y.228.157; 5.Y.228.166; 5.Y.228.169;5.Y.228.172; 5.Y.228.175; 5.Y.228.240; 5.Y.228.244; 5.Y.229.228; 5.Y.229.229;5.Y.229.230; 5.Y.229.231; 5.Y.229.236; 5.Y.229.237; 5.Y.229.238; 5.Y.229.239;5.Y.229.154; 5.Y.229.157; 5.Y.229.166; 5.Y.229.169; 5.Y.229.172; 5.Y.229.175;5.Y.229.240; 5.Y.229.244; 5.Y.230.228; 5.Y.230.229; 5.Y.230.230; 5.Y.230.231;5.Y.230.236; 5.Y.230.237; 5.Y.230.238; 5.Y.230.239; 5.Y.230.154; 5.Y.230.157;5.Y.230.166; 5.Y.230.169; 5.Y.230.172; 5.Y.230.175; 5.Y.230.240; 5.Y.230.244;5.Y.231.228; 5.Y.231.229; 5.Y.231.230; 5.Y.231.231; 5.Y.231.236; 5.Y.231.237;5.Y.231.238; 5.Y.231.239; 5.Y.231.154; 5.Y.231.157; 5.Y.231.166; 5.Y.231.169;5.Y.231.172; 5.Y.231.175; 5.Y.231.240; 5.Y.231.244; 5.Y.236.228; 5.Y.236.229;5.Y.236.230; 5.Y.236.231; 5.Y.236.236; 5.Y.236.237; 5.Y.236.238; 5.Y.236.239;5.Y.236.154; 5.Y.236.157; 5.Y.236.166; 5.Y.236.169; 5.Y.236.172; 5.Y.236.175;5.Y.236.240; 5.Y.236.244; 5.Y.237.228; 5.Y.237.229; 5.Y.237.230; 5.Y.237.231;5.Y.237.236; 5.Y.237.237; 5.Y.237.238; 5.Y.237.239; 5.Y.237.154; 5.Y.237.157;5.Y.237.166; 5.Y.237.169; 5.Y.237.172; 5.Y.237.175; 5.Y.237.240; 5.Y.237.244;5.Y.238.228; 5.Y.238.229; 5.Y.238.230; 5.Y.238.231; 5.Y.238.236; 5.Y.238.237;5.Y.238.238; 5.Y.238.239; 5.Y.238.154; 5.Y.238.157; 5.Y.238.166; 5.Y.238.169;5.Y.238.172; 5.Y.238.175; 5.Y.238.240; 5.Y.238.244; 5.Y.239.228; 5.Y.239.229;5.Y.239.230; 5.Y.239.231; 5.Y.239.236; 5.Y.239.237; 5.Y.239.238; 5.Y.239.239;5.Y.239.154; 5.Y.239.157; 5.Y.239.166; 5.Y.239.169; 5.Y.239.172; 5.Y.239.175;5.Y.239.240; 5.Y.239.244; 5.Y.154.228; 5.Y.154.229; 5.Y.154.230; 5.Y.154.231;5.Y.154.236; 5.Y.154.237; 5.Y.154.238; 5.Y.154.239; 5.Y.154.154; 5.Y.154.157;5.Y.154.166; 5.Y.154.169; 5.Y.154.172; 5.Y.154.175; 5.Y.154.240; 5.Y.154.244;5.Y.157.228; 5.Y.157.229; 5.Y.157.230; 5.Y.157.231; 5.Y.157.236; 5.Y.157.237;5.Y.157.238; 5.Y.157.239; 5.Y.157.154; 5.Y.157.157; 5.Y.157.166; 5.Y.157.169;5.Y.157.172; 5.Y.157.175; 5.Y.157.240; 5.Y.157.244; 5.Y.166.228; 5.Y.166.229;5.Y.166.230; 5.Y.166.231; 5.Y.166.236; 5.Y.166.237; 5.Y.166.238; 5.Y.166.239;5.Y.166.154; 5.Y.166.157; 5.Y.166.166; 5.Y.166.169; 5.Y.166.172; 5.Y.166.175;5.Y.166.240; 5.Y.166.244; 5.Y.169.228; 5.Y.169.229; 5.Y.169.230; 5.Y.169.231;5.Y.169.236; 5.Y.169.237; 5.Y.169.238; 5.Y.169.239; 5.Y.169.154; 5.Y.169.157;5.Y.169.166; 5.Y.169.169; 5.Y.169.172; 5.Y.169.175; 5.Y.169.240; 5.Y.169.244; 5.Y.172.228;5.Y.172.229; 5.Y.172.230; 5.Y.172.231; 5.Y.172.236; 5.Y.172.237; 5.Y.172.238;5.Y.172.239; 5.Y.172.154; 5.Y.172.157; 5.Y.172.166; 5.Y.172.169; 5.Y.172.172;5.Y.172.175; 5.Y.172.240; 5.Y.172.244; 5.Y.175.228; 5.Y.175.229; 5.Y.175.230;5.Y.175.231; 5.Y.175.236; 5.Y.175.237; 5.Y.175.238; 5.Y.175.239; 5.Y.175.154;5.Y.175.157; 5.Y.175.166; 5.Y.175.169; 5.Y.175.172; 5.Y.175.175; 5.Y.175.240;5.Y.175.244; 5.Y.240.228; 5.Y.240.229; 5.Y.240.230; 5.Y.240.231; 5.Y.240.236;5.Y.240.237; 5.Y.240.238; 5.Y.240.239; 5.Y.240.154; 5.Y.240.157; 5.Y.240.166;5.Y.240.169; 5.Y.240.172; 5.Y.240.175; 5.Y.240.240; 5.Y.240.244; 5.Y.244.228;5.Y.244.229; 5.Y.244.230; 5.Y.244.231; 5.Y.244.236; 5.Y.244.237; 5.Y.244.238;5.Y.244.239; 5.Y.244.154; 5.Y.244.157; 5.Y.244.166; 5.Y.244.169; 5.Y.244.172;5.Y.244.175; 5.Y.244.240; 5.Y.244.244;

6.Bのプロドラッグ
6.B.228.228; 6.B.228.229; 6.B.228.230; 6.B.228.231; 6.B.228.236; 6.B.228.237;6.B.228.238; 6.B.228.239; 6.B.228.154; 6.B.228.157; 6.B.228.166; 6.B.228.169;6.B.228.172; 6.B.228.175; 6.B.228.240; 6.B.228.244; 6.B.229.228; 6.B.229.229;6.B.229.230; 6.B.229.231; 6.B.229.236; 6.B.229.237; 6.B.229.238; 6.B.229.239;6.B.229.154; 6.B.229.157; 6.B.229.166; 6.B.229.169; 6.B.229.172; 6.B.229.175;6.B.229.240; 6.B.229.244; 6.B.230.228; 6.B.230.229; 6.B.230.230; 6.B.230.231;6.B.230.236; 6.B.230.237; 6.B.230.238; 6.B.230.239; 6.B.230.154; 6.B.230.157;6.B.230.166; 6.B.230.169; 6.B.230.172; 6.B.230.175; 6.B.230.240; 6.B.230.244;6.B.231.228; 6.B.231.229; 6.B.231.230; 6.B.231.231; 6.B.231.236; 6.B.231.237;6.B.231.238; 6.B.231.239; 6.B.231.154; 6.B.231.157; 6.B.231.166; 6.B.231.169;6.B.231.172; 6.B.231.175; 6.B.231.240; 6.B.231.244; 6.B.236.228; 6.B.236.229;6.B.236.230; 6.B.236.231; 6.B.236.236; 6.B.236.237; 6.B.236.238; 6.B.236.239;6.B.236.154; 6.B.236.157; 6.B.236.166; 6.B.236.169; 6.B.236.172; 6.B.236.175;6.B.236.240; 6.B.236.244; 6.B.237.228; 6.B.237.229; 6.B.237.230; 6.B.237.231;6.B.237.236; 6.B.237.237; 6.B.237.238; 6.B.237.239; 6.B.237.154; 6.B.237.157;6.B.237.166; 6.B.237.169; 6.B.237.172; 6.B.237.175; 6.B.237.240; 6.B.237.244;6.B.238.228; 6.B.238.229; 6.B.238.230; 6.B.238.231; 6.B.238.236; 6.B.238.237;6.B.238.238; 6.B.238.239; 6.B.238.154; 6.B.238.157; 6.B.238.166; 6.B.238.169;6.B.238.172; 6.B.238.175; 6.B.238.240; 6.B.238.244; 6.B.239.228; 6.B.239.229;6.B.239.230; 6.B.239.231; 6.B.239.236; 6.B.239.237; 6.B.239.238; 6.B.239.239;6.B.239.154; 6.B.239.157; 6.B.239.166; 6.B.239.169; 6.B.239.172; 6.B.239.175;6.B.239.240; 6.B.239.244; 6.B.154.228; 6.B.154.229; 6.B.154.230; 6.B.154.231;6.B.154.236; 6.B.154.237; 6.B.154.238; 6.B.154.239; 6.B.154.154; 6.B.154.157;6.B.154.166; 6.B.154.169; 6.B.154.172; 6.B.154.175; 6.B.154.240; 6.B.154.244;6.B.157.228; 6.B.157.229; 6.B.157.230; 6.B.157.231; 6.B.157.236; 6.B.157.237;6.B.157.238; 6.B.157.239; 6.B.157.154; 6.B.157.157; 6.B.157.166; 6.B.157.169;6.B.157.172; 6.B.157.175; 6.B.157.240; 6.B.157.244; 6.B.166.228; 6.B.166.229;6.B.166.230; 6.B.166.231; 6.B.166.236; 6.B.166.237; 6.B.166.238; 6.B.166.239;6.B.166.154; 6.B.166.157; 6.B.166.166; 6.B.166.169; 6.B.166.172; 6.B.166.175;6.B.166.240; 6.B.166.244; 6.B.169.228; 6.B.169.229; 6.B.169.230; 6.B.169.231;6.B.169.236; 6.B.169.237; 6.B.169.238; 6.B.169.239; 6.B.169.154; 6.B.169.157;6.B.169.166; 6.B.169.169; 6.B.169.172; 6.B.169.175; 6.B.169.240; 6.B.169.244;6.B.172.228; 6.B.172.229; 6.B.172.230; 6.B.172.231; 6.B.172.236; 6.B.172.237;6.B.172.238; 6.B.172.239; 6.B.172.154; 6.B.172.157; 6.B.172.166; 6.B.172.169;6.B.172.172; 6.B.172.175; 6.B.172.240; 6.B.172.244; 6.B.175.228; 6.B.175.229;6.B.175.230; 6.B.175.231; 6.B.175.236; 6.B.175.237; 6.B.175.238; 6.B.175.239;6.B.175.154; 6.B.175.157; 6.B.175.166; 6.B.175.169; 6.B.175.172; 6.B.175.175;6.B.175.240; 6.B.175.244; 6.B.240.228; 6.B.240.229; 6.B.240.230; 6.B.240.231;6.B.240.236; 6.B.240.237; 6.B.240.238; 6.B.240.239; 6.B.240.154; 6.B.240.157;6.B.240.166; 6.B.240.169; 6.B.240.172; 6.B.240.175; 6.B.240.240; 6.B.240.244;6.B.244.228; 6.B.244.229; 6.B.244.230; 6.B.244.231; 6.B.244.236; 6.B.244.237;6.B.244.238; 6.B.244.239; 6.B.244.154; 6.B.244.157; 6.B.244.166; 6.B.244.169;6.B.244.172; 6.B.244.175; 6.B.244.240; 6.B.244.244;

6.Dのプロドラッグ
6.D.228.228; 6.D.228.229; 6.D.228.230; 6.D.228.231; 6.D.228.236; 6.D.228.237;6.D.228.238; 6.D.228.239; 6.D.228.154; 6.D.228.157; 6.D.228.166; 6.D.228.169; 6.D.228.172;6.D.228.175; 6.D.228.240; 6.D.228.244; 6.D.229.228; 6.D.229.229; 6.D.229.230;6.D.229.231; 6.D.229.236; 6.D.229.237; 6.D.229.238; 6.D.229.239; 6.D.229.154;6.D.229.157; 6.D.229.166; 6.D.229.169; 6.D.229.172; 6.D.229.175; 6.D.229.240;6.D.229.244; 6.D.230.228; 6.D.230.229; 6.D.230.230; 6.D.230.231; 6.D.230.236;6.D.230.237; 6.D.230.238; 6.D.230.239; 6.D.230.154; 6.D.230.157; 6.D.230.166;6.D.230.169; 6.D.230.172; 6.D.230.175; 6.D.230.240; 6.D.230.244; 6.D.231.228;6.D.231.229; 6.D.231.230; 6.D.231.231; 6.D.231.236; 6.D.231.237; 6.D.231.238;6.D.231.239; 6.D.231.154; 6.D.231.157; 6.D.231.166; 6.D.231.169; 6.D.231.172;6.D.231.175; 6.D.231.240; 6.D.231.244; 6.D.236.228; 6.D.236.229; 6.D.236.230;6.D.236.231; 6.D.236.236; 6.D.236.237; 6.D.236.238; 6.D.236.239; 6.D.236.154;6.D.236.157; 6.D.236.166; 6.D.236.169; 6.D.236.172; 6.D.236.175; 6.D.236.240;6.D.236.244; 6.D.237.228; 6.D.237.229; 6.D.237.230; 6.D.237.231; 6.D.237.236;6.D.237.237; 6.D.237.238; 6.D.237.239; 6.D.237.154; 6.D.237.157; 6.D.237.166;6.D.237.169; 6.D.237.172; 6.D.237.175; 6.D.237.240; 6.D.237.244; 6.D.238.228;6.D.238.229; 6.D.238.230; 6.D.238.231; 6.D.238.236; 6.D.238.237; 6.D.238.238;6.D.238.239; 6.D.238.154; 6.D.238.157; 6.D.238.166; 6.D.238.169; 6.D.238.172;6.D.238.175; 6.D.238.240; 6.D.238.244; 6.D.239.228; 6.D.239.229; 6.D.239.230;6.D.239.231; 6.D.239.236; 6.D.239.237; 6.D.239.238; 6.D.239.239; 6.D.239.154;6.D.239.157; 6.D.239.166; 6.D.239.169; 6.D.239.172; 6.D.239.175; 6.D.239.240;6.D.239.244; 6.D.154.228; 6.D.154.229; 6.D.154.230; 6.D.154.231; 6.D.154.236;6.D.154.237; 6.D.154.238; 6.D.154.239; 6.D.154.154; 6.D.154.157; 6.D.154.166;6.D.154.169; 6.D.154.172; 6.D.154.175; 6.D.154.240; 6.D.154.244; 6.D.157.228;6.D.157.229; 6.D.157.230; 6.D.157.231; 6.D.157.236; 6.D.157.237; 6.D.157.238;6.D.157.239; 6.D.157.154; 6.D.157.157; 6.D.157.166; 6.D.157.169; 6.D.157.172;6.D.157.175; 6.D.157.240; 6.D.157.244; 6.D.166.228; 6.D.166.229; 6.D.166.230;6.D.166.231; 6.D.166.236; 6.D.166.237; 6.D.166.238; 6.D.166.239; 6.D.166.154;6.D.166.157; 6.D.166.166; 6.D.166.169; 6.D.166.172; 6.D.166.175; 6.D.166.240;6.D.166.244; 6.D.169.228; 6.D.169.229; 6.D.169.230; 6.D.169.231; 6.D.169.236;6.D.169.237; 6.D.169.238; 6.D.169.239; 6.D.169.154; 6.D.169.157; 6.D.169.166;6.D.169.169; 6.D.169.172; 6.D.169.175; 6.D.169.240; 6.D.169.244; 6.D.172.228;6.D.172.229; 6.D.172.230; 6.D.172.231; 6.D.172.236; 6.D.172.237; 6.D.172.238;6.D.172.239; 6.D.172.154; 6.D.172.157; 6.D.172.166; 6.D.172.169; 6.D.172.172;6.D.172.175; 6.D.172.240; 6.D.172.244; 6.D.175.228; 6.D.175.229; 6.D.175.230;6.D.175.231; 6.D.175.236; 6.D.175.237; 6.D.175.238; 6.D.175.239; 6.D.175.154;6.D.175.157; 6.D.175.166; 6.D.175.169; 6.D.175.172; 6.D.175.175; 6.D.175.240;6.D.175.244; 6.D.240.228; 6.D.240.229; 6.D.240.230; 6.D.240.231; 6.D.240.236;6.D.240.237; 6.D.240.238; 6.D.240.239; 6.D.240.154; 6.D.240.157; 6.D.240.166;6.D.240.169; 6.D.240.172; 6.D.240.175; 6.D.240.240; 6.D.240.244; 6.D.244.228;6.D.244.229; 6.D.244.230; 6.D.244.231; 6.D.244.236; 6.D.244.237; 6.D.244.238;6.D.244.239; 6.D.244.154; 6.D.244.157; 6.D.244.166; 6.D.244.169; 6.D.244.172;6.D.244.175; 6.D.244.240; 6.D.244.244;

6.Eのプロドラッグ
6.E.228.228; 6.E.228.229; 6.E.228.230; 6.E.228.231; 6.E.228.236; 6.E.228.237;6.E.228.238; 6.E.228.239; 6.E.228.154; 6.E.228.157; 6.E.228.166; 6.E.228.169;6.E.228.172; 6.E.228.175; 6.E.228.240; 6.E.228.244; 6.E.229.228; 6.E.229.229;6.E.229.230; 6.E.229.231; 6.E.229.236; 6.E.229.237; 6.E.229.238; 6.E.229.239;6.E.229.154; 6.E.229.157; 6.E.229.166; 6.E.229.169; 6.E.229.172; 6.E.229.175;6.E.229.240; 6.E.229.244; 6.E.230.228; 6.E.230.229; 6.E.230.230; 6.E.230.231;6.E.230.236; 6.E.230.237; 6.E.230.238; 6.E.230.239; 6.E.230.154; 6.E.230.157;6.E.230.166; 6.E.230.169; 6.E.230.172; 6.E.230.175; 6.E.230.240; 6.E.230.244;6.E.231.228; 6.E.231.229; 6.E.231.230; 6.E.231.231; 6.E.231.236; 6.E.231.237;6.E.231.238; 6.E.231.239; 6.E.231.154; 6.E.231.157; 6.E.231.166; 6.E.231.169;6.E.231.172; 6.E.231.175; 6.E.231.240; 6.E.231.244; 6.E.236.228; 6.E.236.229;6.E.236.230; 6.E.236.231; 6.E.236.236; 6.E.236.237; 6.E.236.238; 6.E.236.239;6.E.236.154; 6.E.236.157; 6.E.236.166; 6.E.236.169; 6.E.236.172; 6.E.236.175;6.E.236.240; 6.E.236.244; 6.E.237.228; 6.E.237.229; 6.E.237.230; 6.E.237.231;6.E.237.236; 6.E.237.237; 6.E.237.238; 6.E.237.239; 6.E.237.154; 6.E.237.157;6.E.237.166; 6.E.237.169; 6.E.237.172; 6.E.237.175; 6.E.237.240; 6.E.237.244;6.E.238.228; 6.E.238.229; 6.E.238.230; 6.E.238.231; 6.E.238.236; 6.E.238.237;6.E.238.238; 6.E.238.239; 6.E.238.154; 6.E.238.157; 6.E.238.166; 6.E.238.169;6.E.238.172; 6.E.238.175; 6.E.238.240; 6.E.238.244; 6.E.239.228; 6.E.239.229;6.E.239.230; 6.E.239.231; 6.E.239.236; 6.E.239.237; 6.E.239.238; 6.E.239.239;6.E.239.154; 6.E.239.157; 6.E.239.166; 6.E.239.169; 6.E.239.172; 6.E.239.175;6.E.239.240; 6.E.239.244; 6.E.154.228; 6.E.154.229; 6.E.154.230; 6.E.154.231;6.E.154.236; 6.E.154.237; 6.E.154.238; 6.E.154.239; 6.E.154.154; 6.E.154.157;6.E.154.166; 6.E.154.169; 6.E.154.172; 6.E.154.175; 6.E.154.240; 6.E.154.244;6.E.157.228; 6.E.157.229; 6.E.157.230; 6.E.157.231; 6.E.157.236; 6.E.157.237;6.E.157.238; 6.E.157.239; 6.E.157.154; 6.E.157.157; 6.E.157.166; 6.E.157.169;6.E.157.172; 6.E.157.175; 6.E.157.240; 6.E.157.244; 6.E.166.228; 6.E.166.229;6.E.166.230; 6.E.166.231; 6.E.166.236; 6.E.166.237; 6.E.166.238; 6.E.166.239; 6.E.166.154;6.E.166.157; 6.E.166.166; 6.E.166.169; 6.E.166.172; 6.E.166.175; 6.E.166.240;6.E.166.244; 6.E.169.228; 6.E.169.229; 6.E.169.230; 6.E.169.231; 6.E.169.236;6.E.169.237; 6.E.169.238; 6.E.169.239; 6.E.169.154; 6.E.169.157; 6.E.169.166;6.E.169.169; 6.E.169.172; 6.E.169.175; 6.E.169.240; 6.E.169.244; 6.E.172.228;6.E.172.229; 6.E.172.230; 6.E.172.231; 6.E.172.236; 6.E.172.237; 6.E.172.238;6.E.172.239; 6.E.172.154; 6.E.172.157; 6.E.172.166; 6.E.172.169; 6.E.172.172;6.E.172.175; 6.E.172.240; 6.E.172.244; 6.E.175.228; 6.E.175.229; 6.E.175.230;6.E.175.231; 6.E.175.236; 6.E.175.237; 6.E.175.238; 6.E.175.239; 6.E.175.154;6.E.175.157; 6.E.175.166; 6.E.175.169; 6.E.175.172; 6.E.175.175; 6.E.175.240;6.E.175.244; 6.E.240.228; 6.E.240.229; 6.E.240.230; 6.E.240.231; 6.E.240.236;6.E.240.237; 6.E.240.238; 6.E.240.239; 6.E.240.154; 6.E.240.157; 6.E.240.166;6.E.240.169; 6.E.240.172; 6.E.240.175; 6.E.240.240; 6.E.240.244; 6.E.244.228;6.E.244.229; 6.E.244.230; 6.E.244.231; 6.E.244.236; 6.E.244.237; 6.E.244.238;6.E.244.239; 6.E.244.154; 6.E.244.157; 6.E.244.166; 6.E.244.169; 6.E.244.172;6.E.244.175; 6.E.244.240; 6.E.244.244;

6.Gのプロドラッグ
6.G.228.228; 6.G.228.229; 6.G.228.230; 6.G.228.231; 6.G.228.236; 6.G.228.237;6.G.228.238; 6.G.228.239; 6.G.228.154; 6.G.228.157; 6.G.228.166; 6.G.228.169;6.G.228.172; 6.G.228.175; 6.G.228.240; 6.G.228.244; 6.G.229.228; 6.G.229.229;6.G.229.230; 6.G.229.231; 6.G.229.236; 6.G.229.237; 6.G.229.238; 6.G.229.239;6.G.229.154; 6.G.229.157; 6.G.229.166; 6.G.229.169; 6.G.229.172; 6.G.229.175;6.G.229.240; 6.G.229.244; 6.G.230.228; 6.G.230.229; 6.G.230.230; 6.G.230.231;6.G.230.236; 6.G.230.237; 6.G.230.238; 6.G.230.239; 6.G.230.154; 6.G.230.157;6.G.230.166; 6.G.230.169; 6.G.230.172; 6.G.230.175; 6.G.230.240; 6.G.230.244;6.G.231.228; 6.G.231.229; 6.G.231.230; 6.G.231.231; 6.G.231.236; 6.G.231.237;6.G.231.238; 6.G.231.239; 6.G.231.154; 6.G.231.157; 6.G.231.166; 6.G.231.169;6.G.231.172; 6.G.231.175; 6.G.231.240; 6.G.231.244; 6.G.236.228; 6.G.236.229;6.G.236.230; 6.G.236.231; 6.G.236.236; 6.G.236.237; 6.G.236.238; 6.G.236.239;6.G.236.154; 6.G.236.157; 6.G.236.166; 6.G.236.169; 6.G.236.172; 6.G.236.175;6.G.236.240; 6.G.236.244; 6.G.237.228; 6.G.237.229; 6.G.237.230; 6.G.237.231;6.G.237.236; 6.G.237.237; 6.G.237.238; 6.G.237.239; 6.G.237.154; 6.G.237.157;6.G.237.166; 6.G.237.169; 6.G.237.172; 6.G.237.175; 6.G.237.240; 6.G.237.244;6.G.238.228; 6.G.238.229; 6.G.238.230; 6.G.238.231; 6.G.238.236; 6.G.238.237;6.G.238.238; 6.G.238.239; 6.G.238.154; 6.G.238.157; 6.G.238.166; 6.G.238.169;6.G.238.172; 6.G.238.175; 6.G.238.240; 6.G.238.244; 6.G.239.228; 6.G.239.229;6.G.239.230; 6.G.239.231; 6.G.239.236; 6.G.239.237; 6.G.239.238; 6.G.239.239;6.G.239.154; 6.G.239.157; 6.G.239.166; 6.G.239.169; 6.G.239.172; 6.G.239.175;6.G.239.240; 6.G.239.244; 6.G.154.228; 6.G.154.229; 6.G.154.230; 6.G.154.231;6.G.154.236; 6.G.154.237; 6.G.154.238; 6.G.154.239; 6.G.154.154; 6.G.154.157;6.G.154.166; 6.G.154.169; 6.G.154.172; 6.G.154.175; 6.G.154.240; 6.G.154.244;6.G.157.228; 6.G.157.229; 6.G.157.230; 6.G.157.231; 6.G.157.236; 6.G.157.237;6.G.157.238; 6.G.157.239; 6.G.157.154; 6.G.157.157; 6.G.157.166; 6.G.157.169;6.G.157.172; 6.G.157.175; 6.G.157.240; 6.G.157.244; 6.G.166.228; 6.G.166.229;6.G.166.230; 6.G.166.231; 6.G.166.236; 6.G.166.237; 6.G.166.238; 6.G.166.239;6.G.166.154; 6.G.166.157; 6.G.166.166; 6.G.166.169; 6.G.166.172; 6.G.166.175;6.G.166.240; 6.G.166.244; 6.G.169.228; 6.G.169.229; 6.G.169.230; 6.G.169.231;6.G.169.236; 6.G.169.237; 6.G.169.238; 6.G.169.239; 6.G.169.154; 6.G.169.157;6.G.169.166; 6.G.169.169; 6.G.169.172; 6.G.169.175; 6.G.169.240; 6.G.169.244;6.G.172.228; 6.G.172.229; 6.G.172.230; 6.G.172.231; 6.G.172.236; 6.G.172.237;6.G.172.238; 6.G.172.239; 6.G.172.154; 6.G.172.157; 6.G.172.166; 6.G.172.169;6.G.172.172; 6.G.172.175; 6.G.172.240; 6.G.172.244; 6.G.175.228; 6.G.175.229;6.G.175.230; 6.G.175.231; 6.G.175.236; 6.G.175.237; 6.G.175.238; 6.G.175.239;6.G.175.154; 6.G.175.157; 6.G.175.166; 6.G.175.169; 6.G.175.172; 6.G.175.175;6.G.175.240; 6.G.175.244; 6.G.240.228; 6.G.240.229; 6.G.240.230; 6.G.240.231;6.G.240.236; 6.G.240.237; 6.G.240.238; 6.G.240.239; 6.G.240.154; 6.G.240.157;6.G.240.166; 6.G.240.169; 6.G.240.172; 6.G.240.175; 6.G.240.240; 6.G.240.244;6.G.244.228; 6.G.244.229; 6.G.244.230; 6.G.244.231; 6.G.244.236; 6.G.244.237;6.G.244.238; 6.G.244.239; 6.G.244.154; 6.G.244.157; 6.G.244.166; 6.G.244.169;6.G.244.172; 6.G.244.175; 6.G.244.240; 6.G.244.244;

6.Iのプロドラッグ
6.I.228.228; 6.I.228.229; 6.I.228.230; 6.I.228.231; 6.I.228.236; 6.I.228.237;6.I.228.238; 6.I.228.239; 6.I.228.154; 6.I.228.157; 6.I.228.166; 6.I.228.169;6.I.228.172; 6.I.228.175; 6.I.228.240; 6.I.228.244; 6.I.229.228; 6.I.229.229;6.I.229.230; 6.I.229.231; 6.I.229.236; 6.I.229.237; 6.I.229.238; 6.I.229.239;6.I.229.154; 6.I.229.157; 6.I.229.166; 6.I.229.169; 6.I.229.172; 6.I.229.175;6.I.229.240; 6.I.229.244; 6.I.230.228; 6.I.230.229; 6.I.230.230; 6.I.230.231;6.I.230.236; 6.I.230.237; 6.I.230.238; 6.I.230.239; 6.I.230.154; 6.I.230.157;6.I.230.166; 6.I.230.169; 6.I.230.172; 6.I.230.175; 6.I.230.240; 6.I.230.244;6.I.231.228; 6.I.231.229; 6.I.231.230; 6.I.231.231; 6.I.231.236; 6.I.231.237;6.I.231.238; 6.I.231.239; 6.I.231.154; 6.I.231.157; 6.I.231.166; 6.I.231.169;6.I.231.172; 6.I.231.175; 6.I.231.240; 6.I.231.244; 6.I.236.228; 6.I.236.229;6.I.236.230; 6.I.236.231; 6.I.236.236; 6.I.236.237; 6.I.236.238; 6.I.236.239;6.I.236.154; 6.I.236.157; 6.I.236.166; 6.I.236.169; 6.I.236.172; 6.I.236.175;6.I.236.240; 6.I.236.244; 6.I.237.228; 6.I.237.229; 6.I.237.230; 6.I.237.231;6.I.237.236; 6.I.237.237; 6.I.237.238; 6.I.237.239; 6.I.237.154; 6.I.237.157;6.I.237.166; 6.I.237.169; 6.I.237.172; 6.I.237.175; 6.I.237.240; 6.I.237.244;6.I.238.228; 6.I.238.229; 6.I.238.230; 6.I.238.231; 6.I.238.236; 6.I.238.237;6.I.238.238; 6.I.238.239; 6.I.238.154; 6.I.238.157; 6.I.238.166; 6.I.238.169;6.I.238.172; 6.I.238.175; 6.I.238.240; 6.I.238.244; 6.I.239.228; 6.I.239.229;6.I.239.230; 6.I.239.231; 6.I.239.236; 6.I.239.237; 6.I.239.238; 6.I.239.239;6.I.239.154; 6.I.239.157; 6.I.239.166; 6.I.239.169; 6.I.239.172; 6.I.239.175;6.I.239.240; 6.I.239.244; 6.I.154.228; 6.I.154.229; 6.I.154.230; 6.I.154.231;6.I.154.236; 6.I.154.237; 6.I.154.238; 6.I.154.239; 6.I.154.154; 6.I.154.157;6.I.154.166; 6.I.154.169; 6.I.154.172; 6.I.154.175; 6.I.154.240; 6.I.154.244;6.I.157.228; 6.I.157.229; 6.I.157.230; 6.I.157.231; 6.I.157.236; 6.I.157.237;6.I.157.238; 6.I.157.239; 6.I.157.154; 6.I.157.157; 6.I.157.166; 6.I.157.169;6.I.157.172; 6.I.157.175; 6.I.157.240; 6.I.157.244; 6.I.166.228; 6.I.166.229;6.I.166.230; 6.I.166.231; 6.I.166.236; 6.I.166.237; 6.I.166.238; 6.I.166.239;6.I.166.154; 6.I.166.157; 6.I.166.166; 6.I.166.169; 6.I.166.172; 6.I.166.175;6.I.166.240; 6.I.166.244; 6.I.169.228; 6.I.169.229; 6.I.169.230; 6.I.169.231;6.I.169.236; 6.I.169.237; 6.I.169.238; 6.I.169.239; 6.I.169.154; 6.I.169.157;6.I.169.166; 6.I.169.169; 6.I.169.172; 6.I.169.175; 6.I.169.240; 6.I.169.244;6.I.172.228; 6.I.172.229; 6.I.172.230; 6.I.172.231; 6.I.172.236; 6.I.172.237;6.I.172.238; 6.I.172.239; 6.I.172.154; 6.I.172.157; 6.I.172.166; 6.I.172.169;6.I.172.172; 6.I.172.175; 6.I.172.240; 6.I.172.244; 6.I.175.228; 6.I.175.229;6.I.175.230; 6.I.175.231; 6.I.175.236; 6.I.175.237; 6.I.175.238; 6.I.175.239;6.I.175.154; 6.I.175.157; 6.I.175.166; 6.I.175.169; 6.I.175.172; 6.I.175.175;6.I.175.240; 6.I.175.244; 6.I.240.228; 6.I.240.229; 6.I.240.230; 6.I.240.231;6.I.240.236; 6.I.240.237; 6.I.240.238; 6.I.240.239; 6.I.240.154; 6.I.240.157;6.I.240.166; 6.I.240.169; 6.I.240.172; 6.I.240.175; 6.I.240.240; 6.I.240.244;6.I.244.228; 6.I.244.229; 6.I.244.230; 6.I.244.231; 6.I.244.236; 6.I.244.237;6.I.244.238; 6.I.244.239; 6.I.244.154; 6.I.244.157; 6.I.244.166; 6.I.244.169;6.I.244.172; 6.I.244.175; 6.I.244.240; 6.I.244.244;

6.Jのプロドラッグ
6.J.228.228; 6.J.228.229; 6.J.228.230; 6.J.228.231; 6.J.228.236; 6.J.228.237;6.J.228.238; 6.J.228.239; 6.J.228.154; 6.J.228.157; 6.J.228.166; 6.J.228.169;6.J.228.172; 6.J.228.175; 6.J.228.240; 6.J.228.244; 6.J.229.228; 6.J.229.229;6.J.229.230; 6.J.229.231; 6.J.229.236; 6.J.229.237; 6.J.229.238; 6.J.229.239;6.J.229.154; 6.J.229.157; 6.J.229.166; 6.J.229.169; 6.J.229.172; 6.J.229.175;6.J.229.240; 6.J.229.244; 6.J.230.228; 6.J.230.229; 6.J.230.230; 6.J.230.231;6.J.230.236; 6.J.230.237; 6.J.230.238; 6.J.230.239; 6.J.230.154; 6.J.230.157;6.J.230.166; 6.J.230.169; 6.J.230.172; 6.J.230.175; 6.J.230.240; 6.J.230.244;6.J.231.228; 6.J.231.229; 6.J.231.230; 6.J.231.231; 6.J.231.236; 6.J.231.237;6.J.231.238; 6.J.231.239; 6.J.231.154; 6.J.231.157; 6.J.231.166; 6.J.231.169;6.J.231.172; 6.J.231.175; 6.J.231.240; 6.J.231.244; 6.J.236.228; 6.J.236.229;6.J.236.230; 6.J.236.231; 6.J.236.236; 6.J.236.237; 6.J.236.238; 6.J.236.239;6.J.236.154; 6.J.236.157; 6.J.236.166; 6.J.236.169; 6.J.236.172; 6.J.236.175;6.J.236.240; 6.J.236.244; 6.J.237.228; 6.J.237.229; 6.J.237.230; 6.J.237.231;6.J.237.236; 6.J.237.237; 6.J.237.238; 6.J.237.239; 6.J.237.154; 6.J.237.157;6.J.237.166; 6.J.237.169; 6.J.237.172; 6.J.237.175; 6.J.237.240; 6.J.237.244;6.J.238.228; 6.J.238.229; 6.J.238.230; 6.J.238.231; 6.J.238.236; 6.J.238.237;6.J.238.238; 6.J.238.239; 6.J.238.154; 6.J.238.157; 6.J.238.166; 6.J.238.169;6.J.238.172; 6.J.238.175; 6.J.238.240; 6.J.238.244; 6.J.239.228; 6.J.239.229;6.J.239.230; 6.J.239.231; 6.J.239.236; 6.J.239.237; 6.J.239.238; 6.J.239.239;6.J.239.154; 6.J.239.157; 6.J.239.166; 6.J.239.169; 6.J.239.172; 6.J.239.175;6.J.239.240; 6.J.239.244; 6.J.154.228; 6.J.154.229; 6.J.154.230; 6.J.154.231;6.J.154.236; 6.J.154.237; 6.J.154.238; 6.J.154.239; 6.J.154.154; 6.J.154.157;6.J.154.166; 6.J.154.169; 6.J.154.172; 6.J.154.175; 6.J.154.240; 6.J.154.244;6.J.157.228; 6.J.157.229; 6.J.157.230; 6.J.157.231; 6.J.157.236; 6.J.157.237;6.J.157.238; 6.J.157.239; 6.J.157.154; 6.J.157.157; 6.J.157.166; 6.J.157.169;6.J.157.172; 6.J.157.175; 6.J.157.240; 6.J.157.244; 6.J.166.228; 6.J.166.229;6.J.166.230; 6.J.166.231; 6.J.166.236; 6.J.166.237; 6.J.166.238; 6.J.166.239;6.J.166.154; 6.J.166.157; 6.J.166.166; 6.J.166.169; 6.J.166.172; 6.J.166.175;6.J.166.240; 6.J.166.244; 6.J.169.228; 6.J.169.229; 6.J.169.230; 6.J.169.231; 6.J.169.236;6.J.169.237; 6.J.169.238; 6.J.169.239; 6.J.169.154; 6.J.169.157; 6.J.169.166;6.J.169.169; 6.J.169.172; 6.J.169.175; 6.J.169.240; 6.J.169.244; 6.J.172.228;6.J.172.229; 6.J.172.230; 6.J.172.231; 6.J.172.236; 6.J.172.237; 6.J.172.238;6.J.172.239; 6.J.172.154; 6.J.172.157; 6.J.172.166; 6.J.172.169; 6.J.172.172;6.J.172.175; 6.J.172.240; 6.J.172.244; 6.J.175.228; 6.J.175.229; 6.J.175.230;6.J.175.231; 6.J.175.236; 6.J.175.237; 6.J.175.238; 6.J.175.239; 6.J.175.154;6.J.175.157; 6.J.175.166; 6.J.175.169; 6.J.175.172; 6.J.175.175; 6.J.175.240;6.J.175.244; 6.J.240.228; 6.J.240.229; 6.J.240.230; 6.J.240.231; 6.J.240.236;6.J.240.237; 6.J.240.238; 6.J.240.239; 6.J.240.154; 6.J.240.157; 6.J.240.166;6.J.240.169; 6.J.240.172; 6.J.240.175; 6.J.240.240; 6.J.240.244; 6.J.244.228;6.J.244.229; 6.J.244.230; 6.J.244.231; 6.J.244.236; 6.J.244.237; 6.J.244.238;6.J.244.239; 6.J.244.154; 6.J.244.157; 6.J.244.166; 6.J.244.169; 6.J.244.172;6.J.244.175; 6.J.244.240; 6.J.244.244;

6.Lのプロドラッグ
6.L.228.228; 6.L.228.229; 6.L.228.230; 6.L.228.231; 6.L.228.236; 6.L.228.237;6.L.228.238; 6.L.228.239; 6.L.228.154; 6.L.228.157; 6.L.228.166; 6.L.228.169;6.L.228.172; 6.L.228.175; 6.L.228.240; 6.L.228.244; 6.L.229.228; 6.L.229.229;6.L.229.230; 6.L.229.231; 6.L.229.236; 6.L.229.237; 6.L.229.238; 6.L.229.239;6.L.229.154; 6.L.229.157; 6.L.229.166; 6.L.229.169; 6.L.229.172; 6.L.229.175;6.L.229.240; 6.L.229.244; 6.L.230.228; 6.L.230.229; 6.L.230.230; 6.L.230.231;6.L.230.236; 6.L.230.237; 6.L.230.238; 6.L.230.239; 6.L.230.154; 6.L.230.157;6.L.230.166; 6.L.230.169; 6.L.230.172; 6.L.230.175; 6.L.230.240; 6.L.230.244;6.L.231.228; 6.L.231.229; 6.L.231.230; 6.L.231.231; 6.L.231.236; 6.L.231.237;6.L.231.238; 6.L.231.239; 6.L.231.154; 6.L.231.157; 6.L.231.166; 6.L.231.169;6.L.231.172; 6.L.231.175; 6.L.231.240; 6.L.231.244; 6.L.236.228; 6.L.236.229;6.L.236.230; 6.L.236.231; 6.L.236.236; 6.L.236.237; 6.L.236.238; 6.L.236.239;6.L.236.154; 6.L.236.157; 6.L.236.166; 6.L.236.169; 6.L.236.172; 6.L.236.175;6.L.236.240; 6.L.236.244; 6.L.237.228; 6.L.237.229; 6.L.237.230; 6.L.237.231;6.L.237.236; 6.L.237.237; 6.L.237.238; 6.L.237.239; 6.L.237.154; 6.L.237.157;6.L.237.166; 6.L.237.169; 6.L.237.172; 6.L.237.175; 6.L.237.240; 6.L.237.244;6.L.238.228; 6.L.238.229; 6.L.238.230; 6.L.238.231; 6.L.238.236; 6.L.238.237;6.L.238.238; 6.L.238.239; 6.L.238.154; 6.L.238.157; 6.L.238.166; 6.L.238.169;6.L.238.172; 6.L.238.175; 6.L.238.240; 6.L.238.244; 6.L.239.228; 6.L.239.229;6.L.239.230; 6.L.239.231; 6.L.239.236; 6.L.239.237; 6.L.239.238; 6.L.239.239;6.L.239.154; 6.L.239.157; 6.L.239.166; 6.L.239.169; 6.L.239.172; 6.L.239.175;6.L.239.240; 6.L.239.244; 6.L.154.228; 6.L.154.229; 6.L.154.230; 6.L.154.231;6.L.154.236; 6.L.154.237; 6.L.154.238; 6.L.154.239; 6.L.154.154; 6.L.154.157;6.L.154.166; 6.L.154.169; 6.L.154.172; 6.L.154.175; 6.L.154.240; 6.L.154.244;6.L.157.228; 6.L.157.229; 6.L.157.230; 6.L.157.231; 6.L.157.236; 6.L.157.237;6.L.157.238; 6.L.157.239; 6.L.157.154; 6.L.157.157; 6.L.157.166; 6.L.157.169;6.L.157.172; 6.L.157.175; 6.L.157.240; 6.L.157.244; 6.L.166.228; 6.L.166.229;6.L.166.230; 6.L.166.231; 6.L.166.236; 6.L.166.237; 6.L.166.238; 6.L.166.239;6.L.166.154; 6.L.166.157; 6.L.166.166; 6.L.166.169; 6.L.166.172; 6.L.166.175;6.L.166.240; 6.L.166.244; 6.L.169.228; 6.L.169.229; 6.L.169.230; 6.L.169.231;6.L.169.236; 6.L.169.237; 6.L.169.238; 6.L.169.239; 6.L.169.154; 6.L.169.157;6.L.169.166; 6.L.169.169; 6.L.169.172; 6.L.169.175; 6.L.169.240; 6.L.169.244;6.L.172.228; 6.L.172.229; 6.L.172.230; 6.L.172.231; 6.L.172.236; 6.L.172.237;6.L.172.238; 6.L.172.239; 6.L.172.154; 6.L.172.157; 6.L.172.166; 6.L.172.169;6.L.172.172; 6.L.172.175; 6.L.172.240; 6.L.172.244; 6.L.175.228; 6.L.175.229;6.L.175.230; 6.L.175.231; 6.L.175.236; 6.L.175.237; 6.L.175.238; 6.L.175.239;6.L.175.154; 6.L.175.157; 6.L.175.166; 6.L.175.169; 6.L.175.172; 6.L.175.175;6.L.175.240; 6.L.175.244; 6.L.240.228; 6.L.240.229; 6.L.240.230; 6.L.240.231;6.L.240.236; 6.L.240.237; 6.L.240.238; 6.L.240.239; 6.L.240.154; 6.L.240.157;6.L.240.166; 6.L.240.169; 6.L.240.172; 6.L.240.175; 6.L.240.240; 6.L.240.244;6.L.244.228; 6.L.244.229; 6.L.244.230; 6.L.244.231; 6.L.244.236; 6.L.244.237;6.L.244.238; 6.L.244.239; 6.L.244.154; 6.L.244.157; 6.L.244.166; 6.L.244.169;6.L.244.172; 6.L.244.175; 6.L.244.240; 6.L.244.244;

6.Oのプロドラッグ
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.157.169; 6.O.157.172;6.O.157.175; 6.O.157.240; 6.O.157.244; 6.O.166.228; 6.O.166.229; 6.O.166.230;6.O.166.231; 6.O.166.236; 6.O.166.237; 6.O.166.238; 6.O.166.239; 6.O.166.154;6.O.166.157; 6.O.166.166; 6.O.166.169; 6.O.166.172; 6.O.166.175; 6.O.166.240;6.O.166.244; 6.O.169.228; 6.O.169.229; 6.O.169.230; 6.O.169.231; 6.O.169.236;6.O.169.237; 6.O.169.238; 6.O.169.239; 6.O.169.154; 6.O.169.157; 6.O.169.166;6.O.169.169; 6.O.169.172; 6.O.169.175; 6.O.169.240; 6.O.169.244; 6.O.172.228;6.O.172.229; 6.O.172.230; 6.O.172.231; 6.O.172.236; 6.O.172.237; 6.O.172.238;6.O.172.239; 6.O.172.154; 6.O.172.157; 6.O.172.166; 6.O.172.169; 6.O.172.172;6.O.172.175; 6.O.172.240; 6.O.172.244; 6.O.175.228; 6.O.175.229; 6.O.175.230;6.O.175.231; 6.O.175.236; 6.O.175.237; 6.O.175.238; 6.O.175.239; 6.O.175.154;6.O.175.157; 6.O.175.166; 6.O.175.169; 6.O.175.172; 6.O.175.175; 6.O.175.240;6.O.175.244; 6.O.240.228; 6.O.240.229; 6.O.240.230; 6.O.240.231; 6.O.240.236;6.O.240.237; 6.O.240.238; 6.O.240.239; 6.O.240.154; 6.O.240.157; 6.O.240.166;6.O.240.169; 6.O.240.172; 6.O.240.175; 6.O.240.240; 6.O.240.244; 6.O.244.228;6.O.244.229; 6.O.244.230; 6.O.244.231; 6.O.244.236; 6.O.244.237; 6.O.244.238;6.O.244.239; 6.O.244.154; 6.O.244.157; 6.O.244.166; 6.O.244.169; 6.O.244.172;6.O.244.175; 6.O.244.240; 6.O.244.244;

6.Pのプロドラッグ
6.P.228.228; 6.P.228.229; 6.P.228.230; 6.P.228.231; 6.P.228.236; 6.P.228.237;6.P.228.238; 6.P.228.239; 6.P.228.154; 6.P.228.157; 6.P.228.166; 6.P.228.169;6.P.228.172; 6.P.228.175; 6.P.228.240; 6.P.228.244; 6.P.229.228; 6.P.229.229;6.P.229.230; 6.P.229.231; 6.P.229.236; 6.P.229.237; 6.P.229.238; 6.P.229.239;6.P.229.154; 6.P.229.157; 6.P.229.166; 6.P.229.169; 6.P.229.172; 6.P.229.175;6.P.229.240; 6.P.229.244; 6.P.230.228; 6.P.230.229; 6.P.230.230; 6.P.230.231;6.P.230.236; 6.P.230.237; 6.P.230.238; 6.P.230.239; 6.P.230.154; 6.P.230.157;6.P.230.166; 6.P.230.169; 6.P.230.172; 6.P.230.175; 6.P.230.240; 6.P.230.244;6.P.231.228; 6.P.231.229; 6.P.231.230; 6.P.231.231; 6.P.231.236; 6.P.231.237;6.P.231.238; 6.P.231.239; 6.P.231.154; 6.P.231.157; 6.P.231.166; 6.P.231.169;6.P.231.172; 6.P.231.175; 6.P.231.240; 6.P.231.244; 6.P.236.228; 6.P.236.229;6.P.236.230; 6.P.236.231; 6.P.236.236; 6.P.236.237; 6.P.236.238; 6.P.236.239;6.P.236.154; 6.P.236.157; 6.P.236.166; 6.P.236.169; 6.P.236.172; 6.P.236.175;6.P.236.240; 6.P.236.244; 6.P.237.228; 6.P.237.229; 6.P.237.230; 6.P.237.231;6.P.237.236; 6.P.237.237; 6.P.237.238; 6.P.237.239; 6.P.237.154; 6.P.237.157;6.P.237.166; 6.P.237.169; 6.P.237.172; 6.P.237.175; 6.P.237.240; 6.P.237.244;6.P.238.228; 6.P.238.229; 6.P.238.230; 6.P.238.231; 6.P.238.236; 6.P.238.237;6.P.238.238; 6.P.238.239; 6.P.238.154; 6.P.238.157; 6.P.238.166; 6.P.238.169;6.P.238.172; 6.P.238.175; 6.P.238.240; 6.P.238.244; 6.P.239.228; 6.P.239.229;6.P.239.230; 6.P.239.231; 6.P.239.236; 6.P.239.237; 6.P.239.238; 6.P.239.239;6.P.239.154; 6.P.239.157; 6.P.239.166; 6.P.239.169; 6.P.239.172; 6.P.239.175;6.P.239.240; 6.P.239.244; 6.P.154.228; 6.P.154.229; 6.P.154.230; 6.P.154.231;6.P.154.236; 6.P.154.237; 6.P.154.238; 6.P.154.239; 6.P.154.154; 6.P.154.157;6.P.154.166; 6.P.154.169; 6.P.154.172; 6.P.154.175; 6.P.154.240; 6.P.154.244;6.P.157.228; 6.P.157.229; 6.P.157.230; 6.P.157.231; 6.P.157.236; 6.P.157.237;6.P.157.238; 6.P.157.239; 6.P.157.154; 6.P.157.157; 6.P.157.166; 6.P.157.169; 6.P.157.172;6.P.157.175; 6.P.157.240; 6.P.157.244; 6.P.166.228; 6.P.166.229; 6.P.166.230;6.P.166.231; 6.P.166.236; 6.P.166.237; 6.P.166.238; 6.P.166.239; 6.P.166.154;6.P.166.157; 6.P.166.166; 6.P.166.169; 6.P.166.172; 6.P.166.175; 6.P.166.240;6.P.166.244; 6.P.169.228; 6.P.169.229; 6.P.169.230; 6.P.169.231; 6.P.169.236;6.P.169.237; 6.P.169.238; 6.P.169.239; 6.P.169.154; 6.P.169.157; 6.P.169.166;6.P.169.169; 6.P.169.172; 6.P.169.175; 6.P.169.240; 6.P.169.244; 6.P.172.228;6.P.172.229; 6.P.172.230; 6.P.172.231; 6.P.172.236; 6.P.172.237; 6.P.172.238;6.P.172.239; 6.P.172.154; 6.P.172.157; 6.P.172.166; 6.P.172.169; 6.P.172.172;6.P.172.175; 6.P.172.240; 6.P.172.244; 6.P.175.228; 6.P.175.229; 6.P.175.230;6.P.175.231; 6.P.175.236; 6.P.175.237; 6.P.175.238; 6.P.175.239; 6.P.175.154;6.P.175.157; 6.P.175.166; 6.P.175.169; 6.P.175.172; 6.P.175.175; 6.P.175.240;6.P.175.244; 6.P.240.228; 6.P.240.229; 6.P.240.230; 6.P.240.231; 6.P.240.236;6.P.240.237; 6.P.240.238; 6.P.240.239; 6.P.240.154; 6.P.240.157; 6.P.240.166;6.P.240.169; 6.P.240.172; 6.P.240.175; 6.P.240.240; 6.P.240.244; 6.P.244.228;6.P.244.229; 6.P.244.230; 6.P.244.231; 6.P.244.236; 6.P.244.237; 6.P.244.238;6.P.244.239; 6.P.244.154; 6.P.244.157; 6.P.244.166; 6.P.244.169; 6.P.244.172;6.P.244.175; 6.P.244.240; 6.P.244.244;

6.Uのプロドラッグ
6.U.228.228; 6.U.228.229; 6.U.228.230; 6.U.228.231; 6.U.228.236; 6.U.228.237;6.U.228.238; 6.U.228.239; 6.U.228.154; 6.U.228.157; 6.U.228.166; 6.U.228.169;6.U.228.172; 6.U.228.175; 6.U.228.240; 6.U.228.244; 6.U.229.228; 6.U.229.229;6.U.229.230; 6.U.229.231; 6.U.229.236; 6.U.229.237; 6.U.229.238; 6.U.229.239;6.U.229.154; 6.U.229.157; 6.U.229.166; 6.U.229.169; 6.U.229.172; 6.U.229.175;6.U.229.240; 6.U.229.244; 6.U.230.228; 6.U.230.229; 6.U.230.230; 6.U.230.231;6.U.230.236; 6.U.230.237; 6.U.230.238; 6.U.230.239; 6.U.230.154; 6.U.230.157;6.U.230.166; 6.U.230.169; 6.U.230.172; 6.U.230.175; 6.U.230.240; 6.U.230.244;6.U.231.228; 6.U.231.229; 6.U.231.230; 6.U.231.231; 6.U.231.236; 6.U.231.237;6.U.231.238; 6.U.231.239; 6.U.231.154; 6.U.231.157; 6.U.231.166; 6.U.231.169;6.U.231.172; 6.U.231.175; 6.U.231.240; 6.U.231.244; 6.U.236.228; 6.U.236.229;6.U.236.230; 6.U.236.231; 6.U.236.236; 6.U.236.237; 6.U.236.238; 6.U.236.239;6.U.236.154; 6.U.236.157; 6.U.236.166; 6.U.236.169; 6.U.236.172; 6.U.236.175;6.U.236.240; 6.U.236.244; 6.U.237.228; 6.U.237.229; 6.U.237.230; 6.U.237.231;6.U.237.236; 6.U.237.237; 6.U.237.238; 6.U.237.239; 6.U.237.154; 6.U.237.157;6.U.237.166; 6.U.237.169; 6.U.237.172; 6.U.237.175; 6.U.237.240; 6.U.237.244;6.U.238.228; 6.U.238.229; 6.U.238.230; 6.U.238.231; 6.U.238.236; 6.U.238.237;6.U.238.238; 6.U.238.239; 6.U.238.154; 6.U.238.157; 6.U.238.166; 6.U.238.169;6.U.238.172; 6.U.238.175; 6.U.238.240; 6.U.238.244; 6.U.239.228; 6.U.239.229;6.U.239.230; 6.U.239.231; 6.U.239.236; 6.U.239.237; 6.U.239.238; 6.U.239.239;6.U.239.154; 6.U.239.157; 6.U.239.166; 6.U.239.169; 6.U.239.172; 6.U.239.175;6.U.239.240; 6.U.239.244; 6.U.154.228; 6.U.154.229; 6.U.154.230; 6.U.154.231;6.U.154.236; 6.U.154.237; 6.U.154.238; 6.U.154.239; 6.U.154.154; 6.U.154.157;6.U.154.166; 6.U.154.169; 6.U.154.172; 6.U.154.175; 6.U.154.240; 6.U.154.244;6.U.157.228; 6.U.157.229; 6.U.157.230; 6.U.157.231; 6.U.157.236; 6.U.157.237;6.U.157.238; 6.U.157.239; 6.U.157.154; 6.U.157.157; 6.U.157.166; 6.U.157.169;6.U.157.172; 6.U.157.175; 6.U.157.240; 6.U.157.244; 6.U.166.228; 6.U.166.229;6.U.166.230; 6.U.166.231; 6.U.166.236; 6.U.166.237; 6.U.166.238; 6.U.166.239;6.U.166.154; 6.U.166.157; 6.U.166.166; 6.U.166.169; 6.U.166.172; 6.U.166.175;6.U.166.240; 6.U.166.244; 6.U.169.228; 6.U.169.229; 6.U.169.230; 6.U.169.231;6.U.169.236; 6.U.169.237; 6.U.169.238; 6.U.169.239; 6.U.169.154; 6.U.169.157;6.U.169.166; 6.U.169.169; 6.U.169.172; 6.U.169.175; 6.U.169.240; 6.U.169.244;6.U.172.228; 6.U.172.229; 6.U.172.230; 6.U.172.231; 6.U.172.236; 6.U.172.237;6.U.172.238; 6.U.172.239; 6.U.172.154; 6.U.172.157; 6.U.172.166; 6.U.172.169;6.U.172.172; 6.U.172.175; 6.U.172.240; 6.U.172.244; 6.U.175.228; 6.U.175.229;6.U.175.230; 6.U.175.231; 6.U.175.236; 6.U.175.237; 6.U.175.238; 6.U.175.239;6.U.175.154; 6.U.175.157; 6.U.175.166; 6.U.175.169; 6.U.175.172; 6.U.175.175;6.U.175.240; 6.U.175.244; 6.U.240.228; 6.U.240.229; 6.U.240.230; 6.U.240.231;6.U.240.236; 6.U.240.237; 6.U.240.238; 6.U.240.239; 6.U.240.154; 6.U.240.157;6.U.240.166; 6.U.240.169; 6.U.240.172; 6.U.240.175; 6.U.240.240; 6.U.240.244;6.U.244.228; 6.U.244.229; 6.U.244.230; 6.U.244.231; 6.U.244.236; 6.U.244.237;6.U.244.238; 6.U.244.239; 6.U.244.154; 6.U.244.157; 6.U.244.166; 6.U.244.169;6.U.244.172; 6.U.244.175; 6.U.244.240; 6.U.244.244;

6.Wのプロドラッグ
6.W.228.228; 6.W.228.229; 6.W.228.230; 6.W.228.231; 6.W.228.236; 6.W.228.237;6.W.228.238; 6.W.228.239; 6.W.228.154; 6.W.228.157; 6.W.228.166; 6.W.228.169;6.W.228.172; 6.W.228.175; 6.W.228.240; 6.W.228.244; 6.W.229.228; 6.W.229.229;6.W.229.230; 6.W.229.231; 6.W.229.236; 6.W.229.237; 6.W.229.238; 6.W.229.239;6.W.229.154; 6.W.229.157; 6.W.229.166; 6.W.229.169; 6.W.229.172; 6.W.229.175;6.W.229.240; 6.W.229.244; 6.W.230.228; 6.W.230.229; 6.W.230.230; 6.W.230.231;6.W.230.236; 6.W.230.237; 6.W.230.238; 6.W.230.239; 6.W.230.154; 6.W.230.157;6.W.230.166; 6.W.230.169; 6.W.230.172; 6.W.230.175; 6.W.230.240; 6.W.230.244;6.W.231.228; 6.W.231.229; 6.W.231.230; 6.W.231.231; 6.W.231.236; 6.W.231.237;6.W.231.238; 6.W.231.239; 6.W.231.154; 6.W.231.157; 6.W.231.166; 6.W.231.169;6.W.231.172; 6.W.231.175; 6.W.231.240; 6.W.231.244; 6.W.236.228; 6.W.236.229;6.W.236.230; 6.W.236.231; 6.W.236.236; 6.W.236.237; 6.W.236.238; 6.W.236.239;6.W.236.154; 6.W.236.157; 6.W.236.166; 6.W.236.169; 6.W.236.172; 6.W.236.175;6.W.236.240; 6.W.236.244; 6.W.237.228; 6.W.237.229; 6.W.237.230; 6.W.237.231;6.W.237.236; 6.W.237.237; 6.W.237.238; 6.W.237.239; 6.W.237.154; 6.W.237.157;6.W.237.166; 6.W.237.169; 6.W.237.172; 6.W.237.175; 6.W.237.240; 6.W.237.244;6.W.238.228; 6.W.238.229; 6.W.238.230; 6.W.238.231; 6.W.238.236; 6.W.238.237;6.W.238.238; 6.W.238.239; 6.W.238.154; 6.W.238.157; 6.W.238.166; 6.W.238.169;6.W.238.172; 6.W.238.175; 6.W.238.240; 6.W.238.244; 6.W.239.228; 6.W.239.229;6.W.239.230; 6.W.239.231; 6.W.239.236; 6.W.239.237; 6.W.239.238; 6.W.239.239;6.W.239.154; 6.W.239.157; 6.W.239.166; 6.W.239.169; 6.W.239.172; 6.W.239.175;6.W.239.240; 6.W.239.244; 6.W.154.228; 6.W.154.229; 6.W.154.230; 6.W.154.231;6.W.154.236; 6.W.154.237; 6.W.154.238; 6.W.154.239; 6.W.154.154; 6.W.154.157;6.W.154.166; 6.W.154.169; 6.W.154.172; 6.W.154.175; 6.W.154.240; 6.W.154.244;6.W.157.228; 6.W.157.229; 6.W.157.230; 6.W.157.231; 6.W.157.236; 6.W.157.237;6.W.157.238; 6.W.157.239; 6.W.157.154; 6.W.157.157; 6.W.157.166; 6.W.157.169;6.W.157.172; 6.W.157.175; 6.W.157.240; 6.W.157.244; 6.W.166.228; 6.W.166.229;6.W.166.230; 6.W.166.231; 6.W.166.236; 6.W.166.237; 6.W.166.238; 6.W.166.239;6.W.166.154; 6.W.166.157; 6.W.166.166; 6.W.166.169; 6.W.166.172; 6.W.166.175;6.W.166.240; 6.W.166.244; 6.W.169.228; 6.W.169.229; 6.W.169.230; 6.W.169.231;6.W.169.236; 6.W.169.237; 6.W.169.238; 6.W.169.239; 6.W.169.154; 6.W.169.157;6.W.169.166; 6.W.169.169; 6.W.169.172; 6.W.169.175; 6.W.169.240; 6.W.169.244;6.W.172.228; 6.W.172.229; 6.W.172.230; 6.W.172.231; 6.W.172.236; 6.W.172.237;6.W.172.238; 6.W.172.239; 6.W.172.154; 6.W.172.157; 6.W.172.166; 6.W.172.169;6.W.172.172; 6.W.172.175; 6.W.172.240; 6.W.172.244; 6.W.175.228; 6.W.175.229;6.W.175.230; 6.W.175.231; 6.W.175.236; 6.W.175.237; 6.W.175.238; 6.W.175.239;6.W.175.154; 6.W.175.157; 6.W.175.166; 6.W.175.169; 6.W.175.172; 6.W.175.175;6.W.175.240; 6.W.175.244; 6.W.240.228; 6.W.240.229; 6.W.240.230; 6.W.240.231;6.W.240.236; 6.W.240.237; 6.W.240.238; 6.W.240.239; 6.W.240.154; 6.W.240.157;6.W.240.166; 6.W.240.169; 6.W.240.172; 6.W.240.175; 6.W.240.240; 6.W.240.244;6.W.244.228; 6.W.244.229; 6.W.244.230; 6.W.244.231; 6.W.244.236; 6.W.244.237;6.W.244.238; 6.W.244.239; 6.W.244.154; 6.W.244.157; 6.W.244.166; 6.W.244.169;6.W.244.172; 6.W.244.175; 6.W.244.240; 6.W.244.244;

6.Yのプロドラッグ
6.Y.228.228; 6.Y.228.229; 6.Y.228.230; 6.Y.228.231; 6.Y.228.236; 6.Y.228.237;6.Y.228.238; 6.Y.228.239; 6.Y.228.154; 6.Y.228.157; 6.Y.228.166; 6.Y.228.169;6.Y.228.172; 6.Y.228.175; 6.Y.228.240; 6.Y.228.244; 6.Y.229.228; 6.Y.229.229;6.Y.229.230; 6.Y.229.231; 6.Y.229.236; 6.Y.229.237; 6.Y.229.238; 6.Y.229.239;6.Y.229.154; 6.Y.229.157; 6.Y.229.166; 6.Y.229.169; 6.Y.229.172; 6.Y.229.175;6.Y.229.240; 6.Y.229.244; 6.Y.230.228; 6.Y.230.229; 6.Y.230.230; 6.Y.230.231;6.Y.230.236; 6.Y.230.237; 6.Y.230.238; 6.Y.230.239; 6.Y.230.154; 6.Y.230.157;6.Y.230.166; 6.Y.230.169; 6.Y.230.172; 6.Y.230.175; 6.Y.230.240; 6.Y.230.244;6.Y.231.228; 6.Y.231.229; 6.Y.231.230; 6.Y.231.231; 6.Y.231.236; 6.Y.231.237;6.Y.231.238; 6.Y.231.239; 6.Y.231.154; 6.Y.231.157; 6.Y.231.166; 6.Y.231.169;6.Y.231.172; 6.Y.231.175; 6.Y.231.240; 6.Y.231.244; 6.Y.236.228; 6.Y.236.229;6.Y.236.230; 6.Y.236.231; 6.Y.236.236; 6.Y.236.237; 6.Y.236.238; 6.Y.236.239;6.Y.236.154; 6.Y.236.157; 6.Y.236.166; 6.Y.236.169; 6.Y.236.172; 6.Y.236.175;6.Y.236.240; 6.Y.236.244; 6.Y.237.228; 6.Y.237.229; 6.Y.237.230; 6.Y.237.231;6.Y.237.236; 6.Y.237.237; 6.Y.237.238; 6.Y.237.239; 6.Y.237.154; 6.Y.237.157;6.Y.237.166; 6.Y.237.169; 6.Y.237.172; 6.Y.237.175; 6.Y.237.240; 6.Y.237.244;6.Y.238.228; 6.Y.238.229; 6.Y.238.230; 6.Y.238.231; 6.Y.238.236; 6.Y.238.237;6.Y.238.238; 6.Y.238.239; 6.Y.238.154; 6.Y.238.157; 6.Y.238.166; 6.Y.238.169;6.Y.238.172; 6.Y.238.175; 6.Y.238.240; 6.Y.238.244; 6.Y.239.228; 6.Y.239.229;6.Y.239.230; 6.Y.239.231; 6.Y.239.236; 6.Y.239.237; 6.Y.239.238; 6.Y.239.239;6.Y.239.154; 6.Y.239.157; 6.Y.239.166; 6.Y.239.169; 6.Y.239.172; 6.Y.239.175;6.Y.239.240; 6.Y.239.244; 6.Y.154.228; 6.Y.154.229; 6.Y.154.230; 6.Y.154.231; 6.Y.154.236;6.Y.154.237; 6.Y.154.238; 6.Y.154.239; 6.Y.154.154; 6.Y.154.157; 6.Y.154.166;6.Y.154.169; 6.Y.154.172; 6.Y.154.175; 6.Y.154.240; 6.Y.154.244; 6.Y.157.228;6.Y.157.229; 6.Y.157.230; 6.Y.157.231; 6.Y.157.236; 6.Y.157.237; 6.Y.157.238;6.Y.157.239; 6.Y.157.154; 6.Y.157.157; 6.Y.157.166; 6.Y.157.169; 6.Y.157.172;6.Y.157.175; 6.Y.157.240; 6.Y.157.244; 6.Y.166.228; 6.Y.166.229; 6.Y.166.230;6.Y.166.231; 6.Y.166.236; 6.Y.166.237; 6.Y.166.238; 6.Y.166.239; 6.Y.166.154;6.Y.166.157; 6.Y.166.166; 6.Y.166.169; 6.Y.166.172; 6.Y.166.175; 6.Y.166.240;6.Y.166.244; 6.Y.169.228; 6.Y.169.229; 6.Y.169.230; 6.Y.169.231; 6.Y.169.236;6.Y.169.237; 6.Y.169.238; 6.Y.169.239; 6.Y.169.154; 6.Y.169.157; 6.Y.169.166;6.Y.169.169; 6.Y.169.172; 6.Y.169.175; 6.Y.169.240; 6.Y.169.244; 6.Y.172.228;6.Y.172.229; 6.Y.172.230; 6.Y.172.231; 6.Y.172.236; 6.Y.172.237; 6.Y.172.238;6.Y.172.239; 6.Y.172.154; 6.Y.172.157; 6.Y.172.166; 6.Y.172.169; 6.Y.172.172;6.Y.172.175; 6.Y.172.240; 6.Y.172.244; 6.Y.175.228; 6.Y.175.229; 6.Y.175.230;6.Y.175.231; 6.Y.175.236; 6.Y.175.237; 6.Y.175.238; 6.Y.175.239; 6.Y.175.154;6.Y.175.157; 6.Y.175.166; 6.Y.175.169; 6.Y.175.172; 6.Y.175.175; 6.Y.175.240;6.Y.175.244; 6.Y.240.228; 6.Y.240.229; 6.Y.240.230; 6.Y.240.231; 6.Y.240.236;6.Y.240.237; 6.Y.240.238; 6.Y.240.239; 6.Y.240.154; 6.Y.240.157; 6.Y.240.166;6.Y.240.169; 6.Y.240.172; 6.Y.240.175; 6.Y.240.240; 6.Y.240.244; 6.Y.244.228;6.Y.244.229; 6.Y.244.230; 6.Y.244.231; 6.Y.244.236; 6.Y.244.237; 6.Y.244.238;6.Y.244.239; 6.Y.244.154; 6.Y.244.157; 6.Y.244.166; 6.Y.244.169; 6.Y.244.172;6.Y.244.175; 6.Y.244.240; 6.Y.244.244;

7.AHのプロドラッグ
7.AH.4.157; 7.AH.4.158; 7.AH.4.196; 7.AH.4.223; 7.AH.4.240; 7.AH.4.244;7.AH.4.243; 7.AH.4.247; 7.AH.5.157; 7.AH.5.158; 7.AH.5.196; 7.AH.5.223;7.AH.5.240; 7.AH.5.244; 7.AH.5.243; 7.AH.5.247; 7.AH.7.157; 7.AH.7.158;7.AH.7.196; 7.AH.7.223; 7.AH.7.240; 7.AH.7.244; 7.AH.7.243; 7.AH.7.247;7.AH.15.157; 7.AH.15.158; 7.AH.15.196; 7.AH.15.223; 7.AH.15.240; 7.AH.15.244;7.AH.15.243; 7.AH.15.247; 7.AH.16.157; 7.AH.16.158; 7.AH.16.196; 7.AH.16.223;7.AH.16.240; 7.AH.16.244; 7.AH.16.243; 7.AH.16.247; 7.AH.18.157; 7.AH.18.158;7.AH.18.196; 7.AH.18.223; 7.AH.18.240; 7.AH.18.244; 7.AH.18.243; 7.AH.18.247;7.AH.26.157; 7.AH.26.158; 7.AH.26.196; 7.AH.26.223; 7.AH.26.240; 7.AH.26.244;7.AH.26.243; 7.AH.26.247; 7.AH.27.157; 7.AH.27.158; 7.AH.27.196; 7.AH.27.223;7.AH.27.240; 7.AH.27.244; 7.AH.27.243; 7.AH.27.247; 7.AH.29.157; 7.AH.29.158;7.AH.29.196; 7.AH.29.223; 7.AH.29.240; 7.AH.29.244; 7.AH.29.243; 7.AH.29.247;7.AH.54.157; 7.AH.54.158; 7.AH.54.196; 7.AH.54.223; 7.AH.54.240; 7.AH.54.244;7.AH.54.243; 7.AH.54.247; 7.AH.55.157; 7.AH.55.158; 7.AH.55.196; 7.AH.55.223;7.AH.55.240; 7.AH.55.244; 7.AH.55.243; 7.AH.55.247; 7.AH.56.157; 7.AH.56.158;7.AH.56.196; 7.AH.56.223; 7.AH.56.240; 7.AH.56.244; 7.AH.56.243; 7.AH.56.247;7.AH.157.157; 7.AH.157.158; 7.AH.157.196; 7.AH.157.223; 7.AH.157.240;7.AH.157.244; 7.AH.157.243; 7.AH.157.247; 7.AH.196.157; 7.AH.196.158;7.AH.196.196; 7.AH.196.223; 7.AH.196.240; 7.AH.196.244; 7.AH.196.243; 7.AH.196.247;7.AH.223.157; 7.AH.223.158; 7.AH.223.196; 7.AH.223.223; 7.AH.223.240;7.AH.223.244; 7.AH.223.243; 7.AH.223.247; 7.AH.240.157; 7.AH.240.158;7.AH.240.196; 7.AH.240.223; 7.AH.240.240; 7.AH.240.244; 7.AH.240.243;7.AH.240.247; 7.AH.244.157; 7.AH.244.158; 7.AH.244.196; 7.AH.244.223;7.AH.244.240; 7.AH.244.244; 7.AH.244.243; 7.AH.244.247; 7.AH.247.157;7.AH.247.158; 7.AH.247.196; 7.AH.247.223; 7.AH.247.240; 7.AH.247.244;7.AH.247.243; 7.AH.247.247;

7.AJのプロドラッグ
7.AJ.4.157; 7.AJ.4.158; 7.AJ.4.196; 7.AJ.4.223; 7.AJ.4.240; 7.AJ.4.244;7.AJ.4.243; 7.AJ.4.247; 7.AJ.5.157; 7.AJ.5.158; 7.AJ.5.196; 7.AJ.5.223;7.AJ.5.240; 7.AJ.5.244; 7.AJ.5.243; 7.AJ.5.247; 7.AJ.7.157; 7.AJ.7.158;7.AJ.7.196; 7.AJ.7.223; 7.AJ.7.240; 7.AJ.7.244; 7.AJ.7.243; 7.AJ.7.247; 7.AJ.15.157;7.AJ.15.158; 7.AJ.15.196; 7.AJ.15.223; 7.AJ.15.240; 7.AJ.15.244; 7.AJ.15.243;7.AJ.15.247; 7.AJ.16.157; 7.AJ.16.158; 7.AJ.16.196; 7.AJ.16.223; 7.AJ.16.240;7.AJ.16.244; 7.AJ.16.243; 7.AJ.16.247; 7.AJ.18.157; 7.AJ.18.158; 7.AJ.18.196;7.AJ.18.223; 7.AJ.18.240; 7.AJ.18.244; 7.AJ.18.243; 7.AJ.18.247; 7.AJ.26.157;7.AJ.26.158; 7.AJ.26.196; 7.AJ.26.223; 7.AJ.26.240; 7.AJ.26.244; 7.AJ.26.243;7.AJ.26.247; 7.AJ.27.157; 7.AJ.27.158; 7.AJ.27.196; 7.AJ.27.223; 7.AJ.27.240;7.AJ.27.244; 7.AJ.27.243; 7.AJ.27.247; 7.AJ.29.157; 7.AJ.29.158; 7.AJ.29.196;7.AJ.29.223; 7.AJ.29.240; 7.AJ.29.244; 7.AJ.29.243; 7.AJ.29.247; 7.AJ.54.157;7.AJ.54.158; 7.AJ.54.196; 7.AJ.54.223; 7.AJ.54.240; 7.AJ.54.244; 7.AJ.54.243;7.AJ.54.247; 7.AJ.55.157; 7.AJ.55.158; 7.AJ.55.196; 7.AJ.55.223; 7.AJ.55.240;7.AJ.55.244; 7.AJ.55.243; 7.AJ.55.247; 7.AJ.56.157; 7.AJ.56.158; 7.AJ.56.196;7.AJ.56.223; 7.AJ.56.240; 7.AJ.56.244; 7.AJ.56.243; 7.AJ.56.247; 7.AJ.157.157;7.AJ.157.158; 7.AJ.157.196; 7.AJ.157.223; 7.AJ.157.240; 7.AJ.157.244; 7.AJ.157.243;7.AJ.157.247; 7.AJ.196.157; 7.AJ.196.158; 7.AJ.196.196; 7.AJ.196.223;7.AJ.196.240; 7.AJ.196.244; 7.AJ.196.243; 7.AJ.196.247; 7.AJ.223.157;7.AJ.223.158; 7.AJ.223.196; 7.AJ.223.223; 7.AJ.223.240; 7.AJ.223.244;7.AJ.223.243; 7.AJ.223.247; 7.AJ.240.157; 7.AJ.240.158; 7.AJ.240.196;7.AJ.240.223; 7.AJ.240.240; 7.AJ.240.244; 7.AJ.240.243; 7.AJ.240.247;7.AJ.244.157; 7.AJ.244.158; 7.AJ.244.196; 7.AJ.244.223; 7.AJ.244.240;7.AJ.244.244; 7.AJ.244.243; 7.AJ.244.247; 7.AJ.247.157; 7.AJ.247.158;7.AJ.247.196; 7.AJ.247.223; 7.AJ.247.240; 7.AJ.247.244; 7.AJ.247.243;7.AJ.247.247;

7.ANのプロドラッグ
7.AN.4.157; 7.AN.4.158; 7.AN.4.196; 7.AN.4.223; 7.AN.4.240; 7.AN.4.244;7.AN.4.243; 7.AN.4.247; 7.AN.5.157; 7.AN.5.158; 7.AN.5.196; 7.AN.5.223;7.AN.5.240; 7.AN.5.244; 7.AN.5.243; 7.AN.5.247; 7.AN.7.157; 7.AN.7.158;7.AN.7.196; 7.AN.7.223; 7.AN.7.240; 7.AN.7.244; 7.AN.7.243; 7.AN.7.247;7.AN.15.157; 7.AN.15.158; 7.AN.15.196; 7.AN.15.223; 7.AN.15.240; 7.AN.15.244;7.AN.15.243; 7.AN.15.247; 7.AN.16.157; 7.AN.16.158; 7.AN.16.196; 7.AN.16.223;7.AN.16.240; 7.AN.16.244; 7.AN.16.243; 7.AN.16.247; 7.AN.18.157; 7.AN.18.158;7.AN.18.196; 7.AN.18.223; 7.AN.18.240; 7.AN.18.244; 7.AN.18.243; 7.AN.18.247;7.AN.26.157; 7.AN.26.158; 7.AN.26.196; 7.AN.26.223; 7.AN.26.240; 7.AN.26.244;7.AN.26.243; 7.AN.26.247; 7.AN.27.157; 7.AN.27.158; 7.AN.27.196; 7.AN.27.223;7.AN.27.240; 7.AN.27.244; 7.AN.27.243; 7.AN.27.247; 7.AN.29.157; 7.AN.29.158;7.AN.29.196; 7.AN.29.223; 7.AN.29.240; 7.AN.29.244; 7.AN.29.243; 7.AN.29.247;7.AN.54.157; 7.AN.54.158; 7.AN.54.196; 7.AN.54.223; 7.AN.54.240; 7.AN.54.244;7.AN.54.243; 7.AN.54.247; 7.AN.55.157; 7.AN.55.158; 7.AN.55.196; 7.AN.55.223;7.AN.55.240; 7.AN.55.244; 7.AN.55.243; 7.AN.55.247; 7.AN.56.157; 7.AN.56.158;7.AN.56.196; 7.AN.56.223; 7.AN.56.240; 7.AN.56.244; 7.AN.56.243; 7.AN.56.247;7.AN.157.157; 7.AN.157.158; 7.AN.157.196; 7.AN.157.223; 7.AN.157.240;7.AN.157.244; 7.AN.157.243; 7.AN.157.247; 7.AN.196.157; 7.AN.196.158;7.AN.196.196; 7.AN.196.223; 7.AN.196.240; 7.AN.196.244; 7.AN.196.243;7.AN.196.247; 7.AN.223.157; 7.AN.223.158; 7.AN.223.196; 7.AN.223.223;7.AN.223.240; 7.AN.223.244; 7.AN.223.243; 7.AN.223.247; 7.AN.240.157;7.AN.240.158; 7.AN.240.196; 7.AN.240.223; 7.AN.240.240; 7.AN.240.244; 7.AN.240.243;7.AN.240.247; 7.AN.244.157; 7.AN.244.158; 7.AN.244.196; 7.AN.244.223;7.AN.244.240; 7.AN.244.244; 7.AN.244.243; 7.AN.244.247; 7.AN.247.157;7.AN.247.158; 7.AN.247.196; 7.AN.247.223; 7.AN.247.240; 7.AN.247.244;7.AN.247.243; 7.AN.247.247;

7.APのプロドラッグ
7.AP.4.157; 7.AP.4.158; 7.AP.4.196; 7.AP.4.223; 7.AP.4.240; 7.AP.4.244;7.AP.4.243; 7.AP.4.247; 7.AP.5.157; 7.AP.5.158; 7.AP.5.196; 7.AP.5.223;7.AP.5.240; 7.AP.5.244; 7.AP.5.243; 7.AP.5.247; 7.AP.7.157; 7.AP.7.158;7.AP.7.196; 7.AP.7.223; 7.AP.7.240; 7.AP.7.244; 7.AP.7.243; 7.AP.7.247;7.AP.15.157; 7.AP.15.158; 7.AP.15.196; 7.AP.15.223; 7.AP.15.240; 7.AP.15.244;7.AP.15.243; 7.AP.15.247; 7.AP.16.157; 7.AP.16.158; 7.AP.16.196; 7.AP.16.223;7.AP.16.240; 7.AP.16.244; 7.AP.16.243; 7.AP.16.247; 7.AP.18.157; 7.AP.18.158;7.AP.18.196; 7.AP.18.223; 7.AP.18.240; 7.AP.18.244; 7.AP.18.243; 7.AP.18.247;7.AP.26.157; 7.AP.26.158; 7.AP.26.196; 7.AP.26.223; 7.AP.26.240; 7.AP.26.244;7.AP.26.243; 7.AP.26.247; 7.AP.27.157; 7.AP.27.158; 7.AP.27.196; 7.AP.27.223;7.AP.27.240; 7.AP.27.244; 7.AP.27.243; 7.AP.27.247; 7.AP.29.157; 7.AP.29.158;7.AP.29.196; 7.AP.29.223; 7.AP.29.240; 7.AP.29.244; 7.AP.29.243; 7.AP.29.247;7.AP.54.157; 7.AP.54.158; 7.AP.54.196; 7.AP.54.223; 7.AP.54.240; 7.AP.54.244;7.AP.54.243; 7.AP.54.247; 7.AP.55.157; 7.AP.55.158; 7.AP.55.196; 7.AP.55.223;7.AP.55.240; 7.AP.55.244; 7.AP.55.243; 7.AP.55.247; 7.AP.56.157; 7.AP.56.158;7.AP.56.196; 7.AP.56.223; 7.AP.56.240; 7.AP.56.244; 7.AP.56.243; 7.AP.56.247;7.AP.157.157; 7.AP.157.158; 7.AP.157.196; 7.AP.157.223; 7.AP.157.240;7.AP.157.244; 7.AP.157.243; 7.AP.157.247; 7.AP.196.157; 7.AP.196.158;7.AP.196.196; 7.AP.196.223; 7.AP.196.240; 7.AP.196.244; 7.AP.196.243;7.AP.196.247; 7.AP.223.157; 7.AP.223.158; 7.AP.223.196; 7.AP.223.223;7.AP.223.240; 7.AP.223.244; 7.AP.223.243; 7.AP.223.247; 7.AP.240.157;7.AP.240.158; 7.AP.240.196; 7.AP.240.223; 7.AP.240.240; 7.AP.240.244;7.AP.240.243; 7.AP.240.247; 7.AP.244.157; 7.AP.244.158; 7.AP.244.196; 7.AP.244.223;7.AP.244.240; 7.AP.244.244; 7.AP.244.243; 7.AP.244.247; 7.AP.247.157;7.AP.247.158; 7.AP.247.196; 7.AP.247.223; 7.AP.247.240; 7.AP.247.244;7.AP.247.243; 7.AP.247.247;

7.AZのプロドラッグ
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のプロドラッグ
7.BF.4.157; 7.BF.4.158; 7.BF.4.196; 7.BF.4.223; 7.BF.4.240; 7.BF.4.244;7.BF.4.243; 7.BF.4.247; 7.BF.5.157; 7.BF.5.158; 7.BF.5.196; 7.BF.5.223;7.BF.5.240; 7.BF.5.244; 7.BF.5.243; 7.BF.5.247; 7.BF.7.157; 7.BF.7.158;7.BF.7.196; 7.BF.7.223; 7.BF.7.240; 7.BF.7.244; 7.BF.7.243; 7.BF.7.247;7.BF.15.157; 7.BF.15.158; 7.BF.15.196; 7.BF.15.223; 7.BF.15.240; 7.BF.15.244;7.BF.15.243; 7.BF.15.247; 7.BF.16.157; 7.BF.16.158; 7.BF.16.196; 7.BF.16.223; 7.BF.16.240;7.BF.16.244; 7.BF.16.243; 7.BF.16.247; 7.BF.18.157; 7.BF.18.158; 7.BF.18.196;7.BF.18.223; 7.BF.18.240; 7.BF.18.244; 7.BF.18.243; 7.BF.18.247; 7.BF.26.157;7.BF.26.158; 7.BF.26.196; 7.BF.26.223; 7.BF.26.240; 7.BF.26.244; 7.BF.26.243;7.BF.26.247; 7.BF.27.157; 7.BF.27.158; 7.BF.27.196; 7.BF.27.223; 7.BF.27.240;7.BF.27.244; 7.BF.27.243; 7.BF.27.247; 7.BF.29.157; 7.BF.29.158; 7.BF.29.196;7.BF.29.223; 7.BF.29.240; 7.BF.29.244; 7.BF.29.243; 7.BF.29.247; 7.BF.54.157;7.BF.54.158; 7.BF.54.196; 7.BF.54.223; 7.BF.54.240; 7.BF.54.244; 7.BF.54.243;7.BF.54.247; 7.BF.55.157; 7.BF.55.158; 7.BF.55.196; 7.BF.55.223; 7.BF.55.240;7.BF.55.244; 7.BF.55.243; 7.BF.55.247; 7.BF.56.157; 7.BF.56.158; 7.BF.56.196;7.BF.56.223; 7.BF.56.240; 7.BF.56.244; 7.BF.56.243; 7.BF.56.247; 7.BF.157.157;7.BF.157.158; 7.BF.157.196; 7.BF.157.223; 7.BF.157.240; 7.BF.157.244;7.BF.157.243; 7.BF.157.247; 7.BF.196.157; 7.BF.196.158; 7.BF.196.196;7.BF.196.223; 7.BF.196.240; 7.BF.196.244; 7.BF.196.243; 7.BF.196.247;7.BF.223.157; 7.BF.223.158; 7.BF.223.196; 7.BF.223.223; 7.BF.223.240;7.BF.223.244; 7.BF.223.243; 7.BF.223.247; 7.BF.240.157; 7.BF.240.158;7.BF.240.196; 7.BF.240.223; 7.BF.240.240; 7.BF.240.244; 7.BF.240.243;7.BF.240.247; 7.BF.244.157; 7.BF.244.158; 7.BF.244.196; 7.BF.244.223;7.BF.244.240; 7.BF.244.244; 7.BF.244.243; 7.BF.244.247; 7.BF.247.157;7.BF.247.158; 7.BF.247.196; 7.BF.247.223; 7.BF.247.240; 7.BF.247.244;7.BF.247.243; 7.BF.247.247;

7.CIのプロドラッグ
7.CI.4.157; 7.CI.4.158; 7.CI.4.196; 7.CI.4.223; 7.CI.4.240; 7.CI.4.244;7.CI.4.243; 7.CI.4.247; 7.CI.5.157; 7.CI.5.158; 7.CI.5.196; 7.CI.5.223;7.CI.5.240; 7.CI.5.244; 7.CI.5.243; 7.CI.5.247; 7.CI.7.157; 7.CI.7.158;7.CI.7.196; 7.CI.7.223; 7.CI.7.240; 7.CI.7.244; 7.CI.7.243; 7.CI.7.247;7.CI.15.157; 7.CI.15.158; 7.CI.15.196; 7.CI.15.223; 7.CI.15.240; 7.CI.15.244;7.CI.15.243; 7.CI.15.247; 7.CI.16.157; 7.CI.16.158; 7.CI.16.196; 7.CI.16.223;7.CI.16.240; 7.CI.16.244; 7.CI.16.243; 7.CI.16.247; 7.CI.18.157; 7.CI.18.158;7.CI.18.196; 7.CI.18.223; 7.CI.18.240; 7.CI.18.244; 7.CI.18.243; 7.CI.18.247;7.CI.26.157; 7.CI.26.158; 7.CI.26.196; 7.CI.26.223; 7.CI.26.240; 7.CI.26.244;7.CI.26.243; 7.CI.26.247; 7.CI.27.157; 7.CI.27.158; 7.CI.27.196; 7.CI.27.223;7.CI.27.240; 7.CI.27.244; 7.CI.27.243; 7.CI.27.247; 7.CI.29.157; 7.CI.29.158;7.CI.29.196; 7.CI.29.223; 7.CI.29.240; 7.CI.29.244; 7.CI.29.243; 7.CI.29.247;7.CI.54.157; 7.CI.54.158; 7.CI.54.196; 7.CI.54.223; 7.CI.54.240; 7.CI.54.244;7.CI.54.243; 7.CI.54.247; 7.CI.55.157; 7.CI.55.158; 7.CI.55.196; 7.CI.55.223;7.CI.55.240; 7.CI.55.244; 7.CI.55.243; 7.CI.55.247; 7.CI.56.157; 7.CI.56.158;7.CI.56.196; 7.CI.56.223; 7.CI.56.240; 7.CI.56.244; 7.CI.56.243; 7.CI.56.247;7.CI.157.157; 7.CI.157.158; 7.CI.157.196; 7.CI.157.223; 7.CI.157.240;7.CI.157.244; 7.CI.157.243; 7.CI.157.247; 7.CI.196.157; 7.CI.196.158;7.CI.196.196; 7.CI.196.223; 7.CI.196.240; 7.CI.196.244; 7.CI.196.243;7.CI.196.247; 7.CI.223.157; 7.CI.223.158; 7.CI.223.196; 7.CI.223.223;7.CI.223.240; 7.CI.223.244; 7.CI.223.243; 7.CI.223.247; 7.CI.240.157;7.CI.240.158; 7.CI.240.196; 7.CI.240.223; 7.CI.240.240; 7.CI.240.244;7.CI.240.243; 7.CI.240.247; 7.CI.244.157; 7.CI.244.158; 7.CI.244.196;7.CI.244.223; 7.CI.244.240; 7.CI.244.244; 7.CI.244.243; 7.CI.244.247;7.CI.247.157; 7.CI.247.158; 7.CI.247.196; 7.CI.247.223; 7.CI.247.240; 7.CI.247.244;7.CI.247.243; 7.CI.247.247;

7.COのプロドラッグ
7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244;7.CO.4.243; 7.CO.4.247; 7.CO.5.157; 7.CO.5.158; 7.CO.5.196; 7.CO.5.223;7.CO.5.240; 7.CO.5.244; 7.CO.5.243; 7.CO.5.247; 7.CO.7.157; 7.CO.7.158;7.CO.7.196; 7.CO.7.223; 7.CO.7.240; 7.CO.7.244; 7.CO.7.243; 7.CO.7.247;7.CO.15.157; 7.CO.15.158; 7.CO.15.196; 7.CO.15.223; 7.CO.15.240; 7.CO.15.244;7.CO.15.243; 7.CO.15.247; 7.CO.16.157; 7.CO.16.158; 7.CO.16.196; 7.CO.16.223;7.CO.16.240; 7.CO.16.244; 7.CO.16.243; 7.CO.16.247; 7.CO.18.157; 7.CO.18.158;7.CO.18.196; 7.CO.18.223; 7.CO.18.240; 7.CO.18.244; 7.CO.18.243; 7.CO.18.247;7.CO.26.157; 7.CO.26.158; 7.CO.26.196; 7.CO.26.223; 7.CO.26.240; 7.CO.26.244;7.CO.26.243; 7.CO.26.247; 7.CO.27.157; 7.CO.27.158; 7.CO.27.196; 7.CO.27.223;7.CO.27.240; 7.CO.27.244; 7.CO.27.243; 7.CO.27.247; 7.CO.29.157; 7.CO.29.158;7.CO.29.196; 7.CO.29.223; 7.CO.29.240; 7.CO.29.244; 7.CO.29.243; 7.CO.29.247;7.CO.54.157; 7.CO.54.158; 7.CO.54.196; 7.CO.54.223; 7.CO.54.240; 7.CO.54.244;7.CO.54.243; 7.CO.54.247; 7.CO.55.157; 7.CO.55.158; 7.CO.55.196; 7.CO.55.223;7.CO.55.240; 7.CO.55.244; 7.CO.55.243; 7.CO.55.247; 7.CO.56.157; 7.CO.56.158;7.CO.56.196; 7.CO.56.223; 7.CO.56.240; 7.CO.56.244; 7.CO.56.243; 7.CO.56.247;7.CO.157.157; 7.CO.157.158; 7.CO.157.196; 7.CO.157.223; 7.CO.157.240;7.CO.157.244; 7.CO.157.243; 7.CO.157.247; 7.CO.196.157; 7.CO.196.158;7.CO.196.196; 7.CO.196.223; 7.CO.196.240; 7.CO.196.244; 7.CO.196.243;7.CO.196.247; 7.CO.223.157; 7.CO.223.158; 7.CO.223.196; 7.CO.223.223;7.CO.223.240; 7.CO.223.244; 7.CO.223.243; 7.CO.223.247; 7.CO.240.157;7.CO.240.158; 7.CO.240.196; 7.CO.240.223; 7.CO.240.240; 7.CO.240.244;7.CO.240.243; 7.CO.240.247; 7.CO.244.157; 7.CO.244.158; 7.CO.244.196;7.CO.244.223; 7.CO.244.240; 7.CO.244.244; 7.CO.244.243; 7.CO.244.247;7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244;7.CO.4.243; 7.CO.4.247;

8.AHのプロドラッグ
8.AH.4.157; 8.AH.4.158; 8.AH.4.196; 8.AH.4.223; 8.AH.4.240; 8.AH.4.244;8.AH.4.243; 8.AH.4.247; 8.AH.5.157; 8.AH.5.158; 8.AH.5.196; 8.AH.5.223;8.AH.5.240; 8.AH.5.244; 8.AH.5.243; 8.AH.5.247; 8.AH.7.157; 8.AH.7.158;8.AH.7.196; 8.AH.7.223; 8.AH.7.240; 8.AH.7.244; 8.AH.7.243; 8.AH.7.247;8.AH.15.157; 8.AH.15.158; 8.AH.15.196; 8.AH.15.223; 8.AH.15.240; 8.AH.15.244;8.AH.15.243; 8.AH.15.247; 8.AH.16.157; 8.AH.16.158; 8.AH.16.196; 8.AH.16.223;8.AH.16.240; 8.AH.16.244; 8.AH.16.243; 8.AH.16.247; 8.AH.18.157; 8.AH.18.158;8.AH.18.196; 8.AH.18.223; 8.AH.18.240; 8.AH.18.244; 8.AH.18.243; 8.AH.18.247; 8.AH.26.157;8.AH.26.158; 8.AH.26.196; 8.AH.26.223; 8.AH.26.240; 8.AH.26.244; 8.AH.26.243;8.AH.26.247; 8.AH.27.157; 8.AH.27.158; 8.AH.27.196; 8.AH.27.223; 8.AH.27.240;8.AH.27.244; 8.AH.27.243; 8.AH.27.247; 8.AH.29.157; 8.AH.29.158; 8.AH.29.196;8.AH.29.223; 8.AH.29.240; 8.AH.29.244; 8.AH.29.243; 8.AH.29.247; 8.AH.54.157;8.AH.54.158; 8.AH.54.196; 8.AH.54.223; 8.AH.54.240; 8.AH.54.244; 8.AH.54.243;8.AH.54.247; 8.AH.55.157; 8.AH.55.158; 8.AH.55.196; 8.AH.55.223; 8.AH.55.240;8.AH.55.244; 8.AH.55.243; 8.AH.55.247; 8.AH.56.157; 8.AH.56.158; 8.AH.56.196;8.AH.56.223; 8.AH.56.240; 8.AH.56.244; 8.AH.56.243; 8.AH.56.247; 8.AH.157.157;8.AH.157.158; 8.AH.157.196; 8.AH.157.223; 8.AH.157.240; 8.AH.157.244;8.AH.157.243; 8.AH.157.247; 8.AH.196.157; 8.AH.196.158; 8.AH.196.196;8.AH.196.223; 8.AH.196.240; 8.AH.196.244; 8.AH.196.243; 8.AH.196.247;8.AH.223.157; 8.AH.223.158; 8.AH.223.196; 8.AH.223.223; 8.AH.223.240;8.AH.223.244; 8.AH.223.243; 8.AH.223.247; 8.AH.240.157; 8.AH.240.158;8.AH.240.196; 8.AH.240.223; 8.AH.240.240; 8.AH.240.244; 8.AH.240.243;8.AH.240.247; 8.AH.244.157; 8.AH.244.158; 8.AH.244.196; 8.AH.244.223;8.AH.244.240; 8.AH.244.244; 8.AH.244.243; 8.AH.244.247; 8.AH.247.157;8.AH.247.158; 8.AH.247.196; 8.AH.247.223; 8.AH.247.240; 8.AH.247.244;8.AH.247.243; 8.AH.247.247;

8.AJのプロドラッグ
8.AJ.4.157; 8.AJ.4.158; 8.AJ.4.196; 8.AJ.4.223; 8.AJ.4.240; 8.AJ.4.244;8.AJ.4.243; 8.AJ.4.247; 8.AJ.5.157; 8.AJ.5.158; 8.AJ.5.196; 8.AJ.5.223;8.AJ.5.240; 8.AJ.5.244; 8.AJ.5.243; 8.AJ.5.247; 8.AJ.7.157; 8.AJ.7.158; 8.AJ.7.196;8.AJ.7.223; 8.AJ.7.240; 8.AJ.7.244; 8.AJ.7.243; 8.AJ.7.247; 8.AJ.15.157;8.AJ.15.158; 8.AJ.15.196; 8.AJ.15.223; 8.AJ.15.240; 8.AJ.15.244; 8.AJ.15.243;8.AJ.15.247; 8.AJ.16.157; 8.AJ.16.158; 8.AJ.16.196; 8.AJ.16.223; 8.AJ.16.240;8.AJ.16.244; 8.AJ.16.243; 8.AJ.16.247; 8.AJ.18.157; 8.AJ.18.158; 8.AJ.18.196;8.AJ.18.223; 8.AJ.18.240; 8.AJ.18.244; 8.AJ.18.243; 8.AJ.18.247; 8.AJ.26.157;8.AJ.26.158; 8.AJ.26.196; 8.AJ.26.223; 8.AJ.26.240; 8.AJ.26.244; 8.AJ.26.243;8.AJ.26.247; 8.AJ.27.157; 8.AJ.27.158; 8.AJ.27.196; 8.AJ.27.223; 8.AJ.27.240;8.AJ.27.244; 8.AJ.27.243; 8.AJ.27.247; 8.AJ.29.157; 8.AJ.29.158; 8.AJ.29.196;8.AJ.29.223; 8.AJ.29.240; 8.AJ.29.244; 8.AJ.29.243; 8.AJ.29.247; 8.AJ.54.157;8.AJ.54.158; 8.AJ.54.196; 8.AJ.54.223; 8.AJ.54.240; 8.AJ.54.244; 8.AJ.54.243;8.AJ.54.247; 8.AJ.55.157; 8.AJ.55.158; 8.AJ.55.196; 8.AJ.55.223; 8.AJ.55.240;8.AJ.55.244; 8.AJ.55.243; 8.AJ.55.247; 8.AJ.56.157; 8.AJ.56.158; 8.AJ.56.196;8.AJ.56.223; 8.AJ.56.240; 8.AJ.56.244; 8.AJ.56.243; 8.AJ.56.247; 8.AJ.157.157;8.AJ.157.158; 8.AJ.157.196; 8.AJ.157.223; 8.AJ.157.240; 8.AJ.157.244;8.AJ.157.243; 8.AJ.157.247; 8.AJ.196.157; 8.AJ.196.158; 8.AJ.196.196;8.AJ.196.223; 8.AJ.196.240; 8.AJ.196.244; 8.AJ.196.243; 8.AJ.196.247;8.AJ.223.157; 8.AJ.223.158; 8.AJ.223.196; 8.AJ.223.223; 8.AJ.223.240;8.AJ.223.244; 8.AJ.223.243; 8.AJ.223.247; 8.AJ.240.157; 8.AJ.240.158;8.AJ.240.196; 8.AJ.240.223; 8.AJ.240.240; 8.AJ.240.244; 8.AJ.240.243;8.AJ.240.247; 8.AJ.244.157; 8.AJ.244.158; 8.AJ.244.196; 8.AJ.244.223;8.AJ.244.240; 8.AJ.244.244; 8.AJ.244.243; 8.AJ.244.247; 8.AJ.247.157;8.AJ.247.158; 8.AJ.247.196; 8.AJ.247.223; 8.AJ.247.240; 8.AJ.247.244;8.AJ.247.243; 8.AJ.247.247;

8.ANのプロドラッグ
8.AN.4.157; 8.AN.4.158; 8.AN.4.196; 8.AN.4.223; 8.AN.4.240; 8.AN.4.244;8.AN.4.243; 8.AN.4.247; 8.AN.5.157; 8.AN.5.158; 8.AN.5.196; 8.AN.5.223;8.AN.5.240; 8.AN.5.244; 8.AN.5.243; 8.AN.5.247; 8.AN.7.157; 8.AN.7.158;8.AN.7.196; 8.AN.7.223; 8.AN.7.240; 8.AN.7.244; 8.AN.7.243; 8.AN.7.247;8.AN.15.157; 8.AN.15.158; 8.AN.15.196; 8.AN.15.223; 8.AN.15.240; 8.AN.15.244;8.AN.15.243; 8.AN.15.247; 8.AN.16.157; 8.AN.16.158; 8.AN.16.196; 8.AN.16.223;8.AN.16.240; 8.AN.16.244; 8.AN.16.243; 8.AN.16.247; 8.AN.18.157; 8.AN.18.158;8.AN.18.196; 8.AN.18.223; 8.AN.18.240; 8.AN.18.244; 8.AN.18.243; 8.AN.18.247;8.AN.26.157; 8.AN.26.158; 8.AN.26.196; 8.AN.26.223; 8.AN.26.240; 8.AN.26.244;8.AN.26.243; 8.AN.26.247; 8.AN.27.157; 8.AN.27.158; 8.AN.27.196; 8.AN.27.223;8.AN.27.240; 8.AN.27.244; 8.AN.27.243; 8.AN.27.247; 8.AN.29.157; 8.AN.29.158;8.AN.29.196; 8.AN.29.223; 8.AN.29.240; 8.AN.29.244; 8.AN.29.243; 8.AN.29.247;8.AN.54.157; 8.AN.54.158; 8.AN.54.196; 8.AN.54.223; 8.AN.54.240; 8.AN.54.244;8.AN.54.243; 8.AN.54.247; 8.AN.55.157; 8.AN.55.158; 8.AN.55.196; 8.AN.55.223;8.AN.55.240; 8.AN.55.244; 8.AN.55.243; 8.AN.55.247; 8.AN.56.157; 8.AN.56.158;8.AN.56.196; 8.AN.56.223; 8.AN.56.240; 8.AN.56.244; 8.AN.56.243; 8.AN.56.247;8.AN.157.157; 8.AN.157.158; 8.AN.157.196; 8.AN.157.223; 8.AN.157.240;8.AN.157.244; 8.AN.157.243; 8.AN.157.247; 8.AN.196.157; 8.AN.196.158;8.AN.196.196; 8.AN.196.223; 8.AN.196.240; 8.AN.196.244; 8.AN.196.243;8.AN.196.247; 8.AN.223.157; 8.AN.223.158; 8.AN.223.196; 8.AN.223.223;8.AN.223.240; 8.AN.223.244; 8.AN.223.243; 8.AN.223.247; 8.AN.240.157;8.AN.240.158; 8.AN.240.196; 8.AN.240.223; 8.AN.240.240; 8.AN.240.244;8.AN.240.243; 8.AN.240.247; 8.AN.244.157; 8.AN.244.158; 8.AN.244.196;8.AN.244.223; 8.AN.244.240; 8.AN.244.244; 8.AN.244.243; 8.AN.244.247;8.AN.247.157; 8.AN.247.158; 8.AN.247.196; 8.AN.247.223; 8.AN.247.240;8.AN.247.244; 8.AN.247.243; 8.AN.247.247;

8.APのプロドラッグ
8.AP.4.157; 8.AP.4.158; 8.AP.4.196; 8.AP.4.223; 8.AP.4.240; 8.AP.4.244;8.AP.4.243; 8.AP.4.247; 8.AP.5.157; 8.AP.5.158; 8.AP.5.196; 8.AP.5.223;8.AP.5.240; 8.AP.5.244; 8.AP.5.243; 8.AP.5.247; 8.AP.7.157; 8.AP.7.158;8.AP.7.196; 8.AP.7.223; 8.AP.7.240; 8.AP.7.244; 8.AP.7.243; 8.AP.7.247;8.AP.15.157; 8.AP.15.158; 8.AP.15.196; 8.AP.15.223; 8.AP.15.240; 8.AP.15.244;8.AP.15.243; 8.AP.15.247; 8.AP.16.157; 8.AP.16.158; 8.AP.16.196; 8.AP.16.223;8.AP.16.240; 8.AP.16.244; 8.AP.16.243; 8.AP.16.247; 8.AP.18.157; 8.AP.18.158;8.AP.18.196; 8.AP.18.223; 8.AP.18.240; 8.AP.18.244; 8.AP.18.243; 8.AP.18.247;8.AP.26.157; 8.AP.26.158; 8.AP.26.196; 8.AP.26.223; 8.AP.26.240; 8.AP.26.244;8.AP.26.243; 8.AP.26.247; 8.AP.27.157; 8.AP.27.158; 8.AP.27.196; 8.AP.27.223;8.AP.27.240; 8.AP.27.244; 8.AP.27.243; 8.AP.27.247; 8.AP.29.157; 8.AP.29.158;8.AP.29.196; 8.AP.29.223; 8.AP.29.240; 8.AP.29.244; 8.AP.29.243; 8.AP.29.247;8.AP.54.157; 8.AP.54.158; 8.AP.54.196; 8.AP.54.223; 8.AP.54.240; 8.AP.54.244;8.AP.54.243; 8.AP.54.247; 8.AP.55.157; 8.AP.55.158; 8.AP.55.196; 8.AP.55.223;8.AP.55.240; 8.AP.55.244; 8.AP.55.243; 8.AP.55.247; 8.AP.56.157; 8.AP.56.158;8.AP.56.196; 8.AP.56.223; 8.AP.56.240; 8.AP.56.244; 8.AP.56.243; 8.AP.56.247;8.AP.157.157; 8.AP.157.158; 8.AP.157.196; 8.AP.157.223; 8.AP.157.240;8.AP.157.244; 8.AP.157.243; 8.AP.157.247; 8.AP.196.157; 8.AP.196.158;8.AP.196.196; 8.AP.196.223; 8.AP.196.240; 8.AP.196.244; 8.AP.196.243;8.AP.196.247; 8.AP.223.157; 8.AP.223.158; 8.AP.223.196; 8.AP.223.223; 8.AP.223.240;8.AP.223.244; 8.AP.223.243; 8.AP.223.247; 8.AP.240.157; 8.AP.240.158;8.AP.240.196; 8.AP.240.223; 8.AP.240.240; 8.AP.240.244; 8.AP.240.243;8.AP.240.247; 8.AP.244.157; 8.AP.244.158; 8.AP.244.196; 8.AP.244.223;8.AP.244.240; 8.AP.244.244; 8.AP.244.243; 8.AP.244.247; 8.AP.247.157;8.AP.247.158; 8.AP.247.196; 8.AP.247.223; 8.AP.247.240; 8.AP.247.244;8.AP.247.243; 8.AP.247.247;

8.AZのプロドラッグ
8.AZ.4.157; 8.AZ.4.158; 8.AZ.4.196; 8.AZ.4.223; 8.AZ.4.240; 8.AZ.4.244;8.AZ.4.243; 8.AZ.4.247; 8.AZ.5.157; 8.AZ.5.158; 8.AZ.5.196; 8.AZ.5.223;8.AZ.5.240; 8.AZ.5.244; 8.AZ.5.243; 8.AZ.5.247; 8.AZ.7.157; 8.AZ.7.158;8.AZ.7.196; 8.AZ.7.223; 8.AZ.7.240; 8.AZ.7.244; 8.AZ.7.243; 8.AZ.7.247; 8.AZ.15.157;8.AZ.15.158; 8.AZ.15.196; 8.AZ.15.223; 8.AZ.15.240; 8.AZ.15.244; 8.AZ.15.243;8.AZ.15.247; 8.AZ.16.157; 8.AZ.16.158; 8.AZ.16.196; 8.AZ.16.223; 8.AZ.16.240;8.AZ.16.244; 8.AZ.16.243; 8.AZ.16.247; 8.AZ.18.157; 8.AZ.18.158; 8.AZ.18.196;8.AZ.18.223; 8.AZ.18.240; 8.AZ.18.244; 8.AZ.18.243; 8.AZ.18.247; 8.AZ.26.157;8.AZ.26.158; 8.AZ.26.196; 8.AZ.26.223; 8.AZ.26.240; 8.AZ.26.244; 8.AZ.26.243;8.AZ.26.247; 8.AZ.27.157; 8.AZ.27.158; 8.AZ.27.196; 8.AZ.27.223; 8.AZ.27.240;8.AZ.27.244; 8.AZ.27.243; 8.AZ.27.247; 8.AZ.29.157; 8.AZ.29.158; 8.AZ.29.196;8.AZ.29.223; 8.AZ.29.240; 8.AZ.29.244; 8.AZ.29.243; 8.AZ.29.247; 8.AZ.54.157;8.AZ.54.158; 8.AZ.54.196; 8.AZ.54.223; 8.AZ.54.240; 8.AZ.54.244; 8.AZ.54.243;8.AZ.54.247; 8.AZ.55.157; 8.AZ.55.158; 8.AZ.55.196; 8.AZ.55.223; 8.AZ.55.240;8.AZ.55.244; 8.AZ.55.243; 8.AZ.55.247; 8.AZ.56.157; 8.AZ.56.158; 8.AZ.56.196;8.AZ.56.223; 8.AZ.56.240; 8.AZ.56.244; 8.AZ.56.243; 8.AZ.56.247; 8.AZ.157.157;8.AZ.157.158; 8.AZ.157.196; 8.AZ.157.223; 8.AZ.157.240; 8.AZ.157.244; 8.AZ.157.243;8.AZ.157.247; 8.AZ.196.157; 8.AZ.196.158; 8.AZ.196.196; 8.AZ.196.223;8.AZ.196.240; 8.AZ.196.244; 8.AZ.196.243; 8.AZ.196.247; 8.AZ.223.157;8.AZ.223.158; 8.AZ.223.196; 8.AZ.223.223; 8.AZ.223.240; 8.AZ.223.244;8.AZ.223.243; 8.AZ.223.247; 8.AZ.240.157; 8.AZ.240.158; 8.AZ.240.196;8.AZ.240.223; 8.AZ.240.240; 8.AZ.240.244; 8.AZ.240.243; 8.AZ.240.247;8.AZ.244.157; 8.AZ.244.158; 8.AZ.244.196; 8.AZ.244.223; 8.AZ.244.240;8.AZ.244.244; 8.AZ.244.243; 8.AZ.244.247; 8.AZ.247.157; 8.AZ.247.158;8.AZ.247.196; 8.AZ.247.223; 8.AZ.247.240; 8.AZ.247.244; 8.AZ.247.243;8.AZ.247.247;

8.BFのプロドラッグ
8.BF.4.157; 8.BF.4.158; 8.BF.4.196; 8.BF.4.223; 8.BF.4.240; 8.BF.4.244;8.BF.4.243; 8.BF.4.247; 8.BF.5.157; 8.BF.5.158; 8.BF.5.196; 8.BF.5.223;8.BF.5.240; 8.BF.5.244; 8.BF.5.243; 8.BF.5.247; 8.BF.7.157; 8.BF.7.158;8.BF.7.196; 8.BF.7.223; 8.BF.7.240; 8.BF.7.244; 8.BF.7.243; 8.BF.7.247;8.BF.15.157; 8.BF.15.158; 8.BF.15.196; 8.BF.15.223; 8.BF.15.240; 8.BF.15.244;8.BF.15.243; 8.BF.15.247; 8.BF.16.157; 8.BF.16.158; 8.BF.16.196; 8.BF.16.223;8.BF.16.240; 8.BF.16.244; 8.BF.16.243; 8.BF.16.247; 8.BF.18.157; 8.BF.18.158;8.BF.18.196; 8.BF.18.223; 8.BF.18.240; 8.BF.18.244; 8.BF.18.243; 8.BF.18.247;8.BF.26.157; 8.BF.26.158; 8.BF.26.196; 8.BF.26.223; 8.BF.26.240; 8.BF.26.244; 8.BF.26.243;8.BF.26.247; 8.BF.27.157; 8.BF.27.158; 8.BF.27.196; 8.BF.27.223; 8.BF.27.240;8.BF.27.244; 8.BF.27.243; 8.BF.27.247; 8.BF.29.157; 8.BF.29.158; 8.BF.29.196;8.BF.29.223; 8.BF.29.240; 8.BF.29.244; 8.BF.29.243; 8.BF.29.247; 8.BF.54.157;8.BF.54.158; 8.BF.54.196; 8.BF.54.223; 8.BF.54.240; 8.BF.54.244; 8.BF.54.243;8.BF.54.247; 8.BF.55.157; 8.BF.55.158; 8.BF.55.196; 8.BF.55.223; 8.BF.55.240;8.BF.55.244; 8.BF.55.243; 8.BF.55.247; 8.BF.56.157; 8.BF.56.158; 8.BF.56.196;8.BF.56.223; 8.BF.56.240; 8.BF.56.244; 8.BF.56.243; 8.BF.56.247; 8.BF.157.157;8.BF.157.158; 8.BF.157.196; 8.BF.157.223; 8.BF.157.240; 8.BF.157.244;8.BF.157.243; 8.BF.157.247; 8.BF.196.157; 8.BF.196.158; 8.BF.196.196;8.BF.196.223; 8.BF.196.240; 8.BF.196.244; 8.BF.196.243; 8.BF.196.247; 8.BF.223.157;8.BF.223.158; 8.BF.223.196; 8.BF.223.223; 8.BF.223.240; 8.BF.223.244;8.BF.223.243; 8.BF.223.247; 8.BF.240.157; 8.BF.240.158; 8.BF.240.196;8.BF.240.223; 8.BF.240.240; 8.BF.240.244; 8.BF.240.243; 8.BF.240.247;8.BF.244.157; 8.BF.244.158; 8.BF.244.196; 8.BF.244.223; 8.BF.244.240;8.BF.244.244; 8.BF.244.243; 8.BF.244.247; 8.BF.247.157; 8.BF.247.158;8.BF.247.196; 8.BF.247.223; 8.BF.247.240; 8.BF.247.244; 8.BF.247.243;8.BF.247.247;

8.CIのプロドラッグ
8.CI.4.157; 8.CI.4.158; 8.CI.4.196; 8.CI.4.223; 8.CI.4.240; 8.CI.4.244;8.CI.4.243; 8.CI.4.247; 8.CI.5.157; 8.CI.5.158; 8.CI.5.196; 8.CI.5.223;8.CI.5.240; 8.CI.5.244; 8.CI.5.243; 8.CI.5.247; 8.CI.7.157; 8.CI.7.158;8.CI.7.196; 8.CI.7.223; 8.CI.7.240; 8.CI.7.244; 8.CI.7.243; 8.CI.7.247;8.CI.15.157; 8.CI.15.158; 8.CI.15.196; 8.CI.15.223; 8.CI.15.240; 8.CI.15.244;8.CI.15.243; 8.CI.15.247; 8.CI.16.157; 8.CI.16.158; 8.CI.16.196; 8.CI.16.223;8.CI.16.240; 8.CI.16.244; 8.CI.16.243; 8.CI.16.247; 8.CI.18.157; 8.CI.18.158;8.CI.18.196; 8.CI.18.223; 8.CI.18.240; 8.CI.18.244; 8.CI.18.243; 8.CI.18.247;8.CI.26.157; 8.CI.26.158; 8.CI.26.196; 8.CI.26.223; 8.CI.26.240; 8.CI.26.244;8.CI.26.243; 8.CI.26.247; 8.CI.27.157; 8.CI.27.158; 8.CI.27.196; 8.CI.27.223;8.CI.27.240; 8.CI.27.244; 8.CI.27.243; 8.CI.27.247; 8.CI.29.157; 8.CI.29.158;8.CI.29.196; 8.CI.29.223; 8.CI.29.240; 8.CI.29.244; 8.CI.29.243; 8.CI.29.247;8.CI.54.157; 8.CI.54.158; 8.CI.54.196; 8.CI.54.223; 8.CI.54.240; 8.CI.54.244;8.CI.54.243; 8.CI.54.247; 8.CI.55.157; 8.CI.55.158; 8.CI.55.196; 8.CI.55.223; 8.CI.55.240;8.CI.55.244; 8.CI.55.243; 8.CI.55.247; 8.CI.56.157; 8.CI.56.158; 8.CI.56.196;8.CI.56.223; 8.CI.56.240; 8.CI.56.244; 8.CI.56.243; 8.CI.56.247; 8.CI.157.157;8.CI.157.158; 8.CI.157.196; 8.CI.157.223; 8.CI.157.240; 8.CI.157.244;8.CI.157.243; 8.CI.157.247; 8.CI.196.157; 8.CI.196.158; 8.CI.196.196;8.CI.196.223; 8.CI.196.240; 8.CI.196.244; 8.CI.196.243; 8.CI.196.247;8.CI.223.157; 8.CI.223.158; 8.CI.223.196; 8.CI.223.223; 8.CI.223.240;8.CI.223.244; 8.CI.223.243; 8.CI.223.247; 8.CI.240.157; 8.CI.240.158;8.CI.240.196; 8.CI.240.223; 8.CI.240.240; 8.CI.240.244; 8.CI.240.243;8.CI.240.247; 8.CI.244.157; 8.CI.244.158; 8.CI.244.196; 8.CI.244.223;8.CI.244.240; 8.CI.244.244; 8.CI.244.243; 8.CI.244.247; 8.CI.247.157;8.CI.247.158; 8.CI.247.196; 8.CI.247.223; 8.CI.247.240; 8.CI.247.244;8.CI.247.243; 8.CI.247.247;

8.COのプロドラッグ
8.CO.4.157; 8.CO.4.158; 8.CO.4.196; 8.CO.4.223; 8.CO.4.240; 8.CO.4.244;8.CO.4.243; 8.CO.4.247; 8.CO.5.157; 8.CO.5.158; 8.CO.5.196; 8.CO.5.223;8.CO.5.240; 8.CO.5.244; 8.CO.5.243; 8.CO.5.247; 8.CO.7.157; 8.CO.7.158;8.CO.7.196; 8.CO.7.223; 8.CO.7.240; 8.CO.7.244; 8.CO.7.243; 8.CO.7.247;8.CO.15.157; 8.CO.15.158; 8.CO.15.196; 8.CO.15.223; 8.CO.15.240; 8.CO.15.244;8.CO.15.243; 8.CO.15.247; 8.CO.16.157; 8.CO.16.158; 8.CO.16.196; 8.CO.16.223;8.CO.16.240; 8.CO.16.244; 8.CO.16.243; 8.CO.16.247; 8.CO.18.157; 8.CO.18.158;8.CO.18.196; 8.CO.18.223; 8.CO.18.240; 8.CO.18.244; 8.CO.18.243; 8.CO.18.247;8.CO.26.157; 8.CO.26.158; 8.CO.26.196; 8.CO.26.223; 8.CO.26.240; 8.CO.26.244;8.CO.26.243; 8.CO.26.247; 8.CO.27.157; 8.CO.27.158; 8.CO.27.196; 8.CO.27.223;8.CO.27.240; 8.CO.27.244; 8.CO.27.243; 8.CO.27.247; 8.CO.29.157; 8.CO.29.158;8.CO.29.196; 8.CO.29.223; 8.CO.29.240; 8.CO.29.244; 8.CO.29.243; 8.CO.29.247;8.CO.54.157; 8.CO.54.158; 8.CO.54.196; 8.CO.54.223; 8.CO.54.240; 8.CO.54.244;8.CO.54.243; 8.CO.54.247; 8.CO.55.157; 8.CO.55.158; 8.CO.55.196; 8.CO.55.223;8.CO.55.240; 8.CO.55.244; 8.CO.55.243; 8.CO.55.247; 8.CO.56.157; 8.CO.56.158;8.CO.56.196; 8.CO.56.223; 8.CO.56.240; 8.CO.56.244; 8.CO.56.243; 8.CO.56.247;8.CO.157.157; 8.CO.157.158; 8.CO.157.196; 8.CO.157.223; 8.CO.157.240;8.CO.157.244; 8.CO.157.243; 8.CO.157.247; 8.CO.196.157; 8.CO.196.158;8.CO.196.196; 8.CO.196.223; 8.CO.196.240; 8.CO.196.244; 8.CO.196.243;8.CO.196.247; 8.CO.223.157; 8.CO.223.158; 8.CO.223.196; 8.CO.223.223;8.CO.223.240; 8.CO.223.244; 8.CO.223.243; 8.CO.223.247; 8.CO.240.157;8.CO.240.158; 8.CO.240.196; 8.CO.240.223; 8.CO.240.240; 8.CO.240.244;8.CO.240.243; 8.CO.240.247; 8.CO.244.157; 8.CO.244.158; 8.CO.244.196;8.CO.244.223; 8.CO.244.240; 8.CO.244.244; 8.CO.244.243; 8.CO.244.247;8.CO.247.157; 8.CO.247.158; 8.CO.247.196; 8.CO.247.223; 8.CO.247.240;8.CO.247.244; 8.CO.247.243; 8.CO.247.247;

9.AHのプロドラッグ
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のプロドラッグ
9.AJ.4.157; 9.AJ.4.158; 9.AJ.4.196; 9.AJ.4.223; 9.AJ.4.240; 9.AJ.4.244;9.AJ.4.243; 9.AJ.4.247; 9.AJ.5.157; 9.AJ.5.158; 9.AJ.5.196; 9.AJ.5.223;9.AJ.5.240; 9.AJ.5.244; 9.AJ.5.243; 9.AJ.5.247; 9.AJ.7.157; 9.AJ.7.158;9.AJ.7.196; 9.AJ.7.223; 9.AJ.7.240; 9.AJ.7.244; 9.AJ.7.243; 9.AJ.7.247;9.AJ.15.157; 9.AJ.15.158; 9.AJ.15.196; 9.AJ.15.223; 9.AJ.15.240; 9.AJ.15.244;9.AJ.15.243; 9.AJ.15.247; 9.AJ.16.157; 9.AJ.16.158; 9.AJ.16.196; 9.AJ.16.223;9.AJ.16.240; 9.AJ.16.244; 9.AJ.16.243; 9.AJ.16.247; 9.AJ.18.157; 9.AJ.18.158;9.AJ.18.196; 9.AJ.18.223; 9.AJ.18.240; 9.AJ.18.244; 9.AJ.18.243; 9.AJ.18.247;9.AJ.26.157; 9.AJ.26.158; 9.AJ.26.196; 9.AJ.26.223; 9.AJ.26.240; 9.AJ.26.244;9.AJ.26.243; 9.AJ.26.247; 9.AJ.27.157; 9.AJ.27.158; 9.AJ.27.196; 9.AJ.27.223;9.AJ.27.240; 9.AJ.27.244; 9.AJ.27.243; 9.AJ.27.247; 9.AJ.29.157; 9.AJ.29.158;9.AJ.29.196; 9.AJ.29.223; 9.AJ.29.240; 9.AJ.29.244; 9.AJ.29.243; 9.AJ.29.247;9.AJ.54.157; 9.AJ.54.158; 9.AJ.54.196; 9.AJ.54.223; 9.AJ.54.240; 9.AJ.54.244;9.AJ.54.243; 9.AJ.54.247; 9.AJ.55.157; 9.AJ.55.158; 9.AJ.55.196; 9.AJ.55.223;9.AJ.55.240; 9.AJ.55.244; 9.AJ.55.243; 9.AJ.55.247; 9.AJ.56.157; 9.AJ.56.158;9.AJ.56.196; 9.AJ.56.223; 9.AJ.56.240; 9.AJ.56.244; 9.AJ.56.243; 9.AJ.56.247;9.AJ.157.157; 9.AJ.157.158; 9.AJ.157.196; 9.AJ.157.223; 9.AJ.157.240;9.AJ.157.244; 9.AJ.157.243; 9.AJ.157.247; 9.AJ.196.157; 9.AJ.196.158;9.AJ.196.196; 9.AJ.196.223; 9.AJ.196.240; 9.AJ.196.244; 9.AJ.196.243;9.AJ.196.247; 9.AJ.223.157; 9.AJ.223.158; 9.AJ.223.196; 9.AJ.223.223;9.AJ.223.240; 9.AJ.223.244; 9.AJ.223.243; 9.AJ.223.247; 9.AJ.240.157;9.AJ.240.158; 9.AJ.240.196; 9.AJ.240.223; 9.AJ.240.240; 9.AJ.240.244;9.AJ.240.243; 9.AJ.240.247; 9.AJ.244.157; 9.AJ.244.158; 9.AJ.244.196; 9.AJ.244.223;9.AJ.244.240; 9.AJ.244.244; 9.AJ.244.243; 9.AJ.244.247; 9.AJ.247.157;9.AJ.247.158; 9.AJ.247.196; 9.AJ.247.223; 9.AJ.247.240; 9.AJ.247.244;9.AJ.247.243; 9.AJ.247.247;

9.ANのプロドラッグ
9.AN.4.157; 9.AN.4.158; 9.AN.4.196; 9.AN.4.223; 9.AN.4.240; 9.AN.4.244;9.AN.4.243; 9.AN.4.247; 9.AN.5.157; 9.AN.5.158; 9.AN.5.196; 9.AN.5.223;9.AN.5.240; 9.AN.5.244; 9.AN.5.243; 9.AN.5.247; 9.AN.7.157; 9.AN.7.158;9.AN.7.196; 9.AN.7.223; 9.AN.7.240; 9.AN.7.244; 9.AN.7.243; 9.AN.7.247;9.AN.15.157; 9.AN.15.158; 9.AN.15.196; 9.AN.15.223; 9.AN.15.240; 9.AN.15.244;9.AN.15.243; 9.AN.15.247; 9.AN.16.157; 9.AN.16.158; 9.AN.16.196; 9.AN.16.223;9.AN.16.240; 9.AN.16.244; 9.AN.16.243; 9.AN.16.247; 9.AN.18.157; 9.AN.18.158;9.AN.18.196; 9.AN.18.223; 9.AN.18.240; 9.AN.18.244; 9.AN.18.243; 9.AN.18.247;9.AN.26.157; 9.AN.26.158; 9.AN.26.196; 9.AN.26.223; 9.AN.26.240; 9.AN.26.244;9.AN.26.243; 9.AN.26.247; 9.AN.27.157; 9.AN.27.158; 9.AN.27.196; 9.AN.27.223;9.AN.27.240; 9.AN.27.244; 9.AN.27.243; 9.AN.27.247; 9.AN.29.157; 9.AN.29.158;9.AN.29.196; 9.AN.29.223; 9.AN.29.240; 9.AN.29.244; 9.AN.29.243; 9.AN.29.247;9.AN.54.157; 9.AN.54.158; 9.AN.54.196; 9.AN.54.223; 9.AN.54.240; 9.AN.54.244;9.AN.54.243; 9.AN.54.247; 9.AN.55.157; 9.AN.55.158; 9.AN.55.196; 9.AN.55.223;9.AN.55.240; 9.AN.55.244; 9.AN.55.243; 9.AN.55.247; 9.AN.56.157; 9.AN.56.158;9.AN.56.196; 9.AN.56.223; 9.AN.56.240; 9.AN.56.244; 9.AN.56.243; 9.AN.56.247;9.AN.157.157; 9.AN.157.158; 9.AN.157.196; 9.AN.157.223; 9.AN.157.240;9.AN.157.244; 9.AN.157.243; 9.AN.157.247; 9.AN.196.157; 9.AN.196.158;9.AN.196.196; 9.AN.196.223; 9.AN.196.240; 9.AN.196.244; 9.AN.196.243;9.AN.196.247; 9.AN.223.157; 9.AN.223.158; 9.AN.223.196; 9.AN.223.223;9.AN.223.240; 9.AN.223.244; 9.AN.223.243; 9.AN.223.247; 9.AN.240.157;9.AN.240.158; 9.AN.240.196; 9.AN.240.223; 9.AN.240.240; 9.AN.240.244;9.AN.240.243; 9.AN.240.247; 9.AN.244.157; 9.AN.244.158; 9.AN.244.196;9.AN.244.223; 9.AN.244.240; 9.AN.244.244; 9.AN.244.243; 9.AN.244.247;9.AN.247.157; 9.AN.247.158; 9.AN.247.196; 9.AN.247.223; 9.AN.247.240;9.AN.247.244; 9.AN.247.243; 9.AN.247.247;

9.APのプロドラッグ
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のプロドラッグ
9.AZ.4.157; 9.AZ.4.158; 9.AZ.4.196; 9.AZ.4.223; 9.AZ.4.240; 9.AZ.4.244;9.AZ.4.243; 9.AZ.4.247; 9.AZ.5.157; 9.AZ.5.158; 9.AZ.5.196; 9.AZ.5.223;9.AZ.5.240; 9.AZ.5.244; 9.AZ.5.243; 9.AZ.5.247; 9.AZ.7.157; 9.AZ.7.158;9.AZ.7.196; 9.AZ.7.223; 9.AZ.7.240; 9.AZ.7.244; 9.AZ.7.243; 9.AZ.7.247; 9.AZ.15.157;9.AZ.15.158; 9.AZ.15.196; 9.AZ.15.223; 9.AZ.15.240; 9.AZ.15.244; 9.AZ.15.243;9.AZ.15.247; 9.AZ.16.157; 9.AZ.16.158; 9.AZ.16.196; 9.AZ.16.223; 9.AZ.16.240;9.AZ.16.244; 9.AZ.16.243; 9.AZ.16.247; 9.AZ.18.157; 9.AZ.18.158; 9.AZ.18.196;9.AZ.18.223; 9.AZ.18.240; 9.AZ.18.244; 9.AZ.18.243; 9.AZ.18.247; 9.AZ.26.157;9.AZ.26.158; 9.AZ.26.196; 9.AZ.26.223; 9.AZ.26.240; 9.AZ.26.244; 9.AZ.26.243;9.AZ.26.247; 9.AZ.27.157; 9.AZ.27.158; 9.AZ.27.196; 9.AZ.27.223; 9.AZ.27.240;9.AZ.27.244; 9.AZ.27.243; 9.AZ.27.247; 9.AZ.29.157; 9.AZ.29.158; 9.AZ.29.196;9.AZ.29.223; 9.AZ.29.240; 9.AZ.29.244; 9.AZ.29.243; 9.AZ.29.247; 9.AZ.54.157;9.AZ.54.158; 9.AZ.54.196; 9.AZ.54.223; 9.AZ.54.240; 9.AZ.54.244; 9.AZ.54.243;9.AZ.54.247; 9.AZ.55.157; 9.AZ.55.158; 9.AZ.55.196; 9.AZ.55.223; 9.AZ.55.240;9.AZ.55.244; 9.AZ.55.243; 9.AZ.55.247; 9.AZ.56.157; 9.AZ.56.158; 9.AZ.56.196;9.AZ.56.223; 9.AZ.56.240; 9.AZ.56.244; 9.AZ.56.243; 9.AZ.56.247; 9.AZ.157.157;9.AZ.157.158; 9.AZ.157.196; 9.AZ.157.223; 9.AZ.157.240; 9.AZ.157.244; 9.AZ.157.243;9.AZ.157.247; 9.AZ.196.157; 9.AZ.196.158; 9.AZ.196.196; 9.AZ.196.223;9.AZ.196.240; 9.AZ.196.244; 9.AZ.196.243; 9.AZ.196.247; 9.AZ.223.157;9.AZ.223.158; 9.AZ.223.196; 9.AZ.223.223; 9.AZ.223.240; 9.AZ.223.244;9.AZ.223.243; 9.AZ.223.247; 9.AZ.240.157; 9.AZ.240.158; 9.AZ.240.196;9.AZ.240.223; 9.AZ.240.240; 9.AZ.240.244; 9.AZ.240.243; 9.AZ.240.247;9.AZ.244.157; 9.AZ.244.158; 9.AZ.244.196; 9.AZ.244.223; 9.AZ.244.240;9.AZ.244.244; 9.AZ.244.243; 9.AZ.244.247; 9.AZ.247.157; 9.AZ.247.158;9.AZ.247.196; 9.AZ.247.223; 9.AZ.247.240; 9.AZ.247.244; 9.AZ.247.243;9.AZ.247.247;

9.BFのプロドラッグ
9.BF.4.157; 9.BF.4.158; 9.BF.4.196; 9.BF.4.223; 9.BF.4.240; 9.BF.4.244;9.BF.4.243; 9.BF.4.247; 9.BF.5.157; 9.BF.5.158; 9.BF.5.196; 9.BF.5.223;9.BF.5.240; 9.BF.5.244; 9.BF.5.243; 9.BF.5.247; 9.BF.7.157; 9.BF.7.158;9.BF.7.196; 9.BF.7.223; 9.BF.7.240; 9.BF.7.244; 9.BF.7.243; 9.BF.7.247;9.BF.15.157; 9.BF.15.158; 9.BF.15.196; 9.BF.15.223; 9.BF.15.240; 9.BF.15.244;9.BF.15.243; 9.BF.15.247; 9.BF.16.157; 9.BF.16.158; 9.BF.16.196; 9.BF.16.223;9.BF.16.240; 9.BF.16.244; 9.BF.16.243; 9.BF.16.247; 9.BF.18.157; 9.BF.18.158;9.BF.18.196; 9.BF.18.223; 9.BF.18.240; 9.BF.18.244; 9.BF.18.243; 9.BF.18.247;9.BF.26.157; 9.BF.26.158; 9.BF.26.196; 9.BF.26.223; 9.BF.26.240; 9.BF.26.244; 9.BF.26.243;9.BF.26.247; 9.BF.27.157; 9.BF.27.158; 9.BF.27.196; 9.BF.27.223; 9.BF.27.240;9.BF.27.244; 9.BF.27.243; 9.BF.27.247; 9.BF.29.157; 9.BF.29.158; 9.BF.29.196;9.BF.29.223; 9.BF.29.240; 9.BF.29.244; 9.BF.29.243; 9.BF.29.247; 9.BF.54.157;9.BF.54.158; 9.BF.54.196; 9.BF.54.223; 9.BF.54.240; 9.BF.54.244; 9.BF.54.243;9.BF.54.247; 9.BF.55.157; 9.BF.55.158; 9.BF.55.196; 9.BF.55.223; 9.BF.55.240;9.BF.55.244; 9.BF.55.243; 9.BF.55.247; 9.BF.56.157; 9.BF.56.158; 9.BF.56.196;9.BF.56.223; 9.BF.56.240; 9.BF.56.244; 9.BF.56.243; 9.BF.56.247; 9.BF.157.157;9.BF.157.158; 9.BF.157.196; 9.BF.157.223; 9.BF.157.240; 9.BF.157.244;9.BF.157.243; 9.BF.157.247; 9.BF.196.157; 9.BF.196.158; 9.BF.196.196;9.BF.196.223; 9.BF.196.240; 9.BF.196.244; 9.BF.196.243; 9.BF.196.247; 9.BF.223.157;9.BF.223.158; 9.BF.223.196; 9.BF.223.223; 9.BF.223.240; 9.BF.223.244;9.BF.223.243; 9.BF.223.247; 9.BF.240.157; 9.BF.240.158; 9.BF.240.196;9.BF.240.223; 9.BF.240.240; 9.BF.240.244; 9.BF.240.243; 9.BF.240.247;9.BF.244.157; 9.BF.244.158; 9.BF.244.196; 9.BF.244.223; 9.BF.244.240;9.BF.244.244; 9.BF.244.243; 9.BF.244.247; 9.BF.247.157; 9.BF.247.158;9.BF.247.196; 9.BF.247.223; 9.BF.247.240; 9.BF.247.244; 9.BF.247.243;9.BF.247.247;

9.CIのプロドラッグ
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のプロドラッグ
9.CO.4.157; 9.CO.4.158; 9.CO.4.196; 9.CO.4.223; 9.CO.4.240; 9.CO.4.244;9.CO.4.243; 9.CO.4.247; 9.CO.5.157; 9.CO.5.158; 9.CO.5.196; 9.CO.5.223;9.CO.5.240; 9.CO.5.244; 9.CO.5.243; 9.CO.5.247; 9.CO.7.157; 9.CO.7.158;9.CO.7.196; 9.CO.7.223; 9.CO.7.240; 9.CO.7.244; 9.CO.7.243; 9.CO.7.247;9.CO.15.157; 9.CO.15.158; 9.CO.15.196; 9.CO.15.223; 9.CO.15.240; 9.CO.15.244;9.CO.15.243; 9.CO.15.247; 9.CO.16.157; 9.CO.16.158; 9.CO.16.196; 9.CO.16.223;9.CO.16.240; 9.CO.16.244; 9.CO.16.243; 9.CO.16.247; 9.CO.18.157; 9.CO.18.158;9.CO.18.196; 9.CO.18.223; 9.CO.18.240; 9.CO.18.244; 9.CO.18.243; 9.CO.18.247;9.CO.26.157; 9.CO.26.158; 9.CO.26.196; 9.CO.26.223; 9.CO.26.240; 9.CO.26.244; 9.CO.26.243;9.CO.26.247; 9.CO.27.157; 9.CO.27.158; 9.CO.27.196; 9.CO.27.223; 9.CO.27.240;9.CO.27.244; 9.CO.27.243; 9.CO.27.247; 9.CO.29.157; 9.CO.29.158; 9.CO.29.196;9.CO.29.223; 9.CO.29.240; 9.CO.29.244; 9.CO.29.243; 9.CO.29.247; 9.CO.54.157;9.CO.54.158; 9.CO.54.196; 9.CO.54.223; 9.CO.54.240; 9.CO.54.244; 9.CO.54.243;9.CO.54.247; 9.CO.55.157; 9.CO.55.158; 9.CO.55.196; 9.CO.55.223; 9.CO.55.240;9.CO.55.244; 9.CO.55.243; 9.CO.55.247; 9.CO.56.157; 9.CO.56.158; 9.CO.56.196;9.CO.56.223; 9.CO.56.240; 9.CO.56.244; 9.CO.56.243; 9.CO.56.247; 9.CO.157.157;9.CO.157.158; 9.CO.157.196; 9.CO.157.223; 9.CO.157.240; 9.CO.157.244;9.CO.157.243; 9.CO.157.247; 9.CO.196.157; 9.CO.196.158; 9.CO.196.196;9.CO.196.223; 9.CO.196.240; 9.CO.196.244; 9.CO.196.243; 9.CO.196.247; 9.CO.223.157;9.CO.223.158; 9.CO.223.196; 9.CO.223.223; 9.CO.223.240; 9.CO.223.244;9.CO.223.243; 9.CO.223.247; 9.CO.240.157; 9.CO.240.158; 9.CO.240.196;9.CO.240.223; 9.CO.240.240; 9.CO.240.244; 9.CO.240.243; 9.CO.240.247;9.CO.244.157; 9.CO.244.158; 9.CO.244.196; 9.CO.244.223; 9.CO.244.240;9.CO.244.244; 9.CO.244.243; 9.CO.244.247; 9.CO.247.157; 9.CO.247.158;9.CO.247.196; 9.CO.247.223; 9.CO.247.240; 9.CO.247.244; 9.CO.247.243;9.CO.247.247;

10.AHのプロドラッグ
10.AH.4.157; 10.AH.4.158; 10.AH.4.196; 10.AH.4.223; 10.AH.4.240; 10.AH.4.244;10.AH.4.243; 10.AH.4.247; 10.AH.5.157; 10.AH.5.158; 10.AH.5.196; 10.AH.5.223;10.AH.5.240; 10.AH.5.244; 10.AH.5.243; 10.AH.5.247; 10.AH.7.157; 10.AH.7.158;10.AH.7.196; 10.AH.7.223; 10.AH.7.240; 10.AH.7.244; 10.AH.7.243; 10.AH.7.247;10.AH.15.157; 10.AH.15.158; 10.AH.15.196; 10.AH.15.223; 10.AH.15.240;10.AH.15.244; 10.AH.15.243; 10.AH.15.247; 10.AH.16.157; 10.AH.16.158;10.AH.16.196; 10.AH.16.223; 10.AH.16.240; 10.AH.16.244; 10.AH.16.243;10.AH.16.247; 10.AH.18.157; 10.AH.18.158; 10.AH.18.196; 10.AH.18.223;10.AH.18.240; 10.AH.18.244; 10.AH.18.243; 10.AH.18.247; 10.AH.26.157;10.AH.26.158; 10.AH.26.196; 10.AH.26.223; 10.AH.26.240; 10.AH.26.244;10.AH.26.243; 10.AH.26.247; 10.AH.27.157; 10.AH.27.158; 10.AH.27.196; 10.AH.27.223;10.AH.27.240; 10.AH.27.244; 10.AH.27.243; 10.AH.27.247; 10.AH.29.157;10.AH.29.158; 10.AH.29.196; 10.AH.29.223; 10.AH.29.240; 10.AH.29.244;10.AH.29.243; 10.AH.29.247; 10.AH.54.157; 10.AH.54.158; 10.AH.54.196;10.AH.54.223; 10.AH.54.240; 10.AH.54.244; 10.AH.54.243; 10.AH.54.247;10.AH.55.157; 10.AH.55.158; 10.AH.55.196; 10.AH.55.223; 10.AH.55.240;10.AH.55.244; 10.AH.55.243; 10.AH.55.247; 10.AH.56.157; 10.AH.56.158;10.AH.56.196; 10.AH.56.223; 10.AH.56.240; 10.AH.56.244; 10.AH.56.243;10.AH.56.247; 10.AH.157.157; 10.AH.157.158; 10.AH.157.196; 10.AH.157.223;10.AH.157.240; 10.AH.157.244; 10.AH.157.243; 10.AH.157.247; 10.AH.196.157;10.AH.196.158; 10.AH.196.196; 10.AH.196.223; 10.AH.196.240; 10.AH.196.244;10.AH.196.243; 10.AH.196.247; 10.AH.223.157; 10.AH.223.158; 10.AH.223.196;10.AH.223.223; 10.AH.223.240; 10.AH.223.244; 10.AH.223.243; 10.AH.223.247;10.AH.240.157; 10.AH.240.158; 10.AH.240.196; 10.AH.240.223; 10.AH.240.240;10.AH.240.244; 10.AH.240.243; 10.AH.240.247; 10.AH.244.157; 10.AH.244.158; 10.AH.244.196;10.AH.244.223; 10.AH.244.240; 10.AH.244.244; 10.AH.244.243; 10.AH.244.247;10.AH.247.157; 10.AH.247.158; 10.AH.247.196; 10.AH.247.223; 10.AH.247.240;10.AH.247.244; 10.AH.247.243; 10.AH.247.247;

10.AJのプロドラッグ
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のプロドラッグ
10.AN.4.157; 10.AN.4.158; 10.AN.4.196; 10.AN.4.223; 10.AN.4.240; 10.AN.4.244;10.AN.4.243; 10.AN.4.247; 10.AN.5.157; 10.AN.5.158; 10.AN.5.196; 10.AN.5.223;10.AN.5.240; 10.AN.5.244; 10.AN.5.243; 10.AN.5.247; 10.AN.7.157; 10.AN.7.158;10.AN.7.196; 10.AN.7.223; 10.AN.7.240; 10.AN.7.244; 10.AN.7.243; 10.AN.7.247;10.AN.15.157; 10.AN.15.158; 10.AN.15.196; 10.AN.15.223; 10.AN.15.240;10.AN.15.244; 10.AN.15.243; 10.AN.15.247; 10.AN.16.157; 10.AN.16.158;10.AN.16.196; 10.AN.16.223; 10.AN.16.240; 10.AN.16.244; 10.AN.16.243; 10.AN.16.247;10.AN.18.157; 10.AN.18.158; 10.AN.18.196; 10.AN.18.223; 10.AN.18.240;10.AN.18.244; 10.AN.18.243; 10.AN.18.247; 10.AN.26.157; 10.AN.26.158;10.AN.26.196; 10.AN.26.223; 10.AN.26.240; 10.AN.26.244; 10.AN.26.243;10.AN.26.247; 10.AN.27.157; 10.AN.27.158; 10.AN.27.196; 10.AN.27.223;10.AN.27.240; 10.AN.27.244; 10.AN.27.243; 10.AN.27.247; 10.AN.29.157;10.AN.29.158; 10.AN.29.196; 10.AN.29.223; 10.AN.29.240; 10.AN.29.244;10.AN.29.243; 10.AN.29.247; 10.AN.54.157; 10.AN.54.158; 10.AN.54.196;10.AN.54.223; 10.AN.54.240; 10.AN.54.244; 10.AN.54.243; 10.AN.54.247;10.AN.55.157; 10.AN.55.158; 10.AN.55.196; 10.AN.55.223; 10.AN.55.240;10.AN.55.244; 10.AN.55.243; 10.AN.55.247; 10.AN.56.157; 10.AN.56.158;10.AN.56.196; 10.AN.56.223; 10.AN.56.240; 10.AN.56.244; 10.AN.56.243;10.AN.56.247; 10.AN.157.157; 10.AN.157.158; 10.AN.157.196; 10.AN.157.223;10.AN.157.240; 10.AN.157.244; 10.AN.157.243; 10.AN.157.247; 10.AN.196.157;10.AN.196.158; 10.AN.196.196; 10.AN.196.223; 10.AN.196.240; 10.AN.196.244;10.AN.196.243; 10.AN.196.247; 10.AN.223.157; 10.AN.223.158; 10.AN.223.196;10.AN.223.223; 10.AN.223.240; 10.AN.223.244; 10.AN.223.243; 10.AN.223.247;10.AN.240.157; 10.AN.240.158; 10.AN.240.196; 10.AN.240.223; 10.AN.240.240;10.AN.240.244; 10.AN.240.243; 10.AN.240.247; 10.AN.244.157; 10.AN.244.158;10.AN.244.196; 10.AN.244.223; 10.AN.244.240; 10.AN.244.244; 10.AN.244.243;10.AN.244.247; 10.AN.247.157; 10.AN.247.158; 10.AN.247.196; 10.AN.247.223;10.AN.247.240; 10.AN.247.244; 10.AN.247.243; 10.AN.247.247;

10.APのプロドラッグ
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のプロドラッグ
10.AZ.4.157; 10.AZ.4.158; 10.AZ.4.196; 10.AZ.4.223; 10.AZ.4.240; 10.AZ.4.244;10.AZ.4.243; 10.AZ.4.247; 10.AZ.5.157; 10.AZ.5.158; 10.AZ.5.196; 10.AZ.5.223;10.AZ.5.240; 10.AZ.5.244; 10.AZ.5.243; 10.AZ.5.247; 10.AZ.7.157; 10.AZ.7.158;10.AZ.7.196; 10.AZ.7.223; 10.AZ.7.240; 10.AZ.7.244; 10.AZ.7.243; 10.AZ.7.247;10.AZ.15.157; 10.AZ.15.158; 10.AZ.15.196; 10.AZ.15.223; 10.AZ.15.240;10.AZ.15.244; 10.AZ.15.243; 10.AZ.15.247; 10.AZ.16.157; 10.AZ.16.158;10.AZ.16.196; 10.AZ.16.223; 10.AZ.16.240; 10.AZ.16.244; 10.AZ.16.243;10.AZ.16.247; 10.AZ.18.157; 10.AZ.18.158; 10.AZ.18.196; 10.AZ.18.223;10.AZ.18.240; 10.AZ.18.244; 10.AZ.18.243; 10.AZ.18.247; 10.AZ.26.157;10.AZ.26.158; 10.AZ.26.196; 10.AZ.26.223; 10.AZ.26.240; 10.AZ.26.244;10.AZ.26.243; 10.AZ.26.247; 10.AZ.27.157; 10.AZ.27.158; 10.AZ.27.196;10.AZ.27.223; 10.AZ.27.240; 10.AZ.27.244; 10.AZ.27.243; 10.AZ.27.247;10.AZ.29.157; 10.AZ.29.158; 10.AZ.29.196; 10.AZ.29.223; 10.AZ.29.240;10.AZ.29.244; 10.AZ.29.243; 10.AZ.29.247; 10.AZ.54.157; 10.AZ.54.158; 10.AZ.54.196;10.AZ.54.223; 10.AZ.54.240; 10.AZ.54.244; 10.AZ.54.243; 10.AZ.54.247;10.AZ.55.157; 10.AZ.55.158; 10.AZ.55.196; 10.AZ.55.223; 10.AZ.55.240;10.AZ.55.244; 10.AZ.55.243; 10.AZ.55.247; 10.AZ.56.157; 10.AZ.56.158;10.AZ.56.196; 10.AZ.56.223; 10.AZ.56.240; 10.AZ.56.244; 10.AZ.56.243;10.AZ.56.247; 10.AZ.157.157; 10.AZ.157.158; 10.AZ.157.196; 10.AZ.157.223;10.AZ.157.240; 10.AZ.157.244; 10.AZ.157.243; 10.AZ.157.247; 10.AZ.196.157;10.AZ.196.158; 10.AZ.196.196; 10.AZ.196.223; 10.AZ.196.240; 10.AZ.196.244;10.AZ.196.243; 10.AZ.196.247; 10.AZ.223.157; 10.AZ.223.158; 10.AZ.223.196;10.AZ.223.223; 10.AZ.223.240; 10.AZ.223.244; 10.AZ.223.243; 10.AZ.223.247;10.AZ.240.157; 10.AZ.240.158; 10.AZ.240.196; 10.AZ.240.223; 10.AZ.240.240;10.AZ.240.244; 10.AZ.240.243; 10.AZ.240.247; 10.AZ.244.157; 10.AZ.244.158;10.AZ.244.196; 10.AZ.244.223; 10.AZ.244.240; 10.AZ.244.244; 10.AZ.244.243;10.AZ.244.247; 10.AZ.247.157; 10.AZ.247.158; 10.AZ.247.196; 10.AZ.247.223;10.AZ.247.240; 10.AZ.247.244; 10.AZ.247.243; 10.AZ.247.247;

10.BFのプロドラッグ
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のプロドラッグ
10.CI.4.157; 10.CI.4.158; 10.CI.4.196; 10.CI.4.223; 10.CI.4.240; 10.CI.4.244;10.CI.4.243; 10.CI.4.247; 10.CI.5.157; 10.CI.5.158; 10.CI.5.196; 10.CI.5.223;10.CI.5.240; 10.CI.5.244; 10.CI.5.243; 10.CI.5.247; 10.CI.7.157; 10.CI.7.158;10.CI.7.196; 10.CI.7.223; 10.CI.7.240; 10.CI.7.244; 10.CI.7.243; 10.CI.7.247;10.CI.15.157; 10.CI.15.158; 10.CI.15.196; 10.CI.15.223; 10.CI.15.240;10.CI.15.244; 10.CI.15.243; 10.CI.15.247; 10.CI.16.157; 10.CI.16.158;10.CI.16.196; 10.CI.16.223; 10.CI.16.240; 10.CI.16.244; 10.CI.16.243;10.CI.16.247; 10.CI.18.157; 10.CI.18.158; 10.CI.18.196; 10.CI.18.223;10.CI.18.240; 10.CI.18.244; 10.CI.18.243; 10.CI.18.247; 10.CI.26.157;10.CI.26.158; 10.CI.26.196; 10.CI.26.223; 10.CI.26.240; 10.CI.26.244; 10.CI.26.243;10.CI.26.247; 10.CI.27.157; 10.CI.27.158; 10.CI.27.196; 10.CI.27.223;10.CI.27.240; 10.CI.27.244; 10.CI.27.243; 10.CI.27.247; 10.CI.29.157;10.CI.29.158; 10.CI.29.196; 10.CI.29.223; 10.CI.29.240; 10.CI.29.244;10.CI.29.243; 10.CI.29.247; 10.CI.54.157; 10.CI.54.158; 10.CI.54.196;10.CI.54.223; 10.CI.54.240; 10.CI.54.244; 10.CI.54.243; 10.CI.54.247;10.CI.55.157; 10.CI.55.158; 10.CI.55.196; 10.CI.55.223; 10.CI.55.240;10.CI.55.244; 10.CI.55.243; 10.CI.55.247; 10.CI.56.157; 10.CI.56.158; 10.CI.56.196;10.CI.56.223; 10.CI.56.240; 10.CI.56.244; 10.CI.56.243; 10.CI.56.247;10.CI.157.157; 10.CI.157.158; 10.CI.157.196; 10.CI.157.223; 10.CI.157.240;10.CI.157.244; 10.CI.157.243; 10.CI.157.247; 10.CI.196.157; 10.CI.196.158;10.CI.196.196; 10.CI.196.223; 10.CI.196.240; 10.CI.196.244; 10.CI.196.243;10.CI.196.247; 10.CI.223.157; 10.CI.223.158; 10.CI.223.196; 10.CI.223.223;10.CI.223.240; 10.CI.223.244; 10.CI.223.243; 10.CI.223.247; 10.CI.240.157;10.CI.240.158; 10.CI.240.196; 10.CI.240.223; 10.CI.240.240; 10.CI.240.244;10.CI.240.243; 10.CI.240.247; 10.CI.244.157; 10.CI.244.158; 10.CI.244.196;10.CI.244.223; 10.CI.244.240; 10.CI.244.244; 10.CI.244.243; 10.CI.244.247;10.CI.247.157; 10.CI.247.158; 10.CI.247.196; 10.CI.247.223; 10.CI.247.240;10.CI.247.244; 10.CI.247.243; 10.CI.247.247;

10.COのプロドラッグ
10.CO.4.157; 10.CO.4.158; 10.CO.4.196; 10.CO.4.223; 10.CO.4.240; 10.CO.4.244;10.CO.4.243; 10.CO.4.247; 10.CO.5.157; 10.CO.5.158; 10.CO.5.196; 10.CO.5.223;10.CO.5.240; 10.CO.5.244; 10.CO.5.243; 10.CO.5.247; 10.CO.7.157; 10.CO.7.158;10.CO.7.196; 10.CO.7.223; 10.CO.7.240; 10.CO.7.244; 10.CO.7.243; 10.CO.7.247;10.CO.15.157; 10.CO.15.158; 10.CO.15.196; 10.CO.15.223; 10.CO.15.240;10.CO.15.244; 10.CO.15.243; 10.CO.15.247; 10.CO.16.157; 10.CO.16.158;10.CO.16.196; 10.CO.16.223; 10.CO.16.240; 10.CO.16.244; 10.CO.16.243;10.CO.16.247; 10.CO.18.157; 10.CO.18.158; 10.CO.18.196; 10.CO.18.223;10.CO.18.240; 10.CO.18.244; 10.CO.18.243; 10.CO.18.247; 10.CO.26.157;10.CO.26.158; 10.CO.26.196; 10.CO.26.223; 10.CO.26.240; 10.CO.26.244;10.CO.26.243; 10.CO.26.247; 10.CO.27.157; 10.CO.27.158; 10.CO.27.196;10.CO.27.223; 10.CO.27.240; 10.CO.27.244; 10.CO.27.243; 10.CO.27.247;10.CO.29.157; 10.CO.29.158; 10.CO.29.196; 10.CO.29.223; 10.CO.29.240;10.CO.29.244; 10.CO.29.243; 10.CO.29.247; 10.CO.54.157; 10.CO.54.158;10.CO.54.196; 10.CO.54.223; 10.CO.54.240; 10.CO.54.244; 10.CO.54.243;10.CO.54.247; 10.CO.55.157; 10.CO.55.158; 10.CO.55.196; 10.CO.55.223;10.CO.55.240; 10.CO.55.244; 10.CO.55.243; 10.CO.55.247; 10.CO.56.157;10.CO.56.158; 10.CO.56.196; 10.CO.56.223; 10.CO.56.240; 10.CO.56.244;10.CO.56.243; 10.CO.56.247; 10.CO.157.157; 10.CO.157.158; 10.CO.157.196;10.CO.157.223; 10.CO.157.240; 10.CO.157.244; 10.CO.157.243; 10.CO.157.247;10.CO.196.157; 10.CO.196.158; 10.CO.196.196; 10.CO.196.223; 10.CO.196.240;10.CO.196.244; 10.CO.196.243; 10.CO.196.247; 10.CO.223.157; 10.CO.223.158;10.CO.223.196; 10.CO.223.223; 10.CO.223.240; 10.CO.223.244; 10.CO.223.243;10.CO.223.247; 10.CO.240.157; 10.CO.240.158; 10.CO.240.196; 10.CO.240.223;10.CO.240.240; 10.CO.240.244; 10.CO.240.243; 10.CO.240.247; 10.CO.244.157;10.CO.244.158; 10.CO.244.196; 10.CO.244.223; 10.CO.244.240; 10.CO.244.244;10.CO.244.243; 10.CO.244.247; 10.CO.247.157; 10.CO.247.158; 10.CO.247.196;10.CO.247.223; 10.CO.247.240; 10.CO.247.244; 10.CO.247.243; 10.CO.247.247;

11.AHのプロドラッグ
11.AH.4.157; 11.AH.4.158; 11.AH.4.196; 11.AH.4.223; 11.AH.4.240; 11.AH.4.244;11.AH.4.243; 11.AH.4.247; 11.AH.5.157; 11.AH.5.158; 11.AH.5.196; 11.AH.5.223;11.AH.5.240; 11.AH.5.244; 11.AH.5.243; 11.AH.5.247; 11.AH.7.157; 11.AH.7.158;11.AH.7.196; 11.AH.7.223; 11.AH.7.240; 11.AH.7.244; 11.AH.7.243; 11.AH.7.247;11.AH.15.157; 11.AH.15.158; 11.AH.15.196; 11.AH.15.223; 11.AH.15.240;11.AH.15.244; 11.AH.15.243; 11.AH.15.247; 11.AH.16.157; 11.AH.16.158;11.AH.16.196; 11.AH.16.223; 11.AH.16.240; 11.AH.16.244; 11.AH.16.243;11.AH.16.247; 11.AH.18.157; 11.AH.18.158; 11.AH.18.196; 11.AH.18.223;11.AH.18.240; 11.AH.18.244; 11.AH.18.243; 11.AH.18.247; 11.AH.26.157;11.AH.26.158; 11.AH.26.196; 11.AH.26.223; 11.AH.26.240; 11.AH.26.244;11.AH.26.243; 11.AH.26.247; 11.AH.27.157; 11.AH.27.158; 11.AH.27.196;11.AH.27.223; 11.AH.27.240; 11.AH.27.244; 11.AH.27.243; 11.AH.27.247;11.AH.29.157; 11.AH.29.158; 11.AH.29.196; 11.AH.29.223; 11.AH.29.240; 11.AH.29.244;11.AH.29.243; 11.AH.29.247; 11.AH.54.157; 11.AH.54.158; 11.AH.54.196;11.AH.54.223; 11.AH.54.240; 11.AH.54.244; 11.AH.54.243; 11.AH.54.247;11.AH.55.157; 11.AH.55.158; 11.AH.55.196; 11.AH.55.223; 11.AH.55.240;11.AH.55.244; 11.AH.55.243; 11.AH.55.247; 11.AH.56.157; 11.AH.56.158;11.AH.56.196; 11.AH.56.223; 11.AH.56.240; 11.AH.56.244; 11.AH.56.243;11.AH.56.247; 11.AH.157.157; 11.AH.157.158; 11.AH.157.196; 11.AH.157.223;11.AH.157.240; 11.AH.157.244; 11.AH.157.243; 11.AH.157.247; 11.AH.196.157;11.AH.196.158; 11.AH.196.196; 11.AH.196.223; 11.AH.196.240; 11.AH.196.244;11.AH.196.243; 11.AH.196.247; 11.AH.223.157; 11.AH.223.158; 11.AH.223.196;11.AH.223.223; 11.AH.223.240; 11.AH.223.244; 11.AH.223.243; 11.AH.223.247;11.AH.240.157; 11.AH.240.158; 11.AH.240.196; 11.AH.240.223; 11.AH.240.240;11.AH.240.244; 11.AH.240.243; 11.AH.240.247; 11.AH.244.157; 11.AH.244.158;11.AH.244.196; 11.AH.244.223; 11.AH.244.240; 11.AH.244.244; 11.AH.244.243;11.AH.244.247; 11.AH.247.157; 11.AH.247.158; 11.AH.247.196; 11.AH.247.223;11.AH.247.240; 11.AH.247.244; 11.AH.247.243; 11.AH.247.247;

11.AJのプロドラッグ
11.AJ.4.157; 11.AJ.4.158; 11.AJ.4.196; 11.AJ.4.223; 11.AJ.4.240; 11.AJ.4.244;11.AJ.4.243; 11.AJ.4.247; 11.AJ.5.157; 11.AJ.5.158; 11.AJ.5.196; 11.AJ.5.223;11.AJ.5.240; 11.AJ.5.244; 11.AJ.5.243; 11.AJ.5.247; 11.AJ.7.157; 11.AJ.7.158;11.AJ.7.196; 11.AJ.7.223; 11.AJ.7.240; 11.AJ.7.244; 11.AJ.7.243; 11.AJ.7.247;11.AJ.15.157; 11.AJ.15.158; 11.AJ.15.196; 11.AJ.15.223; 11.AJ.15.240;11.AJ.15.244; 11.AJ.15.243; 11.AJ.15.247; 11.AJ.16.157; 11.AJ.16.158;11.AJ.16.196; 11.AJ.16.223; 11.AJ.16.240; 11.AJ.16.244; 11.AJ.16.243;11.AJ.16.247; 11.AJ.18.157; 11.AJ.18.158; 11.AJ.18.196; 11.AJ.18.223;11.AJ.18.240; 11.AJ.18.244; 11.AJ.18.243; 11.AJ.18.247; 11.AJ.26.157;11.AJ.26.158; 11.AJ.26.196; 11.AJ.26.223; 11.AJ.26.240; 11.AJ.26.244;11.AJ.26.243; 11.AJ.26.247; 11.AJ.27.157; 11.AJ.27.158; 11.AJ.27.196;11.AJ.27.223; 11.AJ.27.240; 11.AJ.27.244; 11.AJ.27.243; 11.AJ.27.247;11.AJ.29.157; 11.AJ.29.158; 11.AJ.29.196; 11.AJ.29.223; 11.AJ.29.240;11.AJ.29.244; 11.AJ.29.243; 11.AJ.29.247; 11.AJ.54.157; 11.AJ.54.158;11.AJ.54.196; 11.AJ.54.223; 11.AJ.54.240; 11.AJ.54.244; 11.AJ.54.243;11.AJ.54.247; 11.AJ.55.157; 11.AJ.55.158; 11.AJ.55.196; 11.AJ.55.223;11.AJ.55.240; 11.AJ.55.244; 11.AJ.55.243; 11.AJ.55.247; 11.AJ.56.157;11.AJ.56.158; 11.AJ.56.196; 11.AJ.56.223; 11.AJ.56.240; 11.AJ.56.244;11.AJ.56.243; 11.AJ.56.247; 11.AJ.157.157; 11.AJ.157.158; 11.AJ.157.196;11.AJ.157.223; 11.AJ.157.240; 11.AJ.157.244; 11.AJ.157.243; 11.AJ.157.247;11.AJ.196.157; 11.AJ.196.158; 11.AJ.196.196; 11.AJ.196.223; 11.AJ.196.240;11.AJ.196.244; 11.AJ.196.243; 11.AJ.196.247; 11.AJ.223.157; 11.AJ.223.158;11.AJ.223.196; 11.AJ.223.223; 11.AJ.223.240; 11.AJ.223.244; 11.AJ.223.243;11.AJ.223.247; 11.AJ.240.157; 11.AJ.240.158; 11.AJ.240.196; 11.AJ.240.223;11.AJ.240.240; 11.AJ.240.244; 11.AJ.240.243; 11.AJ.240.247; 11.AJ.244.157;11.AJ.244.158; 11.AJ.244.196; 11.AJ.244.223; 11.AJ.244.240; 11.AJ.244.244;11.AJ.244.243; 11.AJ.244.247; 11.AJ.247.157; 11.AJ.247.158; 11.AJ.247.196;11.AJ.247.223; 11.AJ.247.240; 11.AJ.247.244; 11.AJ.247.243; 11.AJ.247.247;

11.ANのプロドラッグ
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のプロドラッグ
11.AP.4.157; 11.AP.4.158; 11.AP.4.196; 11.AP.4.223; 11.AP.4.240; 11.AP.4.244;11.AP.4.243; 11.AP.4.247; 11.AP.5.157; 11.AP.5.158; 11.AP.5.196; 11.AP.5.223;11.AP.5.240; 11.AP.5.244; 11.AP.5.243; 11.AP.5.247; 11.AP.7.157; 11.AP.7.158;11.AP.7.196; 11.AP.7.223; 11.AP.7.240; 11.AP.7.244; 11.AP.7.243; 11.AP.7.247;11.AP.15.157; 11.AP.15.158; 11.AP.15.196; 11.AP.15.223; 11.AP.15.240;11.AP.15.244; 11.AP.15.243; 11.AP.15.247; 11.AP.16.157; 11.AP.16.158;11.AP.16.196; 11.AP.16.223; 11.AP.16.240; 11.AP.16.244; 11.AP.16.243;11.AP.16.247; 11.AP.18.157; 11.AP.18.158; 11.AP.18.196; 11.AP.18.223;11.AP.18.240; 11.AP.18.244; 11.AP.18.243; 11.AP.18.247; 11.AP.26.157;11.AP.26.158; 11.AP.26.196; 11.AP.26.223; 11.AP.26.240; 11.AP.26.244;11.AP.26.243; 11.AP.26.247; 11.AP.27.157; 11.AP.27.158; 11.AP.27.196;11.AP.27.223; 11.AP.27.240; 11.AP.27.244; 11.AP.27.243; 11.AP.27.247;11.AP.29.157; 11.AP.29.158; 11.AP.29.196; 11.AP.29.223; 11.AP.29.240;11.AP.29.244; 11.AP.29.243; 11.AP.29.247; 11.AP.54.157; 11.AP.54.158;11.AP.54.196; 11.AP.54.223; 11.AP.54.240; 11.AP.54.244; 11.AP.54.243;11.AP.54.247; 11.AP.55.157; 11.AP.55.158; 11.AP.55.196; 11.AP.55.223;11.AP.55.240; 11.AP.55.244; 11.AP.55.243; 11.AP.55.247; 11.AP.56.157;11.AP.56.158; 11.AP.56.196; 11.AP.56.223; 11.AP.56.240; 11.AP.56.244;11.AP.56.243; 11.AP.56.247; 11.AP.157.157; 11.AP.157.158; 11.AP.157.196;11.AP.157.223; 11.AP.157.240; 11.AP.157.244; 11.AP.157.243; 11.AP.157.247;11.AP.196.157; 11.AP.196.158; 11.AP.196.196; 11.AP.196.223; 11.AP.196.240;11.AP.196.244; 11.AP.196.243; 11.AP.196.247; 11.AP.223.157; 11.AP.223.158;11.AP.223.196; 11.AP.223.223; 11.AP.223.240; 11.AP.223.244; 11.AP.223.243;11.AP.223.247; 11.AP.240.157; 11.AP.240.158; 11.AP.240.196; 11.AP.240.223;11.AP.240.240; 11.AP.240.244; 11.AP.240.243; 11.AP.240.247; 11.AP.244.157;11.AP.244.158; 11.AP.244.196; 11.AP.244.223; 11.AP.244.240; 11.AP.244.244;11.AP.244.243; 11.AP.244.247; 11.AP.247.157; 11.AP.247.158; 11.AP.247.196;11.AP.247.223; 11.AP.247.240; 11.AP.247.244; 11.AP.247.243; 11.AP.247.247;

11.AZのプロドラッグ
11.AZ.4.157; 11.AZ.4.158; 11.AZ.4.196; 11.AZ.4.223; 11.AZ.4.240; 11.AZ.4.244;11.AZ.4.243; 11.AZ.4.247; 11.AZ.5.157; 11.AZ.5.158; 11.AZ.5.196; 11.AZ.5.223;11.AZ.5.240; 11.AZ.5.244; 11.AZ.5.243; 11.AZ.5.247; 11.AZ.7.157; 11.AZ.7.158;11.AZ.7.196; 11.AZ.7.223; 11.AZ.7.240; 11.AZ.7.244; 11.AZ.7.243; 11.AZ.7.247;11.AZ.15.157; 11.AZ.15.158; 11.AZ.15.196; 11.AZ.15.223; 11.AZ.15.240;11.AZ.15.244; 11.AZ.15.243; 11.AZ.15.247; 11.AZ.16.157; 11.AZ.16.158;11.AZ.16.196; 11.AZ.16.223; 11.AZ.16.240; 11.AZ.16.244; 11.AZ.16.243;11.AZ.16.247; 11.AZ.18.157; 11.AZ.18.158; 11.AZ.18.196; 11.AZ.18.223;11.AZ.18.240; 11.AZ.18.244; 11.AZ.18.243; 11.AZ.18.247; 11.AZ.26.157;11.AZ.26.158; 11.AZ.26.196; 11.AZ.26.223; 11.AZ.26.240; 11.AZ.26.244;11.AZ.26.243; 11.AZ.26.247; 11.AZ.27.157; 11.AZ.27.158; 11.AZ.27.196;11.AZ.27.223; 11.AZ.27.240; 11.AZ.27.244; 11.AZ.27.243; 11.AZ.27.247;11.AZ.29.157; 11.AZ.29.158; 11.AZ.29.196; 11.AZ.29.223; 11.AZ.29.240;11.AZ.29.244; 11.AZ.29.243; 11.AZ.29.247; 11.AZ.54.157; 11.AZ.54.158;11.AZ.54.196; 11.AZ.54.223; 11.AZ.54.240; 11.AZ.54.244; 11.AZ.54.243;11.AZ.54.247; 11.AZ.55.157; 11.AZ.55.158; 11.AZ.55.196; 11.AZ.55.223;11.AZ.55.240; 11.AZ.55.244; 11.AZ.55.243; 11.AZ.55.247; 11.AZ.56.157;11.AZ.56.158; 11.AZ.56.196; 11.AZ.56.223; 11.AZ.56.240; 11.AZ.56.244;11.AZ.56.243; 11.AZ.56.247; 11.AZ.157.157; 11.AZ.157.158; 11.AZ.157.196;11.AZ.157.223; 11.AZ.157.240; 11.AZ.157.244; 11.AZ.157.243; 11.AZ.157.247;11.AZ.196.157; 11.AZ.196.158; 11.AZ.196.196; 11.AZ.196.223; 11.AZ.196.240;11.AZ.196.244; 11.AZ.196.243; 11.AZ.196.247; 11.AZ.223.157; 11.AZ.223.158;11.AZ.223.196; 11.AZ.223.223; 11.AZ.223.240; 11.AZ.223.244; 11.AZ.223.243;11.AZ.223.247; 11.AZ.240.157; 11.AZ.240.158; 11.AZ.240.196; 11.AZ.240.223;11.AZ.240.240; 11.AZ.240.244; 11.AZ.240.243; 11.AZ.240.247; 11.AZ.244.157;11.AZ.244.158; 11.AZ.244.196; 11.AZ.244.223; 11.AZ.244.240; 11.AZ.244.244;11.AZ.244.243; 11.AZ.244.247; 11.AZ.247.157; 11.AZ.247.158; 11.AZ.247.196;11.AZ.247.223; 11.AZ.247.240; 11.AZ.247.244; 11.AZ.247.243; 11.AZ.247.247;

11.BFのプロドラッグ
11.BF.4.157; 11.BF.4.158; 11.BF.4.196; 11.BF.4.223; 11.BF.4.240; 11.BF.4.244;11.BF.4.243; 11.BF.4.247; 11.BF.5.157; 11.BF.5.158; 11.BF.5.196; 11.BF.5.223;11.BF.5.240; 11.BF.5.244; 11.BF.5.243; 11.BF.5.247; 11.BF.7.157; 11.BF.7.158;11.BF.7.196; 11.BF.7.223; 11.BF.7.240; 11.BF.7.244; 11.BF.7.243; 11.BF.7.247;11.BF.15.157; 11.BF.15.158; 11.BF.15.196; 11.BF.15.223; 11.BF.15.240;11.BF.15.244; 11.BF.15.243; 11.BF.15.247; 11.BF.16.157; 11.BF.16.158;11.BF.16.196; 11.BF.16.223; 11.BF.16.240; 11.BF.16.244; 11.BF.16.243;11.BF.16.247; 11.BF.18.157; 11.BF.18.158; 11.BF.18.196; 11.BF.18.223;11.BF.18.240; 11.BF.18.244; 11.BF.18.243; 11.BF.18.247; 11.BF.26.157;11.BF.26.158; 11.BF.26.196; 11.BF.26.223; 11.BF.26.240; 11.BF.26.244;11.BF.26.243; 11.BF.26.247; 11.BF.27.157; 11.BF.27.158; 11.BF.27.196;11.BF.27.223; 11.BF.27.240; 11.BF.27.244; 11.BF.27.243; 11.BF.27.247; 11.BF.29.157;11.BF.29.158; 11.BF.29.196; 11.BF.29.223; 11.BF.29.240; 11.BF.29.244;11.BF.29.243; 11.BF.29.247; 11.BF.54.157; 11.BF.54.158; 11.BF.54.196;11.BF.54.223; 11.BF.54.240; 11.BF.54.244; 11.BF.54.243; 11.BF.54.247;11.BF.55.157; 11.BF.55.158; 11.BF.55.196; 11.BF.55.223; 11.BF.55.240;11.BF.55.244; 11.BF.55.243; 11.BF.55.247; 11.BF.56.157; 11.BF.56.158;11.BF.56.196; 11.BF.56.223; 11.BF.56.240; 11.BF.56.244; 11.BF.56.243;11.BF.56.247; 11.BF.157.157; 11.BF.157.158; 11.BF.157.196; 11.BF.157.223; 11.BF.157.240;11.BF.157.244; 11.BF.157.243; 11.BF.157.247; 11.BF.196.157; 11.BF.196.158;11.BF.196.196; 11.BF.196.223; 11.BF.196.240; 11.BF.196.244; 11.BF.196.243;11.BF.196.247; 11.BF.223.157; 11.BF.223.158; 11.BF.223.196; 11.BF.223.223;11.BF.223.240; 11.BF.223.244; 11.BF.223.243; 11.BF.223.247; 11.BF.240.157;11.BF.240.158; 11.BF.240.196; 11.BF.240.223; 11.BF.240.240; 11.BF.240.244;11.BF.240.243; 11.BF.240.247; 11.BF.244.157; 11.BF.244.158; 11.BF.244.196;11.BF.244.223; 11.BF.244.240; 11.BF.244.244; 11.BF.244.243; 11.BF.244.247;11.BF.247.157; 11.BF.247.158; 11.BF.247.196; 11.BF.247.223; 11.BF.247.240;11.BF.247.244; 11.BF.247.243; 11.BF.247.247;

11.CIのプロドラッグ
11.CI.4.157; 11.CI.4.158; 11.CI.4.196; 11.CI.4.223; 11.CI.4.240; 11.CI.4.244;11.CI.4.243; 11.CI.4.247; 11.CI.5.157; 11.CI.5.158; 11.CI.5.196; 11.CI.5.223;11.CI.5.240; 11.CI.5.244; 11.CI.5.243; 11.CI.5.247; 11.CI.7.157; 11.CI.7.158;11.CI.7.196; 11.CI.7.223; 11.CI.7.240; 11.CI.7.244; 11.CI.7.243; 11.CI.7.247;11.CI.15.157; 11.CI.15.158; 11.CI.15.196; 11.CI.15.223; 11.CI.15.240;11.CI.15.244; 11.CI.15.243; 11.CI.15.247; 11.CI.16.157; 11.CI.16.158;11.CI.16.196; 11.CI.16.223; 11.CI.16.240; 11.CI.16.244; 11.CI.16.243;11.CI.16.247; 11.CI.18.157; 11.CI.18.158; 11.CI.18.196; 11.CI.18.223; 11.CI.18.240;11.CI.18.244; 11.CI.18.243; 11.CI.18.247; 11.CI.26.157; 11.CI.26.158;11.CI.26.196; 11.CI.26.223; 11.CI.26.240; 11.CI.26.244; 11.CI.26.243;11.CI.26.247; 11.CI.27.157; 11.CI.27.158; 11.CI.27.196; 11.CI.27.223;11.CI.27.240; 11.CI.27.244; 11.CI.27.243; 11.CI.27.247; 11.CI.29.157;11.CI.29.158; 11.CI.29.196; 11.CI.29.223; 11.CI.29.240; 11.CI.29.244;11.CI.29.243; 11.CI.29.247; 11.CI.54.157; 11.CI.54.158; 11.CI.54.196;11.CI.54.223; 11.CI.54.240; 11.CI.54.244; 11.CI.54.243; 11.CI.54.247;11.CI.55.157; 11.CI.55.158; 11.CI.55.196; 11.CI.55.223; 11.CI.55.240;11.CI.55.244; 11.CI.55.243; 11.CI.55.247; 11.CI.56.157; 11.CI.56.158;11.CI.56.196; 11.CI.56.223; 11.CI.56.240; 11.CI.56.244; 11.CI.56.243;11.CI.56.247; 11.CI.157.157; 11.CI.157.158; 11.CI.157.196; 11.CI.157.223;11.CI.157.240; 11.CI.157.244; 11.CI.157.243; 11.CI.157.247; 11.CI.196.157;11.CI.196.158; 11.CI.196.196; 11.CI.196.223; 11.CI.196.240; 11.CI.196.244;11.CI.196.243; 11.CI.196.247; 11.CI.223.157; 11.CI.223.158; 11.CI.223.196;11.CI.223.223; 11.CI.223.240; 11.CI.223.244; 11.CI.223.243; 11.CI.223.247;11.CI.240.157; 11.CI.240.158; 11.CI.240.196; 11.CI.240.223; 11.CI.240.240;11.CI.240.244; 11.CI.240.243; 11.CI.240.247; 11.CI.244.157; 11.CI.244.158;11.CI.244.196; 11.CI.244.223; 11.CI.244.240; 11.CI.244.244; 11.CI.244.243;11.CI.244.247; 11.CI.247.157; 11.CI.247.158; 11.CI.247.196; 11.CI.247.223;11.CI.247.240; 11.CI.247.244; 11.CI.247.243; 11.CI.247.247;

11.COのプロドラッグ
11.CO.4.157; 11.CO.4.158; 11.CO.4.196; 11.CO.4.223; 11.CO.4.240; 11.CO.4.244; 11.CO.4.243;11.CO.4.247; 11.CO.5.157; 11.CO.5.158; 11.CO.5.196; 11.CO.5.223; 11.CO.5.240;11.CO.5.244; 11.CO.5.243; 11.CO.5.247; 11.CO.7.157; 11.CO.7.158; 11.CO.7.196;11.CO.7.223; 11.CO.7.240; 11.CO.7.244; 11.CO.7.243; 11.CO.7.247; 11.CO.15.157;11.CO.15.158; 11.CO.15.196; 11.CO.15.223; 11.CO.15.240; 11.CO.15.244;11.CO.15.243; 11.CO.15.247; 11.CO.16.157; 11.CO.16.158; 11.CO.16.196;11.CO.16.223; 11.CO.16.240; 11.CO.16.244; 11.CO.16.243; 11.CO.16.247;11.CO.18.157; 11.CO.18.158; 11.CO.18.196; 11.CO.18.223; 11.CO.18.240;11.CO.18.244; 11.CO.18.243; 11.CO.18.247; 11.CO.26.157; 11.CO.26.158;11.CO.26.196; 11.CO.26.223; 11.CO.26.240; 11.CO.26.244; 11.CO.26.243;11.CO.26.247; 11.CO.27.157; 11.CO.27.158; 11.CO.27.196; 11.CO.27.223;11.CO.27.240; 11.CO.27.244; 11.CO.27.243; 11.CO.27.247; 11.CO.29.157;11.CO.29.158; 11.CO.29.196; 11.CO.29.223; 11.CO.29.240; 11.CO.29.244;11.CO.29.243; 11.CO.29.247; 11.CO.54.157; 11.CO.54.158; 11.CO.54.196;11.CO.54.223; 11.CO.54.240; 11.CO.54.244; 11.CO.54.243; 11.CO.54.247; 11.CO.55.157;11.CO.55.158; 11.CO.55.196; 11.CO.55.223; 11.CO.55.240; 11.CO.55.244;11.CO.55.243; 11.CO.55.247; 11.CO.56.157; 11.CO.56.158; 11.CO.56.196;11.CO.56.223; 11.CO.56.240; 11.CO.56.244; 11.CO.56.243; 11.CO.56.247;11.CO.157.157; 11.CO.157.158; 11.CO.157.196; 11.CO.157.223; 11.CO.157.240;11.CO.157.244; 11.CO.157.243; 11.CO.157.247; 11.CO.196.157; 11.CO.196.158;11.CO.196.196; 11.CO.196.223; 11.CO.196.240; 11.CO.196.244; 11.CO.196.243;11.CO.196.247; 11.CO.223.157; 11.CO.223.158; 11.CO.223.196; 11.CO.223.223;11.CO.223.240; 11.CO.223.244; 11.CO.223.243; 11.CO.223.247; 11.CO.240.157;11.CO.240.158; 11.CO.240.196; 11.CO.240.223; 11.CO.240.240; 11.CO.240.244;11.CO.240.243; 11.CO.240.247; 11.CO.244.157; 11.CO.244.158; 11.CO.244.196;11.CO.244.223; 11.CO.244.240; 11.CO.244.244; 11.CO.244.243; 11.CO.244.247;11.CO.247.157; 11.CO.247.158; 11.CO.247.196; 11.CO.247.223; 11.CO.247.240;11.CO.247.244; 11.CO.247.243; 11.CO.247.247;

12.AHのプロドラッグ
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のプロドラッグ
12.AJ.4.157; 12.AJ.4.158; 12.AJ.4.196; 12.AJ.4.223; 12.AJ.4.240; 12.AJ.4.244;12.AJ.4.243; 12.AJ.4.247; 12.AJ.5.157; 12.AJ.5.158; 12.AJ.5.196; 12.AJ.5.223;12.AJ.5.240; 12.AJ.5.244; 12.AJ.5.243; 12.AJ.5.247; 12.AJ.7.157; 12.AJ.7.158;12.AJ.7.196; 12.AJ.7.223; 12.AJ.7.240; 12.AJ.7.244; 12.AJ.7.243; 12.AJ.7.247;12.AJ.15.157; 12.AJ.15.158; 12.AJ.15.196; 12.AJ.15.223; 12.AJ.15.240;12.AJ.15.244; 12.AJ.15.243; 12.AJ.15.247; 12.AJ.16.157; 12.AJ.16.158;12.AJ.16.196; 12.AJ.16.223; 12.AJ.16.240; 12.AJ.16.244; 12.AJ.16.243;12.AJ.16.247; 12.AJ.18.157; 12.AJ.18.158; 12.AJ.18.196; 12.AJ.18.223;12.AJ.18.240; 12.AJ.18.244; 12.AJ.18.243; 12.AJ.18.247; 12.AJ.26.157;12.AJ.26.158; 12.AJ.26.196; 12.AJ.26.223; 12.AJ.26.240; 12.AJ.26.244;12.AJ.26.243; 12.AJ.26.247; 12.AJ.27.157; 12.AJ.27.158; 12.AJ.27.196; 12.AJ.27.223;12.AJ.27.240; 12.AJ.27.244; 12.AJ.27.243; 12.AJ.27.247; 12.AJ.29.157;12.AJ.29.158; 12.AJ.29.196; 12.AJ.29.223; 12.AJ.29.240; 12.AJ.29.244;12.AJ.29.243; 12.AJ.29.247; 12.AJ.54.157; 12.AJ.54.158; 12.AJ.54.196;12.AJ.54.223; 12.AJ.54.240; 12.AJ.54.244; 12.AJ.54.243; 12.AJ.54.247;12.AJ.55.157; 12.AJ.55.158; 12.AJ.55.196; 12.AJ.55.223; 12.AJ.55.240;12.AJ.55.244; 12.AJ.55.243; 12.AJ.55.247; 12.AJ.56.157; 12.AJ.56.158;12.AJ.56.196; 12.AJ.56.223; 12.AJ.56.240; 12.AJ.56.244; 12.AJ.56.243;12.AJ.56.247; 12.AJ.157.157; 12.AJ.157.158; 12.AJ.157.196; 12.AJ.157.223;12.AJ.157.240; 12.AJ.157.244; 12.AJ.157.243; 12.AJ.157.247; 12.AJ.196.157;12.AJ.196.158; 12.AJ.196.196; 12.AJ.196.223; 12.AJ.196.240; 12.AJ.196.244;12.AJ.196.243; 12.AJ.196.247; 12.AJ.223.157; 12.AJ.223.158; 12.AJ.223.196;12.AJ.223.223; 12.AJ.223.240; 12.AJ.223.244; 12.AJ.223.243; 12.AJ.223.247;12.AJ.240.157; 12.AJ.240.158; 12.AJ.240.196; 12.AJ.240.223; 12.AJ.240.240;12.AJ.240.244; 12.AJ.240.243; 12.AJ.240.247; 12.AJ.244.157; 12.AJ.244.158; 12.AJ.244.196;12.AJ.244.223; 12.AJ.244.240; 12.AJ.244.244; 12.AJ.244.243; 12.AJ.244.247;12.AJ.247.157; 12.AJ.247.158; 12.AJ.247.196; 12.AJ.247.223; 12.AJ.247.240;12.AJ.247.244; 12.AJ.247.243; 12.AJ.247.247;

12.ANのプロドラッグ
12.AN.4.157; 12.AN.4.158; 12.AN.4.196; 12.AN.4.223; 12.AN.4.240; 12.AN.4.244;12.AN.4.243; 12.AN.4.247; 12.AN.5.157; 12.AN.5.158; 12.AN.5.196; 12.AN.5.223;12.AN.5.240; 12.AN.5.244; 12.AN.5.243; 12.AN.5.247; 12.AN.7.157; 12.AN.7.158;12.AN.7.196; 12.AN.7.223; 12.AN.7.240; 12.AN.7.244; 12.AN.7.243; 12.AN.7.247;12.AN.15.157; 12.AN.15.158; 12.AN.15.196; 12.AN.15.223; 12.AN.15.240;12.AN.15.244; 12.AN.15.243; 12.AN.15.247; 12.AN.16.157; 12.AN.16.158;12.AN.16.196; 12.AN.16.223; 12.AN.16.240; 12.AN.16.244; 12.AN.16.243;12.AN.16.247; 12.AN.18.157; 12.AN.18.158; 12.AN.18.196; 12.AN.18.223;12.AN.18.240; 12.AN.18.244; 12.AN.18.243; 12.AN.18.247; 12.AN.26.157;12.AN.26.158; 12.AN.26.196; 12.AN.26.223; 12.AN.26.240; 12.AN.26.244;12.AN.26.243; 12.AN.26.247; 12.AN.27.157; 12.AN.27.158; 12.AN.27.196;12.AN.27.223; 12.AN.27.240; 12.AN.27.244; 12.AN.27.243; 12.AN.27.247;12.AN.29.157; 12.AN.29.158; 12.AN.29.196; 12.AN.29.223; 12.AN.29.240;12.AN.29.244; 12.AN.29.243; 12.AN.29.247; 12.AN.54.157; 12.AN.54.158;12.AN.54.196; 12.AN.54.223; 12.AN.54.240; 12.AN.54.244; 12.AN.54.243;12.AN.54.247; 12.AN.55.157; 12.AN.55.158; 12.AN.55.196; 12.AN.55.223;12.AN.55.240; 12.AN.55.244; 12.AN.55.243; 12.AN.55.247; 12.AN.56.157;12.AN.56.158; 12.AN.56.196; 12.AN.56.223; 12.AN.56.240; 12.AN.56.244;12.AN.56.243; 12.AN.56.247; 12.AN.157.157; 12.AN.157.158; 12.AN.157.196;12.AN.157.223; 12.AN.157.240; 12.AN.157.244; 12.AN.157.243; 12.AN.157.247;12.AN.196.157; 12.AN.196.158; 12.AN.196.196; 12.AN.196.223; 12.AN.196.240;12.AN.196.244; 12.AN.196.243; 12.AN.196.247; 12.AN.223.157; 12.AN.223.158;12.AN.223.196; 12.AN.223.223; 12.AN.223.240; 12.AN.223.244; 12.AN.223.243;12.AN.223.247; 12.AN.240.157; 12.AN.240.158; 12.AN.240.196; 12.AN.240.223;12.AN.240.240; 12.AN.240.244; 12.AN.240.243; 12.AN.240.247; 12.AN.244.157; 12.AN.244.158;12.AN.244.196; 12.AN.244.223; 12.AN.244.240; 12.AN.244.244; 12.AN.244.243;12.AN.244.247; 12.AN.247.157; 12.AN.247.158; 12.AN.247.196; 12.AN.247.223;12.AN.247.240; 12.AN.247.244; 12.AN.247.243; 12.AN.247.247;

12.APのプロドラッグ
12.AP.4.157; 12.AP.4.158; 12.AP.4.196; 12.AP.4.223; 12.AP.4.240; 12.AP.4.244;12.AP.4.243; 12.AP.4.247; 12.AP.5.157; 12.AP.5.158; 12.AP.5.196; 12.AP.5.223;12.AP.5.240; 12.AP.5.244; 12.AP.5.243; 12.AP.5.247; 12.AP.7.157; 12.AP.7.158;12.AP.7.196; 12.AP.7.223; 12.AP.7.240; 12.AP.7.244; 12.AP.7.243; 12.AP.7.247;12.AP.15.157; 12.AP.15.158; 12.AP.15.196; 12.AP.15.223; 12.AP.15.240;12.AP.15.244; 12.AP.15.243; 12.AP.15.247; 12.AP.16.157; 12.AP.16.158;12.AP.16.196; 12.AP.16.223; 12.AP.16.240; 12.AP.16.244; 12.AP.16.243; 12.AP.16.247;12.AP.18.157; 12.AP.18.158; 12.AP.18.196; 12.AP.18.223; 12.AP.18.240;12.AP.18.244; 12.AP.18.243; 12.AP.18.247; 12.AP.26.157; 12.AP.26.158;12.AP.26.196; 12.AP.26.223; 12.AP.26.240; 12.AP.26.244; 12.AP.26.243;12.AP.26.247; 12.AP.27.157; 12.AP.27.158; 12.AP.27.196; 12.AP.27.223;12.AP.27.240; 12.AP.27.244; 12.AP.27.243; 12.AP.27.247; 12.AP.29.157;12.AP.29.158; 12.AP.29.196; 12.AP.29.223; 12.AP.29.240; 12.AP.29.244;12.AP.29.243; 12.AP.29.247; 12.AP.54.157; 12.AP.54.158; 12.AP.54.196; 12.AP.54.223;12.AP.54.240; 12.AP.54.244; 12.AP.54.243; 12.AP.54.247; 12.AP.55.157;12.AP.55.158; 12.AP.55.196; 12.AP.55.223; 12.AP.55.240; 12.AP.55.244;12.AP.55.243; 12.AP.55.247; 12.AP.56.157; 12.AP.56.158; 12.AP.56.196;12.AP.56.223; 12.AP.56.240; 12.AP.56.244; 12.AP.56.243; 12.AP.56.247;12.AP.157.157; 12.AP.157.158; 12.AP.157.196; 12.AP.157.223; 12.AP.157.240;12.AP.157.244; 12.AP.157.243; 12.AP.157.247; 12.AP.196.157; 12.AP.196.158;12.AP.196.196; 12.AP.196.223; 12.AP.196.240; 12.AP.196.244; 12.AP.196.243; 12.AP.196.247;12.AP.223.157; 12.AP.223.158; 12.AP.223.196; 12.AP.223.223; 12.AP.223.240;12.AP.223.244; 12.AP.223.243; 12.AP.223.247; 12.AP.240.157; 12.AP.240.158;12.AP.240.196; 12.AP.240.223; 12.AP.240.240; 12.AP.240.244; 12.AP.240.243;12.AP.240.247; 12.AP.244.157; 12.AP.244.158; 12.AP.244.196; 12.AP.244.223;12.AP.244.240; 12.AP.244.244; 12.AP.244.243; 12.AP.244.247; 12.AP.247.157;12.AP.247.158; 12.AP.247.196; 12.AP.247.223; 12.AP.247.240; 12.AP.247.244;12.AP.247.243; 12.AP.247.247;

12.AZのプロドラッグ
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のプロドラッグ
12.BF.4.157; 12.BF.4.158; 12.BF.4.196; 12.BF.4.223; 12.BF.4.240; 12.BF.4.244;12.BF.4.243; 12.BF.4.247; 12.BF.5.157; 12.BF.5.158; 12.BF.5.196; 12.BF.5.223;12.BF.5.240; 12.BF.5.244; 12.BF.5.243; 12.BF.5.247; 12.BF.7.157; 12.BF.7.158;12.BF.7.196; 12.BF.7.223; 12.BF.7.240; 12.BF.7.244; 12.BF.7.243; 12.BF.7.247;12.BF.15.157; 12.BF.15.158; 12.BF.15.196; 12.BF.15.223; 12.BF.15.240;12.BF.15.244; 12.BF.15.243; 12.BF.15.247; 12.BF.16.157; 12.BF.16.158;12.BF.16.196; 12.BF.16.223; 12.BF.16.240; 12.BF.16.244; 12.BF.16.243;12.BF.16.247; 12.BF.18.157; 12.BF.18.158; 12.BF.18.196; 12.BF.18.223;12.BF.18.240; 12.BF.18.244; 12.BF.18.243; 12.BF.18.247; 12.BF.26.157;12.BF.26.158; 12.BF.26.196; 12.BF.26.223; 12.BF.26.240; 12.BF.26.244;12.BF.26.243; 12.BF.26.247; 12.BF.27.157; 12.BF.27.158; 12.BF.27.196;12.BF.27.223; 12.BF.27.240; 12.BF.27.244; 12.BF.27.243; 12.BF.27.247;12.BF.29.157; 12.BF.29.158; 12.BF.29.196; 12.BF.29.223; 12.BF.29.240;12.BF.29.244; 12.BF.29.243; 12.BF.29.247; 12.BF.54.157; 12.BF.54.158;12.BF.54.196; 12.BF.54.223; 12.BF.54.240; 12.BF.54.244; 12.BF.54.243;12.BF.54.247; 12.BF.55.157; 12.BF.55.158; 12.BF.55.196; 12.BF.55.223;12.BF.55.240; 12.BF.55.244; 12.BF.55.243; 12.BF.55.247; 12.BF.56.157;12.BF.56.158; 12.BF.56.196; 12.BF.56.223; 12.BF.56.240; 12.BF.56.244;12.BF.56.243; 12.BF.56.247; 12.BF.157.157; 12.BF.157.158; 12.BF.157.196;12.BF.157.223; 12.BF.157.240; 12.BF.157.244; 12.BF.157.243; 12.BF.157.247;12.BF.196.157; 12.BF.196.158; 12.BF.196.196; 12.BF.196.223; 12.BF.196.240;12.BF.196.244; 12.BF.196.243; 12.BF.196.247; 12.BF.223.157; 12.BF.223.158;12.BF.223.196; 12.BF.223.223; 12.BF.223.240; 12.BF.223.244; 12.BF.223.243;12.BF.223.247; 12.BF.240.157; 12.BF.240.158; 12.BF.240.196; 12.BF.240.223;12.BF.240.240; 12.BF.240.244; 12.BF.240.243; 12.BF.240.247; 12.BF.244.157;12.BF.244.158; 12.BF.244.196; 12.BF.244.223; 12.BF.244.240; 12.BF.244.244;12.BF.244.243; 12.BF.244.247; 12.BF.247.157; 12.BF.247.158; 12.BF.247.196;12.BF.247.223; 12.BF.247.240; 12.BF.247.244; 12.BF.247.243; 12.BF.247.247;

12.CIのプロドラッグ
12.CI.4.157; 12.CI.4.158; 12.CI.4.196; 12.CI.4.223; 12.CI.4.240; 12.CI.4.244;12.CI.4.243; 12.CI.4.247; 12.CI.5.157; 12.CI.5.158; 12.CI.5.196; 12.CI.5.223;12.CI.5.240; 12.CI.5.244; 12.CI.5.243; 12.CI.5.247; 12.CI.7.157; 12.CI.7.158;12.CI.7.196; 12.CI.7.223; 12.CI.7.240; 12.CI.7.244; 12.CI.7.243; 12.CI.7.247;12.CI.15.157; 12.CI.15.158; 12.CI.15.196; 12.CI.15.223; 12.CI.15.240;12.CI.15.244; 12.CI.15.243; 12.CI.15.247; 12.CI.16.157; 12.CI.16.158;12.CI.16.196; 12.CI.16.223; 12.CI.16.240; 12.CI.16.244; 12.CI.16.243;12.CI.16.247; 12.CI.18.157; 12.CI.18.158; 12.CI.18.196; 12.CI.18.223;12.CI.18.240; 12.CI.18.244; 12.CI.18.243; 12.CI.18.247; 12.CI.26.157;12.CI.26.158; 12.CI.26.196; 12.CI.26.223; 12.CI.26.240; 12.CI.26.244; 12.CI.26.243;12.CI.26.247; 12.CI.27.157; 12.CI.27.158; 12.CI.27.196; 12.CI.27.223;12.CI.27.240; 12.CI.27.244; 12.CI.27.243; 12.CI.27.247; 12.CI.29.157;12.CI.29.158; 12.CI.29.196; 12.CI.29.223; 12.CI.29.240; 12.CI.29.244;12.CI.29.243; 12.CI.29.247; 12.CI.54.157; 12.CI.54.158; 12.CI.54.196;12.CI.54.223; 12.CI.54.240; 12.CI.54.244; 12.CI.54.243; 12.CI.54.247;12.CI.55.157; 12.CI.55.158; 12.CI.55.196; 12.CI.55.223; 12.CI.55.240;12.CI.55.244; 12.CI.55.243; 12.CI.55.247; 12.CI.56.157; 12.CI.56.158;12.CI.56.196; 12.CI.56.223; 12.CI.56.240; 12.CI.56.244; 12.CI.56.243;12.CI.56.247; 12.CI.157.157; 12.CI.157.158; 12.CI.157.196; 12.CI.157.223;12.CI.157.240; 12.CI.157.244; 12.CI.157.243; 12.CI.157.247; 12.CI.196.157;12.CI.196.158; 12.CI.196.196; 12.CI.196.223; 12.CI.196.240; 12.CI.196.244;12.CI.196.243; 12.CI.196.247; 12.CI.223.157; 12.CI.223.158; 12.CI.223.196;12.CI.223.223; 12.CI.223.240; 12.CI.223.244; 12.CI.223.243; 12.CI.223.247;12.CI.240.157; 12.CI.240.158; 12.CI.240.196; 12.CI.240.223; 12.CI.240.240;12.CI.240.244; 12.CI.240.243; 12.CI.240.247; 12.CI.244.157; 12.CI.244.158;12.CI.244.196; 12.CI.244.223; 12.CI.244.240; 12.CI.244.244; 12.CI.244.243;12.CI.244.247; 12.CI.247.157; 12.CI.247.158; 12.CI.247.196; 12.CI.247.223;12.CI.247.240; 12.CI.247.244; 12.CI.247.243; 12.CI.247.247;

12.COのプロドラッグ
12.CO.4.157; 12.CO.4.158; 12.CO.4.196; 12.CO.4.223; 12.CO.4.240; 12.CO.4.244;12.CO.4.243; 12.CO.4.247; 12.CO.5.157; 12.CO.5.158; 12.CO.5.196; 12.CO.5.223;12.CO.5.240; 12.CO.5.244; 12.CO.5.243; 12.CO.5.247; 12.CO.7.157; 12.CO.7.158;12.CO.7.196; 12.CO.7.223; 12.CO.7.240; 12.CO.7.244; 12.CO.7.243; 12.CO.7.247;12.CO.15.157; 12.CO.15.158; 12.CO.15.196; 12.CO.15.223; 12.CO.15.240;12.CO.15.244; 12.CO.15.243; 12.CO.15.247; 12.CO.16.157; 12.CO.16.158;12.CO.16.196; 12.CO.16.223; 12.CO.16.240; 12.CO.16.244; 12.CO.16.243;12.CO.16.247; 12.CO.18.157; 12.CO.18.158; 12.CO.18.196; 12.CO.18.223;12.CO.18.240; 12.CO.18.244; 12.CO.18.243; 12.CO.18.247; 12.CO.26.157;12.CO.26.158; 12.CO.26.196; 12.CO.26.223; 12.CO.26.240; 12.CO.26.244;12.CO.26.243; 12.CO.26.247; 12.CO.27.157; 12.CO.27.158; 12.CO.27.196;12.CO.27.223; 12.CO.27.240; 12.CO.27.244; 12.CO.27.243; 12.CO.27.247;12.CO.29.157; 12.CO.29.158; 12.CO.29.196; 12.CO.29.223; 12.CO.29.240;12.CO.29.244; 12.CO.29.243; 12.CO.29.247; 12.CO.54.157; 12.CO.54.158;12.CO.54.196; 12.CO.54.223; 12.CO.54.240; 12.CO.54.244; 12.CO.54.243;12.CO.54.247; 12.CO.55.157; 12.CO.55.158; 12.CO.55.196; 12.CO.55.223;12.CO.55.240; 12.CO.55.244; 12.CO.55.243; 12.CO.55.247; 12.CO.56.157;12.CO.56.158; 12.CO.56.196; 12.CO.56.223; 12.CO.56.240; 12.CO.56.244;12.CO.56.243; 12.CO.56.247; 12.CO.157.157; 12.CO.157.158; 12.CO.157.196;12.CO.157.223; 12.CO.157.240; 12.CO.157.244; 12.CO.157.243; 12.CO.157.247;12.CO.196.157; 12.CO.196.158; 12.CO.196.196; 12.CO.196.223; 12.CO.196.240;12.CO.196.244; 12.CO.196.243; 12.CO.196.247; 12.CO.223.157; 12.CO.223.158;12.CO.223.196; 12.CO.223.223; 12.CO.223.240; 12.CO.223.244; 12.CO.223.243;12.CO.223.247; 12.CO.240.157; 12.CO.240.158; 12.CO.240.196; 12.CO.240.223;12.CO.240.240; 12.CO.240.244; 12.CO.240.243; 12.CO.240.247; 12.CO.244.157;12.CO.244.158; 12.CO.244.196; 12.CO.244.223; 12.CO.244.240; 12.CO.244.244;12.CO.244.243; 12.CO.244.247; 12.CO.247.157; 12.CO.247.158; 12.CO.247.196;12.CO.247.223; 12.CO.247.240; 12.CO.247.244; 12.CO.247.243; 12.CO.247.247.

13.Bのプロドラッグ
13.B.228.228; 13.B.228.229; 13.B.228.230; 13.B.228.231; 13.B.228.236;13.B.228.237; 13.B.228.238; 13.B.228.239; 13.B.228.154; 13.B.228.157;13.B.228.166; 13.B.228.169; 13.B.228.172; 13.B.228.175; 13.B.228.240;13.B.228.244; 13.B.229.228; 13.B.229.229; 13.B.229.230; 13.B.229.231;13.B.229.236; 13.B.229.237; 13.B.229.238; 13.B.229.239; 13.B.229.154;13.B.229.157; 13.B.229.166; 13.B.229.169; 13.B.229.172; 13.B.229.175;13.B.229.240; 13.B.229.244; 13.B.230.228; 13.B.230.229; 13.B.230.230;13.B.230.231; 13.B.230.236; 13.B.230.237; 13.B.230.238; 13.B.230.239;13.B.230.154; 13.B.230.157; 13.B.230.166; 13.B.230.169; 13.B.230.172;13.B.230.175; 13.B.230.240; 13.B.230.244; 13.B.231.228; 13.B.231.229;13.B.231.230; 13.B.231.231; 13.B.231.236; 13.B.231.237; 13.B.231.238;13.B.231.239; 13.B.231.154; 13.B.231.157; 13.B.231.166; 13.B.231.169;13.B.231.172; 13.B.231.175; 13.B.231.240; 13.B.231.244; 13.B.236.228;13.B.236.229; 13.B.236.230; 13.B.236.231; 13.B.236.236; 13.B.236.237;13.B.236.238; 13.B.236.239; 13.B.236.154; 13.B.236.157; 13.B.236.166;13.B.236.169; 13.B.236.172; 13.B.236.175; 13.B.236.240; 13.B.236.244;13.B.237.228; 13.B.237.229; 13.B.237.230; 13.B.237.231; 13.B.237.236;13.B.237.237; 13.B.237.238; 13.B.237.239; 13.B.237.154; 13.B.237.157;13.B.237.166; 13.B.237.169; 13.B.237.172; 13.B.237.175; 13.B.237.240;13.B.237.244; 13.B.238.228; 13.B.238.229; 13.B.238.230; 13.B.238.231;13.B.238.236; 13.B.238.237; 13.B.238.238; 13.B.238.239; 13.B.238.154;13.B.238.157; 13.B.238.166; 13.B.238.169; 13.B.238.172; 13.B.238.175;13.B.238.240; 13.B.238.244; 13.B.239.228; 13.B.239.229; 13.B.239.230;13.B.239.231; 13.B.239.236; 13.B.239.237; 13.B.239.238; 13.B.239.239;13.B.239.154; 13.B.239.157; 13.B.239.166; 13.B.239.169; 13.B.239.172;13.B.239.175; 13.B.239.240; 13.B.239.244; 13.B.154.228; 13.B.154.229;13.B.154.230; 13.B.154.231; 13.B.154.236; 13.B.154.237; 13.B.154.238;13.B.154.239; 13.B.154.154; 13.B.154.157; 13.B.154.166; 13.B.154.169;13.B.154.172; 13.B.154.175; 13.B.154.240; 13.B.154.244; 13.B.157.228;13.B.157.229; 13.B.157.230; 13.B.157.231; 13.B.157.236; 13.B.157.237;13.B.157.238; 13.B.157.239; 13.B.157.154; 13.B.157.157; 13.B.157.166;13.B.157.169; 13.B.157.172; 13.B.157.175; 13.B.157.240; 13.B.157.244;13.B.166.228; 13.B.166.229; 13.B.166.230; 13.B.166.231; 13.B.166.236;13.B.166.237; 13.B.166.238; 13.B.166.239; 13.B.166.154; 13.B.166.157;13.B.166.166; 13.B.166.169; 13.B.166.172; 13.B.166.175; 13.B.166.240;13.B.166.244; 13.B.169.228; 13.B.169.229; 13.B.169.230; 13.B.169.231;13.B.169.236; 13.B.169.237; 13.B.169.238; 13.B.169.239; 13.B.169.154;13.B.169.157; 13.B.169.166; 13.B.169.169; 13.B.169.172; 13.B.169.175;13.B.169.240; 13.B.169.244; 13.B.172.228; 13.B.172.229; 13.B.172.230;13.B.172.231; 13.B.172.236; 13.B.172.237; 13.B.172.238; 13.B.172.239;13.B.172.154; 13.B.172.157; 13.B.172.166; 13.B.172.169; 13.B.172.172;13.B.172.175; 13.B.172.240; 13.B.172.244; 13.B.175.228; 13.B.175.229;13.B.175.230; 13.B.175.231; 13.B.175.236; 13.B.175.237; 13.B.175.238; 13.B.175.239;13.B.175.154; 13.B.175.157; 13.B.175.166; 13.B.175.169; 13.B.175.172;13.B.175.175; 13.B.175.240; 13.B.175.244; 13.B.240.228; 13.B.240.229;13.B.240.230; 13.B.240.231; 13.B.240.236; 13.B.240.237; 13.B.240.238;13.B.240.239; 13.B.240.154; 13.B.240.157; 13.B.240.166; 13.B.240.169;13.B.240.172; 13.B.240.175; 13.B.240.240; 13.B.240.244; 13.B.244.228;13.B.244.229; 13.B.244.230; 13.B.244.231; 13.B.244.236; 13.B.244.237;13.B.244.238; 13.B.244.239; 13.B.244.154; 13.B.244.157; 13.B.244.166;13.B.244.169; 13.B.244.172; 13.B.244.175; 13.B.244.240; 13.B.244.244;

13.Dのプロドラッグ
13.D.228.228; 13.D.228.229; 13.D.228.230; 13.D.228.231; 13.D.228.236;13.D.228.237; 13.D.228.238; 13.D.228.239; 13.D.228.154; 13.D.228.157;13.D.228.166; 13.D.228.169; 13.D.228.172; 13.D.228.175; 13.D.228.240;13.D.228.244; 13.D.229.228; 13.D.229.229; 13.D.229.230; 13.D.229.231;13.D.229.236; 13.D.229.237; 13.D.229.238; 13.D.229.239; 13.D.229.154;13.D.229.157; 13.D.229.166; 13.D.229.169; 13.D.229.172; 13.D.229.175;13.D.229.240; 13.D.229.244; 13.D.230.228; 13.D.230.229; 13.D.230.230;13.D.230.231; 13.D.230.236; 13.D.230.237; 13.D.230.238; 13.D.230.239;13.D.230.154; 13.D.230.157; 13.D.230.166; 13.D.230.169; 13.D.230.172;13.D.230.175; 13.D.230.240; 13.D.230.244; 13.D.231.228; 13.D.231.229;13.D.231.230; 13.D.231.231; 13.D.231.236; 13.D.231.237; 13.D.231.238;13.D.231.239; 13.D.231.154; 13.D.231.157; 13.D.231.166; 13.D.231.169;13.D.231.172; 13.D.231.175; 13.D.231.240; 13.D.231.244; 13.D.236.228;13.D.236.229; 13.D.236.230; 13.D.236.231; 13.D.236.236; 13.D.236.237;13.D.236.238; 13.D.236.239; 13.D.236.154; 13.D.236.157; 13.D.236.166;13.D.236.169; 13.D.236.172; 13.D.236.175; 13.D.236.240; 13.D.236.244;13.D.237.228; 13.D.237.229; 13.D.237.230; 13.D.237.231; 13.D.237.236;13.D.237.237; 13.D.237.238; 13.D.237.239; 13.D.237.154; 13.D.237.157;13.D.237.166; 13.D.237.169; 13.D.237.172; 13.D.237.175; 13.D.237.240;13.D.237.244; 13.D.238.228; 13.D.238.229; 13.D.238.230; 13.D.238.231;13.D.238.236; 13.D.238.237; 13.D.238.238; 13.D.238.239; 13.D.238.154;13.D.238.157; 13.D.238.166; 13.D.238.169; 13.D.238.172; 13.D.238.175;13.D.238.240; 13.D.238.244; 13.D.239.228; 13.D.239.229; 13.D.239.230;13.D.239.231; 13.D.239.236; 13.D.239.237; 13.D.239.238; 13.D.239.239;13.D.239.154; 13.D.239.157; 13.D.239.166; 13.D.239.169; 13.D.239.172;13.D.239.175; 13.D.239.240; 13.D.239.244; 13.D.154.228; 13.D.154.229;13.D.154.230; 13.D.154.231; 13.D.154.236; 13.D.154.237; 13.D.154.238;13.D.154.239; 13.D.154.154; 13.D.154.157; 13.D.154.166; 13.D.154.169;13.D.154.172; 13.D.154.175; 13.D.154.240; 13.D.154.244; 13.D.157.228;13.D.157.229; 13.D.157.230; 13.D.157.231; 13.D.157.236; 13.D.157.237;13.D.157.238; 13.D.157.239; 13.D.157.154; 13.D.157.157; 13.D.157.166;13.D.157.169; 13.D.157.172; 13.D.157.175; 13.D.157.240; 13.D.157.244;13.D.166.228; 13.D.166.229; 13.D.166.230; 13.D.166.231; 13.D.166.236;13.D.166.237; 13.D.166.238; 13.D.166.239; 13.D.166.154; 13.D.166.157;13.D.166.166; 13.D.166.169; 13.D.166.172; 13.D.166.175; 13.D.166.240;13.D.166.244; 13.D.169.228; 13.D.169.229; 13.D.169.230; 13.D.169.231;13.D.169.236; 13.D.169.237; 13.D.169.238; 13.D.169.239; 13.D.169.154;13.D.169.157; 13.D.169.166; 13.D.169.169; 13.D.169.172; 13.D.169.175;13.D.169.240; 13.D.169.244; 13.D.172.228; 13.D.172.229; 13.D.172.230;13.D.172.231; 13.D.172.236; 13.D.172.237; 13.D.172.238; 13.D.172.239;13.D.172.154; 13.D.172.157; 13.D.172.166; 13.D.172.169; 13.D.172.172;13.D.172.175; 13.D.172.240; 13.D.172.244; 13.D.175.228; 13.D.175.229;13.D.175.230; 13.D.175.231; 13.D.175.236; 13.D.175.237; 13.D.175.238;13.D.175.239; 13.D.175.154; 13.D.175.157; 13.D.175.166; 13.D.175.169;13.D.175.172; 13.D.175.175; 13.D.175.240; 13.D.175.244; 13.D.240.228;13.D.240.229; 13.D.240.230; 13.D.240.231; 13.D.240.236; 13.D.240.237;13.D.240.238; 13.D.240.239; 13.D.240.154; 13.D.240.157; 13.D.240.166;13.D.240.169; 13.D.240.172; 13.D.240.175; 13.D.240.240; 13.D.240.244;13.D.244.228; 13.D.244.229; 13.D.244.230; 13.D.244.231; 13.D.244.236;13.D.244.237; 13.D.244.238; 13.D.244.239; 13.D.244.154; 13.D.244.157;13.D.244.166; 13.D.244.169; 13.D.244.172; 13.D.244.175; 13.D.244.240;13.D.244.244;

13.Eのプロドラッグ
13.E.228.228; 13.E.228.229; 13.E.228.230; 13.E.228.231; 13.E.228.236;13.E.228.237; 13.E.228.238; 13.E.228.239; 13.E.228.154; 13.E.228.157;13.E.228.166; 13.E.228.169; 13.E.228.172; 13.E.228.175; 13.E.228.240;13.E.228.244; 13.E.229.228; 13.E.229.229; 13.E.229.230; 13.E.229.231;13.E.229.236; 13.E.229.237; 13.E.229.238; 13.E.229.239; 13.E.229.154;13.E.229.157; 13.E.229.166; 13.E.229.169; 13.E.229.172; 13.E.229.175; 13.E.229.240;13.E.229.244; 13.E.230.228; 13.E.230.229; 13.E.230.230; 13.E.230.231;13.E.230.236; 13.E.230.237; 13.E.230.238; 13.E.230.239; 13.E.230.154;13.E.230.157; 13.E.230.166; 13.E.230.169; 13.E.230.172; 13.E.230.175;13.E.230.240; 13.E.230.244; 13.E.231.228; 13.E.231.229; 13.E.231.230;13.E.231.231; 13.E.231.236; 13.E.231.237; 13.E.231.238; 13.E.231.239;13.E.231.154; 13.E.231.157; 13.E.231.166; 13.E.231.169; 13.E.231.172;13.E.231.175; 13.E.231.240; 13.E.231.244; 13.E.236.228; 13.E.236.229; 13.E.236.230;13.E.236.231; 13.E.236.236; 13.E.236.237; 13.E.236.238; 13.E.236.239;13.E.236.154; 13.E.236.157; 13.E.236.166; 13.E.236.169; 13.E.236.172;13.E.236.175; 13.E.236.240; 13.E.236.244; 13.E.237.228; 13.E.237.229;13.E.237.230; 13.E.237.231; 13.E.237.236; 13.E.237.237; 13.E.237.238;13.E.237.239; 13.E.237.154; 13.E.237.157; 13.E.237.166; 13.E.237.169;13.E.237.172; 13.E.237.175; 13.E.237.240; 13.E.237.244; 13.E.238.228;13.E.238.229; 13.E.238.230; 13.E.238.231; 13.E.238.236; 13.E.238.237;13.E.238.238; 13.E.238.239; 13.E.238.154; 13.E.238.157; 13.E.238.166;13.E.238.169; 13.E.238.172; 13.E.238.175; 13.E.238.240; 13.E.238.244;13.E.239.228; 13.E.239.229; 13.E.239.230; 13.E.239.231; 13.E.239.236;13.E.239.237; 13.E.239.238; 13.E.239.239; 13.E.239.154; 13.E.239.157;13.E.239.166; 13.E.239.169; 13.E.239.172; 13.E.239.175; 13.E.239.240;13.E.239.244; 13.E.154.228; 13.E.154.229; 13.E.154.230; 13.E.154.231;13.E.154.236; 13.E.154.237; 13.E.154.238; 13.E.154.239; 13.E.154.154;13.E.154.157; 13.E.154.166; 13.E.154.169; 13.E.154.172; 13.E.154.175;13.E.154.240; 13.E.154.244; 13.E.157.228; 13.E.157.229; 13.E.157.230;13.E.157.231; 13.E.157.236; 13.E.157.237; 13.E.157.238; 13.E.157.239;13.E.157.154; 13.E.157.157; 13.E.157.166; 13.E.157.169; 13.E.157.172;13.E.157.175; 13.E.157.240; 13.E.157.244; 13.E.166.228; 13.E.166.229;13.E.166.230; 13.E.166.231; 13.E.166.236; 13.E.166.237; 13.E.166.238;13.E.166.239; 13.E.166.154; 13.E.166.157; 13.E.166.166; 13.E.166.169;13.E.166.172; 13.E.166.175; 13.E.166.240; 13.E.166.244; 13.E.169.228;13.E.169.229; 13.E.169.230; 13.E.169.231; 13.E.169.236; 13.E.169.237;13.E.169.238; 13.E.169.239; 13.E.169.154; 13.E.169.157; 13.E.169.166;13.E.169.169; 13.E.169.172; 13.E.169.175; 13.E.169.240; 13.E.169.244;13.E.172.228; 13.E.172.229; 13.E.172.230; 13.E.172.231; 13.E.172.236;13.E.172.237; 13.E.172.238; 13.E.172.239; 13.E.172.154; 13.E.172.157;13.E.172.166; 13.E.172.169; 13.E.172.172; 13.E.172.175; 13.E.172.240;13.E.172.244; 13.E.175.228; 13.E.175.229; 13.E.175.230; 13.E.175.231;13.E.175.236; 13.E.175.237; 13.E.175.238; 13.E.175.239; 13.E.175.154;13.E.175.157; 13.E.175.166; 13.E.175.169; 13.E.175.172; 13.E.175.175;13.E.175.240; 13.E.175.244; 13.E.240.228; 13.E.240.229; 13.E.240.230;13.E.240.231; 13.E.240.236; 13.E.240.237; 13.E.240.238; 13.E.240.239;13.E.240.154; 13.E.240.157; 13.E.240.166; 13.E.240.169; 13.E.240.172;13.E.240.175; 13.E.240.240; 13.E.240.244; 13.E.244.228; 13.E.244.229;13.E.244.230; 13.E.244.231; 13.E.244.236; 13.E.244.237; 13.E.244.238;13.E.244.239; 13.E.244.154; 13.E.244.157; 13.E.244.166; 13.E.244.169;13.E.244.172; 13.E.244.175; 13.E.244.240; 13.E.244.244;

13.Gのプロドラッグ
13.G.228.228; 13.G.228.229; 13.G.228.230; 13.G.228.231; 13.G.228.236;13.G.228.237; 13.G.228.238; 13.G.228.239; 13.G.228.154; 13.G.228.157;13.G.228.166; 13.G.228.169; 13.G.228.172; 13.G.228.175; 13.G.228.240;13.G.228.244; 13.G.229.228; 13.G.229.229; 13.G.229.230; 13.G.229.231;13.G.229.236; 13.G.229.237; 13.G.229.238; 13.G.229.239; 13.G.229.154;13.G.229.157; 13.G.229.166; 13.G.229.169; 13.G.229.172; 13.G.229.175;13.G.229.240; 13.G.229.244; 13.G.230.228; 13.G.230.229; 13.G.230.230;13.G.230.231; 13.G.230.236; 13.G.230.237; 13.G.230.238; 13.G.230.239;13.G.230.154; 13.G.230.157; 13.G.230.166; 13.G.230.169; 13.G.230.172;13.G.230.175; 13.G.230.240; 13.G.230.244; 13.G.231.228; 13.G.231.229;13.G.231.230; 13.G.231.231; 13.G.231.236; 13.G.231.237; 13.G.231.238;13.G.231.239; 13.G.231.154; 13.G.231.157; 13.G.231.166; 13.G.231.169;13.G.231.172; 13.G.231.175; 13.G.231.240; 13.G.231.244; 13.G.236.228;13.G.236.229; 13.G.236.230; 13.G.236.231; 13.G.236.236; 13.G.236.237;13.G.236.238; 13.G.236.239; 13.G.236.154; 13.G.236.157; 13.G.236.166;13.G.236.169; 13.G.236.172; 13.G.236.175; 13.G.236.240; 13.G.236.244;13.G.237.228; 13.G.237.229; 13.G.237.230; 13.G.237.231; 13.G.237.236;13.G.237.237; 13.G.237.238; 13.G.237.239; 13.G.237.154; 13.G.237.157;13.G.237.166; 13.G.237.169; 13.G.237.172; 13.G.237.175; 13.G.237.240;13.G.237.244; 13.G.238.228; 13.G.238.229; 13.G.238.230; 13.G.238.231;13.G.238.236; 13.G.238.237; 13.G.238.238; 13.G.238.239; 13.G.238.154;13.G.238.157; 13.G.238.166; 13.G.238.169; 13.G.238.172; 13.G.238.175;13.G.238.240; 13.G.238.244; 13.G.239.228; 13.G.239.229; 13.G.239.230;13.G.239.231; 13.G.239.236; 13.G.239.237; 13.G.239.238; 13.G.239.239;13.G.239.154; 13.G.239.157; 13.G.239.166; 13.G.239.169; 13.G.239.172;13.G.239.175; 13.G.239.240; 13.G.239.244; 13.G.154.228; 13.G.154.229;13.G.154.230; 13.G.154.231; 13.G.154.236; 13.G.154.237; 13.G.154.238;13.G.154.239; 13.G.154.154; 13.G.154.157; 13.G.154.166; 13.G.154.169;13.G.154.172; 13.G.154.175; 13.G.154.240; 13.G.154.244; 13.G.157.228;13.G.157.229; 13.G.157.230; 13.G.157.231; 13.G.157.236; 13.G.157.237;13.G.157.238; 13.G.157.239; 13.G.157.154; 13.G.157.157; 13.G.157.166;13.G.157.169; 13.G.157.172; 13.G.157.175; 13.G.157.240; 13.G.157.244;13.G.166.228; 13.G.166.229; 13.G.166.230; 13.G.166.231; 13.G.166.236;13.G.166.237; 13.G.166.238; 13.G.166.239; 13.G.166.154; 13.G.166.157;13.G.166.166; 13.G.166.169; 13.G.166.172; 13.G.166.175; 13.G.166.240;13.G.166.244; 13.G.169.228; 13.G.169.229; 13.G.169.230; 13.G.169.231;13.G.169.236; 13.G.169.237; 13.G.169.238; 13.G.169.239; 13.G.169.154;13.G.169.157; 13.G.169.166; 13.G.169.169; 13.G.169.172; 13.G.169.175;13.G.169.240; 13.G.169.244; 13.G.172.228; 13.G.172.229; 13.G.172.230;13.G.172.231; 13.G.172.236; 13.G.172.237; 13.G.172.238; 13.G.172.239;13.G.172.154; 13.G.172.157; 13.G.172.166; 13.G.172.169; 13.G.172.172;13.G.172.175; 13.G.172.240; 13.G.172.244; 13.G.175.228; 13.G.175.229;13.G.175.230; 13.G.175.231; 13.G.175.236; 13.G.175.237; 13.G.175.238;13.G.175.239; 13.G.175.154; 13.G.175.157; 13.G.175.166; 13.G.175.169;13.G.175.172; 13.G.175.175; 13.G.175.240; 13.G.175.244; 13.G.240.228;13.G.240.229; 13.G.240.230; 13.G.240.231; 13.G.240.236; 13.G.240.237;13.G.240.238; 13.G.240.239; 13.G.240.154; 13.G.240.157; 13.G.240.166;13.G.240.169; 13.G.240.172; 13.G.240.175; 13.G.240.240; 13.G.240.244;13.G.244.228; 13.G.244.229; 13.G.244.230; 13.G.244.231; 13.G.244.236; 13.G.244.237;13.G.244.238; 13.G.244.239; 13.G.244.154; 13.G.244.157; 13.G.244.166;13.G.244.169; 13.G.244.172; 13.G.244.175; 13.G.244.240; 13.G.244.244;

13.Iのプロドラッグ
13.I.228.228; 13.I.228.229; 13.I.228.230; 13.I.228.231; 13.I.228.236;13.I.228.237; 13.I.228.238; 13.I.228.239; 13.I.228.154; 13.I.228.157;13.I.228.166; 13.I.228.169; 13.I.228.172; 13.I.228.175; 13.I.228.240;13.I.228.244; 13.I.229.228; 13.I.229.229; 13.I.229.230; 13.I.229.231;13.I.229.236; 13.I.229.237; 13.I.229.238; 13.I.229.239; 13.I.229.154;13.I.229.157; 13.I.229.166; 13.I.229.169; 13.I.229.172; 13.I.229.175;13.I.229.240; 13.I.229.244; 13.I.230.228; 13.I.230.229; 13.I.230.230;13.I.230.231; 13.I.230.236; 13.I.230.237; 13.I.230.238; 13.I.230.239;13.I.230.154; 13.I.230.157; 13.I.230.166; 13.I.230.169; 13.I.230.172;13.I.230.175; 13.I.230.240; 13.I.230.244; 13.I.231.228; 13.I.231.229;13.I.231.230; 13.I.231.231; 13.I.231.236; 13.I.231.237; 13.I.231.238;13.I.231.239; 13.I.231.154; 13.I.231.157; 13.I.231.166; 13.I.231.169;13.I.231.172; 13.I.231.175; 13.I.231.240; 13.I.231.244; 13.I.236.228;13.I.236.229; 13.I.236.230; 13.I.236.231; 13.I.236.236; 13.I.236.237;13.I.236.238; 13.I.236.239; 13.I.236.154; 13.I.236.157; 13.I.236.166;13.I.236.169; 13.I.236.172; 13.I.236.175; 13.I.236.240; 13.I.236.244;13.I.237.228; 13.I.237.229; 13.I.237.230; 13.I.237.231; 13.I.237.236;13.I.237.237; 13.I.237.238; 13.I.237.239; 13.I.237.154; 13.I.237.157;13.I.237.166; 13.I.237.169; 13.I.237.172; 13.I.237.175; 13.I.237.240;13.I.237.244; 13.I.238.228; 13.I.238.229; 13.I.238.230; 13.I.238.231;13.I.238.236; 13.I.238.237; 13.I.238.238; 13.I.238.239; 13.I.238.154;13.I.238.157; 13.I.238.166; 13.I.238.169; 13.I.238.172; 13.I.238.175;13.I.238.240; 13.I.238.244; 13.I.239.228; 13.I.239.229; 13.I.239.230;13.I.239.231; 13.I.239.236; 13.I.239.237; 13.I.239.238; 13.I.239.239;13.I.239.154; 13.I.239.157; 13.I.239.166; 13.I.239.169; 13.I.239.172;13.I.239.175; 13.I.239.240; 13.I.239.244; 13.I.154.228; 13.I.154.229;13.I.154.230; 13.I.154.231; 13.I.154.236; 13.I.154.237; 13.I.154.238;13.I.154.239; 13.I.154.154; 13.I.154.157; 13.I.154.166; 13.I.154.169;13.I.154.172; 13.I.154.175; 13.I.154.240; 13.I.154.244; 13.I.157.228;13.I.157.229; 13.I.157.230; 13.I.157.231; 13.I.157.236; 13.I.157.237;13.I.157.238; 13.I.157.239; 13.I.157.154; 13.I.157.157; 13.I.157.166;13.I.157.169; 13.I.157.172; 13.I.157.175; 13.I.157.240; 13.I.157.244;13.I.166.228; 13.I.166.229; 13.I.166.230; 13.I.166.231; 13.I.166.236;13.I.166.237; 13.I.166.238; 13.I.166.239; 13.I.166.154; 13.I.166.157;13.I.166.166; 13.I.166.169; 13.I.166.172; 13.I.166.175; 13.I.166.240;13.I.166.244; 13.I.169.228; 13.I.169.229; 13.I.169.230; 13.I.169.231;13.I.169.236; 13.I.169.237; 13.I.169.238; 13.I.169.239; 13.I.169.154;13.I.169.157; 13.I.169.166; 13.I.169.169; 13.I.169.172; 13.I.169.175;13.I.169.240; 13.I.169.244; 13.I.172.228; 13.I.172.229; 13.I.172.230;13.I.172.231; 13.I.172.236; 13.I.172.237; 13.I.172.238; 13.I.172.239;13.I.172.154; 13.I.172.157; 13.I.172.166; 13.I.172.169; 13.I.172.172;13.I.172.175; 13.I.172.240; 13.I.172.244; 13.I.175.228; 13.I.175.229;13.I.175.230; 13.I.175.231; 13.I.175.236; 13.I.175.237; 13.I.175.238;13.I.175.239; 13.I.175.154; 13.I.175.157; 13.I.175.166; 13.I.175.169;13.I.175.172; 13.I.175.175; 13.I.175.240; 13.I.175.244; 13.I.240.228;13.I.240.229; 13.I.240.230; 13.I.240.231; 13.I.240.236; 13.I.240.237;13.I.240.238; 13.I.240.239; 13.I.240.154; 13.I.240.157; 13.I.240.166;13.I.240.169; 13.I.240.172; 13.I.240.175; 13.I.240.240; 13.I.240.244; 13.I.244.228;13.I.244.229; 13.I.244.230; 13.I.244.231; 13.I.244.236; 13.I.244.237;13.I.244.238; 13.I.244.239; 13.I.244.154; 13.I.244.157; 13.I.244.166;13.I.244.169; 13.I.244.172; 13.I.244.175; 13.I.244.240; 13.I.244.244;

13.Jのプロドラッグ
13.J.228.228; 13.J.228.229; 13.J.228.230; 13.J.228.231; 13.J.228.236;13.J.228.237; 13.J.228.238; 13.J.228.239; 13.J.228.154; 13.J.228.157;13.J.228.166; 13.J.228.169; 13.J.228.172; 13.J.228.175; 13.J.228.240;13.J.228.244; 13.J.229.228; 13.J.229.229; 13.J.229.230; 13.J.229.231;13.J.229.236; 13.J.229.237; 13.J.229.238; 13.J.229.239; 13.J.229.154;13.J.229.157; 13.J.229.166; 13.J.229.169; 13.J.229.172; 13.J.229.175;13.J.229.240; 13.J.229.244; 13.J.230.228; 13.J.230.229; 13.J.230.230;13.J.230.231; 13.J.230.236; 13.J.230.237; 13.J.230.238; 13.J.230.239;13.J.230.154; 13.J.230.157; 13.J.230.166; 13.J.230.169; 13.J.230.172;13.J.230.175; 13.J.230.240; 13.J.230.244; 13.J.231.228; 13.J.231.229;13.J.231.230; 13.J.231.231; 13.J.231.236; 13.J.231.237; 13.J.231.238;13.J.231.239; 13.J.231.154; 13.J.231.157; 13.J.231.166; 13.J.231.169;13.J.231.172; 13.J.231.175; 13.J.231.240; 13.J.231.244; 13.J.236.228;13.J.236.229; 13.J.236.230; 13.J.236.231; 13.J.236.236; 13.J.236.237;13.J.236.238; 13.J.236.239; 13.J.236.154; 13.J.236.157; 13.J.236.166;13.J.236.169; 13.J.236.172; 13.J.236.175; 13.J.236.240; 13.J.236.244;13.J.237.228; 13.J.237.229; 13.J.237.230; 13.J.237.231; 13.J.237.236;13.J.237.237; 13.J.237.238; 13.J.237.239; 13.J.237.154; 13.J.237.157;13.J.237.166; 13.J.237.169; 13.J.237.172; 13.J.237.175; 13.J.237.240;13.J.237.244; 13.J.238.228; 13.J.238.229; 13.J.238.230; 13.J.238.231;13.J.238.236; 13.J.238.237; 13.J.238.238; 13.J.238.239; 13.J.238.154;13.J.238.157; 13.J.238.166; 13.J.238.169; 13.J.238.172; 13.J.238.175;13.J.238.240; 13.J.238.244; 13.J.239.228; 13.J.239.229; 13.J.239.230;13.J.239.231; 13.J.239.236; 13.J.239.237; 13.J.239.238; 13.J.239.239;13.J.239.154; 13.J.239.157; 13.J.239.166; 13.J.239.169; 13.J.239.172;13.J.239.175; 13.J.239.240; 13.J.239.244; 13.J.154.228; 13.J.154.229;13.J.154.230; 13.J.154.231; 13.J.154.236; 13.J.154.237; 13.J.154.238;13.J.154.239; 13.J.154.154; 13.J.154.157; 13.J.154.166; 13.J.154.169;13.J.154.172; 13.J.154.175; 13.J.154.240; 13.J.154.244; 13.J.157.228;13.J.157.229; 13.J.157.230; 13.J.157.231; 13.J.157.236; 13.J.157.237;13.J.157.238; 13.J.157.239; 13.J.157.154; 13.J.157.157; 13.J.157.166;13.J.157.169; 13.J.157.172; 13.J.157.175; 13.J.157.240; 13.J.157.244;13.J.166.228; 13.J.166.229; 13.J.166.230; 13.J.166.231; 13.J.166.236;13.J.166.237; 13.J.166.238; 13.J.166.239; 13.J.166.154; 13.J.166.157;13.J.166.166; 13.J.166.169; 13.J.166.172; 13.J.166.175; 13.J.166.240;13.J.166.244; 13.J.169.228; 13.J.169.229; 13.J.169.230; 13.J.169.231;13.J.169.236; 13.J.169.237; 13.J.169.238; 13.J.169.239; 13.J.169.154;13.J.169.157; 13.J.169.166; 13.J.169.169; 13.J.169.172; 13.J.169.175;13.J.169.240; 13.J.169.244; 13.J.172.228; 13.J.172.229; 13.J.172.230;13.J.172.231; 13.J.172.236; 13.J.172.237; 13.J.172.238; 13.J.172.239;13.J.172.154; 13.J.172.157; 13.J.172.166; 13.J.172.169; 13.J.172.172;13.J.172.175; 13.J.172.240; 13.J.172.244; 13.J.175.228; 13.J.175.229;13.J.175.230; 13.J.175.231; 13.J.175.236; 13.J.175.237; 13.J.175.238;13.J.175.239; 13.J.175.154; 13.J.175.157; 13.J.175.166; 13.J.175.169;13.J.175.172; 13.J.175.175; 13.J.175.240; 13.J.175.244; 13.J.240.228;13.J.240.229; 13.J.240.230; 13.J.240.231; 13.J.240.236; 13.J.240.237;13.J.240.238; 13.J.240.239; 13.J.240.154; 13.J.240.157; 13.J.240.166;13.J.240.169; 13.J.240.172; 13.J.240.175; 13.J.240.240; 13.J.240.244;13.J.244.228; 13.J.244.229; 13.J.244.230; 13.J.244.231; 13.J.244.236;13.J.244.237; 13.J.244.238; 13.J.244.239; 13.J.244.154; 13.J.244.157;13.J.244.166; 13.J.244.169; 13.J.244.172; 13.J.244.175; 13.J.244.240;13.J.244.244;

13.Lのプロドラッグ
13.L.228.228;13.L.228.229; 13.L.228.230; 13.L.228.231; 13.L.228.236; 13.L.228.237;13.L.228.238; 13.L.228.239; 13.L.228.154; 13.L.228.157; 13.L.228.166;13.L.228.169; 13.L.228.172; 13.L.228.175; 13.L.228.240; 13.L.228.244;13.L.229.228; 13.L.229.229; 13.L.229.230; 13.L.229.231; 13.L.229.236;13.L.229.237; 13.L.229.238; 13.L.229.239; 13.L.229.154; 13.L.229.157;13.L.229.166; 13.L.229.169; 13.L.229.172; 13.L.229.175; 13.L.229.240;13.L.229.244; 13.L.230.228; 13.L.230.229; 13.L.230.230; 13.L.230.231; 13.L.230.236;13.L.230.237; 13.L.230.238; 13.L.230.239; 13.L.230.154; 13.L.230.157;13.L.230.166; 13.L.230.169; 13.L.230.172; 13.L.230.175; 13.L.230.240;13.L.230.244; 13.L.231.228; 13.L.231.229; 13.L.231.230; 13.L.231.231;13.L.231.236; 13.L.231.237; 13.L.231.238; 13.L.231.239; 13.L.231.154;13.L.231.157; 13.L.231.166; 13.L.231.169; 13.L.231.172; 13.L.231.175;13.L.231.240; 13.L.231.244; 13.L.236.228; 13.L.236.229; 13.L.236.230;13.L.236.231; 13.L.236.236; 13.L.236.237; 13.L.236.238; 13.L.236.239;13.L.236.154; 13.L.236.157; 13.L.236.166; 13.L.236.169; 13.L.236.172;13.L.236.175; 13.L.236.240; 13.L.236.244; 13.L.237.228; 13.L.237.229;13.L.237.230; 13.L.237.231; 13.L.237.236; 13.L.237.237; 13.L.237.238;13.L.237.239; 13.L.237.154; 13.L.237.157; 13.L.237.166; 13.L.237.169;13.L.237.172; 13.L.237.175; 13.L.237.240; 13.L.237.244; 13.L.238.228;13.L.238.229; 13.L.238.230; 13.L.238.231; 13.L.238.236; 13.L.238.237;13.L.238.238; 13.L.238.239; 13.L.238.154; 13.L.238.157; 13.L.238.166;13.L.238.169; 13.L.238.172; 13.L.238.175; 13.L.238.240; 13.L.238.244;13.L.239.228; 13.L.239.229; 13.L.239.230; 13.L.239.231; 13.L.239.236;13.L.239.237; 13.L.239.238; 13.L.239.239; 13.L.239.154; 13.L.239.157;13.L.239.166; 13.L.239.169; 13.L.239.172; 13.L.239.175; 13.L.239.240;13.L.239.244; 13.L.154.228; 13.L.154.229; 13.L.154.230; 13.L.154.231;13.L.154.236; 13.L.154.237; 13.L.154.238; 13.L.154.239; 13.L.154.154;13.L.154.157; 13.L.154.166; 13.L.154.169; 13.L.154.172; 13.L.154.175;13.L.154.240; 13.L.154.244; 13.L.157.228; 13.L.157.229; 13.L.157.230;13.L.157.231; 13.L.157.236; 13.L.157.237; 13.L.157.238; 13.L.157.239;13.L.157.154; 13.L.157.157; 13.L.157.166; 13.L.157.169; 13.L.157.172;13.L.157.175; 13.L.157.240; 13.L.157.244; 13.L.166.228; 13.L.166.229;13.L.166.230; 13.L.166.231; 13.L.166.236; 13.L.166.237; 13.L.166.238;13.L.166.239; 13.L.166.154; 13.L.166.157; 13.L.166.166; 13.L.166.169;13.L.166.172; 13.L.166.175; 13.L.166.240; 13.L.166.244; 13.L.169.228;13.L.169.229; 13.L.169.230; 13.L.169.231; 13.L.169.236; 13.L.169.237;13.L.169.238; 13.L.169.239; 13.L.169.154; 13.L.169.157; 13.L.169.166;13.L.169.169; 13.L.169.172; 13.L.169.175; 13.L.169.240; 13.L.169.244;13.L.172.228; 13.L.172.229; 13.L.172.230; 13.L.172.231; 13.L.172.236;13.L.172.237; 13.L.172.238; 13.L.172.239; 13.L.172.154; 13.L.172.157;13.L.172.166; 13.L.172.169; 13.L.172.172; 13.L.172.175; 13.L.172.240;13.L.172.244; 13.L.175.228; 13.L.175.229; 13.L.175.230; 13.L.175.231;13.L.175.236; 13.L.175.237; 13.L.175.238; 13.L.175.239; 13.L.175.154;13.L.175.157; 13.L.175.166; 13.L.175.169; 13.L.175.172; 13.L.175.175;13.L.175.240; 13.L.175.244; 13.L.240.228; 13.L.240.229; 13.L.240.230;13.L.240.231; 13.L.240.236; 13.L.240.237; 13.L.240.238; 13.L.240.239;13.L.240.154; 13.L.240.157; 13.L.240.166; 13.L.240.169; 13.L.240.172;13.L.240.175; 13.L.240.240; 13.L.240.244; 13.L.244.228; 13.L.244.229;13.L.244.230; 13.L.244.231; 13.L.244.236; 13.L.244.237; 13.L.244.238;13.L.244.239; 13.L.244.154; 13.L.244.157; 13.L.244.166; 13.L.244.169;13.L.244.172; 13.L.244.175; 13.L.244.240; 13.L.244.244;

13.Oのプロドラッグ
13.O.228.228; 13.O.228.229; 13.O.228.230; 13.O.228.231; 13.O.228.236;13.O.228.237; 13.O.228.238; 13.O.228.239; 13.O.228.154; 13.O.228.157;13.O.228.166; 13.O.228.169; 13.O.228.172; 13.O.228.175; 13.O.228.240;13.O.228.244; 13.O.229.228; 13.O.229.229; 13.O.229.230; 13.O.229.231;13.O.229.236; 13.O.229.237; 13.O.229.238; 13.O.229.239; 13.O.229.154;13.O.229.157; 13.O.229.166; 13.O.229.169; 13.O.229.172; 13.O.229.175;13.O.229.240; 13.O.229.244; 13.O.230.228; 13.O.230.229; 13.O.230.230; 13.O.230.231;13.O.230.236; 13.O.230.237; 13.O.230.238; 13.O.230.239; 13.O.230.154;13.O.230.157; 13.O.230.166; 13.O.230.169; 13.O.230.172; 13.O.230.175;13.O.230.240; 13.O.230.244; 13.O.231.228; 13.O.231.229; 13.O.231.230;13.O.231.231; 13.O.231.236; 13.O.231.237; 13.O.231.238; 13.O.231.239;13.O.231.154; 13.O.231.157; 13.O.231.166; 13.O.231.169; 13.O.231.172;13.O.231.175; 13.O.231.240; 13.O.231.244; 13.O.236.228; 13.O.236.229;13.O.236.230; 13.O.236.231; 13.O.236.236; 13.O.236.237; 13.O.236.238;13.O.236.239; 13.O.236.154; 13.O.236.157; 13.O.236.166; 13.O.236.169;13.O.236.172; 13.O.236.175; 13.O.236.240; 13.O.236.244; 13.O.237.228;13.O.237.229; 13.O.237.230; 13.O.237.231; 13.O.237.236; 13.O.237.237;13.O.237.238; 13.O.237.239; 13.O.237.154; 13.O.237.157; 13.O.237.166;13.O.237.169; 13.O.237.172; 13.O.237.175; 13.O.237.240; 13.O.237.244;13.O.238.228; 13.O.238.229; 13.O.238.230; 13.O.238.231; 13.O.238.236;13.O.238.237; 13.O.238.238; 13.O.238.239; 13.O.238.154; 13.O.238.157;13.O.238.166; 13.O.238.169; 13.O.238.172; 13.O.238.175; 13.O.238.240;13.O.238.244; 13.O.239.228; 13.O.239.229; 13.O.239.230; 13.O.239.231;13.O.239.236; 13.O.239.237; 13.O.239.238; 13.O.239.239; 13.O.239.154;13.O.239.157; 13.O.239.166; 13.O.239.169; 13.O.239.172; 13.O.239.175; 13.O.239.240;13.O.239.244; 13.O.154.228; 13.O.154.229; 13.O.154.230; 13.O.154.231;13.O.154.236; 13.O.154.237; 13.O.154.238; 13.O.154.239; 13.O.154.154;13.O.154.157; 13.O.154.166; 13.O.154.169; 13.O.154.172; 13.O.154.175;13.O.154.240; 13.O.154.244; 13.O.157.228; 13.O.157.229; 13.O.157.230;13.O.157.231; 13.O.157.236; 13.O.157.237; 13.O.157.238; 13.O.157.239;13.O.157.154; 13.O.157.157; 13.O.157.166; 13.O.157.169; 13.O.157.172;13.O.157.175; 13.O.157.240; 13.O.157.244; 13.O.166.228; 13.O.166.229;13.O.166.230; 13.O.166.231; 13.O.166.236; 13.O.166.237; 13.O.166.238;13.O.166.239; 13.O.166.154; 13.O.166.157; 13.O.166.166; 13.O.166.169;13.O.166.172; 13.O.166.175; 13.O.166.240; 13.O.166.244; 13.O.169.228;13.O.169.229; 13.O.169.230; 13.O.169.231; 13.O.169.236; 13.O.169.237;13.O.169.238; 13.O.169.239; 13.O.169.154; 13.O.169.157; 13.O.169.166;13.O.169.169; 13.O.169.172; 13.O.169.175; 13.O.169.240; 13.O.169.244;13.O.172.228; 13.O.172.229; 13.O.172.230; 13.O.172.231; 13.O.172.236;13.O.172.237; 13.O.172.238; 13.O.172.239; 13.O.172.154; 13.O.172.157;13.O.172.166; 13.O.172.169; 13.O.172.172; 13.O.172.175; 13.O.172.240;13.O.172.244; 13.O.175.228; 13.O.175.229; 13.O.175.230; 13.O.175.231;13.O.175.236; 13.O.175.237; 13.O.175.238; 13.O.175.239; 13.O.175.154;13.O.175.157; 13.O.175.166; 13.O.175.169; 13.O.175.172; 13.O.175.175;13.O.175.240; 13.O.175.244; 13.O.240.228; 13.O.240.229; 13.O.240.230;13.O.240.231; 13.O.240.236; 13.O.240.237; 13.O.240.238; 13.O.240.239;13.O.240.154; 13.O.240.157; 13.O.240.166; 13.O.240.169; 13.O.240.172;13.O.240.175; 13.O.240.240; 13.O.240.244; 13.O.244.228; 13.O.244.229;13.O.244.230; 13.O.244.231; 13.O.244.236; 13.O.244.237; 13.O.244.238;13.O.244.239; 13.O.244.154; 13.O.244.157; 13.O.244.166; 13.O.244.169;13.O.244.172; 13.O.244.175; 13.O.244.240; 13.O.244.244;

13.Pのプロドラッグ
13.P.228.228; 13.P.228.229; 13.P.228.230; 13.P.228.231; 13.P.228.236;13.P.228.237; 13.P.228.238; 13.P.228.239; 13.P.228.154; 13.P.228.157;13.P.228.166; 13.P.228.169; 13.P.228.172; 13.P.228.175; 13.P.228.240; 13.P.228.244;13.P.229.228; 13.P.229.229; 13.P.229.230; 13.P.229.231; 13.P.229.236;13.P.229.237; 13.P.229.238; 13.P.229.239; 13.P.229.154; 13.P.229.157;13.P.229.166; 13.P.229.169; 13.P.229.172; 13.P.229.175; 13.P.229.240;13.P.229.244; 13.P.230.228; 13.P.230.229; 13.P.230.230; 13.P.230.231;13.P.230.236; 13.P.230.237; 13.P.230.238; 13.P.230.239; 13.P.230.154;13.P.230.157; 13.P.230.166; 13.P.230.169; 13.P.230.172; 13.P.230.175;13.P.230.240; 13.P.230.244; 13.P.231.228; 13.P.231.229; 13.P.231.230;13.P.231.231; 13.P.231.236; 13.P.231.237; 13.P.231.238; 13.P.231.239;13.P.231.154; 13.P.231.157; 13.P.231.166; 13.P.231.169; 13.P.231.172;13.P.231.175; 13.P.231.240; 13.P.231.244; 13.P.236.228; 13.P.236.229;13.P.236.230; 13.P.236.231; 13.P.236.236; 13.P.236.237; 13.P.236.238;13.P.236.239; 13.P.236.154; 13.P.236.157; 13.P.236.166; 13.P.236.169;13.P.236.172; 13.P.236.175; 13.P.236.240; 13.P.236.244; 13.P.237.228;13.P.237.229; 13.P.237.230; 13.P.237.231; 13.P.237.236; 13.P.237.237;13.P.237.238; 13.P.237.239; 13.P.237.154; 13.P.237.157; 13.P.237.166;13.P.237.169; 13.P.237.172; 13.P.237.175; 13.P.237.240; 13.P.237.244;13.P.238.228; 13.P.238.229; 13.P.238.230; 13.P.238.231; 13.P.238.236;13.P.238.237; 13.P.238.238; 13.P.238.239; 13.P.238.154; 13.P.238.157;13.P.238.166; 13.P.238.169; 13.P.238.172; 13.P.238.175; 13.P.238.240;13.P.238.244; 13.P.239.228; 13.P.239.229; 13.P.239.230; 13.P.239.231;13.P.239.236; 13.P.239.237; 13.P.239.238; 13.P.239.239; 13.P.239.154;13.P.239.157; 13.P.239.166; 13.P.239.169; 13.P.239.172; 13.P.239.175;13.P.239.240; 13.P.239.244; 13.P.154.228; 13.P.154.229; 13.P.154.230;13.P.154.231; 13.P.154.236; 13.P.154.237; 13.P.154.238; 13.P.154.239;13.P.154.154; 13.P.154.157; 13.P.154.166; 13.P.154.169; 13.P.154.172;13.P.154.175; 13.P.154.240; 13.P.154.244; 13.P.157.228; 13.P.157.229;13.P.157.230; 13.P.157.231; 13.P.157.236; 13.P.157.237; 13.P.157.238;13.P.157.239; 13.P.157.154; 13.P.157.157; 13.P.157.166; 13.P.157.169;13.P.157.172; 13.P.157.175; 13.P.157.240; 13.P.157.244; 13.P.166.228;13.P.166.229; 13.P.166.230; 13.P.166.231; 13.P.166.236; 13.P.166.237;13.P.166.238; 13.P.166.239; 13.P.166.154; 13.P.166.157; 13.P.166.166;13.P.166.169; 13.P.166.172; 13.P.166.175; 13.P.166.240; 13.P.166.244;13.P.169.228; 13.P.169.229; 13.P.169.230; 13.P.169.231; 13.P.169.236;13.P.169.237; 13.P.169.238; 13.P.169.239; 13.P.169.154; 13.P.169.157;13.P.169.166; 13.P.169.169; 13.P.169.172; 13.P.169.175; 13.P.169.240;13.P.169.244; 13.P.172.228; 13.P.172.229; 13.P.172.230; 13.P.172.231;13.P.172.236; 13.P.172.237; 13.P.172.238; 13.P.172.239; 13.P.172.154;13.P.172.157; 13.P.172.166; 13.P.172.169; 13.P.172.172; 13.P.172.175;13.P.172.240; 13.P.172.244; 13.P.175.228; 13.P.175.229; 13.P.175.230;13.P.175.231; 13.P.175.236; 13.P.175.237; 13.P.175.238; 13.P.175.239; 13.P.175.154;13.P.175.157; 13.P.175.166; 13.P.175.169; 13.P.175.172; 13.P.175.175;13.P.175.240; 13.P.175.244; 13.P.240.228; 13.P.240.229; 13.P.240.230;13.P.240.231; 13.P.240.236; 13.P.240.237; 13.P.240.238; 13.P.240.239;13.P.240.154; 13.P.240.157; 13.P.240.166; 13.P.240.169; 13.P.240.172;13.P.240.175; 13.P.240.240; 13.P.240.244; 13.P.244.228; 13.P.244.229;13.P.244.230; 13.P.244.231; 13.P.244.236; 13.P.244.237; 13.P.244.238;13.P.244.239; 13.P.244.154; 13.P.244.157; 13.P.244.166; 13.P.244.169;13.P.244.172; 13.P.244.175; 13.P.244.240; 13.P.244.244;

13.Uのプロドラッグ
13.U.228.228; 13.U.228.229; 13.U.228.230; 13.U.228.231; 13.U.228.236;13.U.228.237; 13.U.228.238; 13.U.228.239; 13.U.228.154; 13.U.228.157;13.U.228.166; 13.U.228.169; 13.U.228.172; 13.U.228.175; 13.U.228.240;13.U.228.244; 13.U.229.228; 13.U.229.229; 13.U.229.230; 13.U.229.231;13.U.229.236; 13.U.229.237; 13.U.229.238; 13.U.229.239; 13.U.229.154;13.U.229.157; 13.U.229.166; 13.U.229.169; 13.U.229.172; 13.U.229.175;13.U.229.240; 13.U.229.244; 13.U.230.228; 13.U.230.229; 13.U.230.230;13.U.230.231; 13.U.230.236; 13.U.230.237; 13.U.230.238; 13.U.230.239;13.U.230.154; 13.U.230.157; 13.U.230.166; 13.U.230.169; 13.U.230.172;13.U.230.175; 13.U.230.240; 13.U.230.244; 13.U.231.228; 13.U.231.229; 13.U.231.230;13.U.231.231; 13.U.231.236; 13.U.231.237; 13.U.231.238; 13.U.231.239;13.U.231.154; 13.U.231.157; 13.U.231.166; 13.U.231.169; 13.U.231.172;13.U.231.175; 13.U.231.240; 13.U.231.244; 13.U.236.228; 13.U.236.229;13.U.236.230; 13.U.236.231; 13.U.236.236; 13.U.236.237; 13.U.236.238;13.U.236.239; 13.U.236.154; 13.U.236.157; 13.U.236.166; 13.U.236.169;13.U.236.172; 13.U.236.175; 13.U.236.240; 13.U.236.244; 13.U.237.228;13.U.237.229; 13.U.237.230; 13.U.237.231; 13.U.237.236; 13.U.237.237;13.U.237.238; 13.U.237.239; 13.U.237.154; 13.U.237.157; 13.U.237.166;13.U.237.169; 13.U.237.172; 13.U.237.175; 13.U.237.240; 13.U.237.244;13.U.238.228; 13.U.238.229; 13.U.238.230; 13.U.238.231; 13.U.238.236;13.U.238.237; 13.U.238.238; 13.U.238.239; 13.U.238.154; 13.U.238.157;13.U.238.166; 13.U.238.169; 13.U.238.172; 13.U.238.175; 13.U.238.240;13.U.238.244; 13.U.239.228; 13.U.239.229; 13.U.239.230; 13.U.239.231;13.U.239.236; 13.U.239.237; 13.U.239.238; 13.U.239.239; 13.U.239.154;13.U.239.157; 13.U.239.166; 13.U.239.169; 13.U.239.172; 13.U.239.175;13.U.239.240; 13.U.239.244; 13.U.154.228; 13.U.154.229; 13.U.154.230;13.U.154.231; 13.U.154.236; 13.U.154.237; 13.U.154.238; 13.U.154.239;13.U.154.154; 13.U.154.157; 13.U.154.166; 13.U.154.169; 13.U.154.172;13.U.154.175; 13.U.154.240; 13.U.154.244; 13.U.157.228; 13.U.157.229;13.U.157.230; 13.U.157.231; 13.U.157.236; 13.U.157.237; 13.U.157.238;13.U.157.239; 13.U.157.154; 13.U.157.157; 13.U.157.166; 13.U.157.169;13.U.157.172; 13.U.157.175; 13.U.157.240; 13.U.157.244; 13.U.166.228;13.U.166.229; 13.U.166.230; 13.U.166.231; 13.U.166.236; 13.U.166.237;13.U.166.238; 13.U.166.239; 13.U.166.154; 13.U.166.157; 13.U.166.166;13.U.166.169; 13.U.166.172; 13.U.166.175; 13.U.166.240; 13.U.166.244;13.U.169.228; 13.U.169.229; 13.U.169.230; 13.U.169.231; 13.U.169.236;13.U.169.237; 13.U.169.238; 13.U.169.239; 13.U.169.154; 13.U.169.157;13.U.169.166; 13.U.169.169; 13.U.169.172; 13.U.169.175; 13.U.169.240;13.U.169.244; 13.U.172.228; 13.U.172.229; 13.U.172.230; 13.U.172.231;13.U.172.236; 13.U.172.237; 13.U.172.238; 13.U.172.239; 13.U.172.154;13.U.172.157; 13.U.172.166; 13.U.172.169; 13.U.172.172; 13.U.172.175;13.U.172.240; 13.U.172.244; 13.U.175.228; 13.U.175.229; 13.U.175.230;13.U.175.231; 13.U.175.236; 13.U.175.237; 13.U.175.238; 13.U.175.239;13.U.175.154; 13.U.175.157; 13.U.175.166; 13.U.175.169; 13.U.175.172;13.U.175.175; 13.U.175.240; 13.U.175.244; 13.U.240.228; 13.U.240.229;13.U.240.230; 13.U.240.231; 13.U.240.236; 13.U.240.237; 13.U.240.238;13.U.240.239; 13.U.240.154; 13.U.240.157; 13.U.240.166; 13.U.240.169;13.U.240.172; 13.U.240.175; 13.U.240.240; 13.U.240.244; 13.U.244.228;13.U.244.229; 13.U.244.230; 13.U.244.231; 13.U.244.236; 13.U.244.237;13.U.244.238; 13.U.244.239; 13.U.244.154; 13.U.244.157; 13.U.244.166;13.U.244.169; 13.U.244.172; 13.U.244.175; 13.U.244.240; 13.U.244.244;

13.Wのプロドラッグ
13.W.228.228; 13.W.228.229; 13.W.228.230; 13.W.228.231; 13.W.228.236;13.W.228.237; 13.W.228.238; 13.W.228.239; 13.W.228.154; 13.W.228.157;13.W.228.166; 13.W.228.169; 13.W.228.172; 13.W.228.175; 13.W.228.240;13.W.228.244; 13.W.229.228; 13.W.229.229; 13.W.229.230; 13.W.229.231;13.W.229.236; 13.W.229.237; 13.W.229.238; 13.W.229.239; 13.W.229.154;13.W.229.157; 13.W.229.166; 13.W.229.169; 13.W.229.172; 13.W.229.175;13.W.229.240; 13.W.229.244; 13.W.230.228; 13.W.230.229; 13.W.230.230;13.W.230.231; 13.W.230.236; 13.W.230.237; 13.W.230.238; 13.W.230.239;13.W.230.154; 13.W.230.157; 13.W.230.166; 13.W.230.169; 13.W.230.172;13.W.230.175; 13.W.230.240; 13.W.230.244; 13.W.231.228; 13.W.231.229;13.W.231.230; 13.W.231.231; 13.W.231.236; 13.W.231.237; 13.W.231.238;13.W.231.239; 13.W.231.154; 13.W.231.157; 13.W.231.166; 13.W.231.169;13.W.231.172; 13.W.231.175; 13.W.231.240; 13.W.231.244; 13.W.236.228;13.W.236.229; 13.W.236.230; 13.W.236.231; 13.W.236.236; 13.W.236.237;13.W.236.238; 13.W.236.239; 13.W.236.154; 13.W.236.157; 13.W.236.166;13.W.236.169; 13.W.236.172; 13.W.236.175; 13.W.236.240; 13.W.236.244;13.W.237.228; 13.W.237.229; 13.W.237.230; 13.W.237.231; 13.W.237.236;13.W.237.237; 13.W.237.238; 13.W.237.239; 13.W.237.154; 13.W.237.157;13.W.237.166; 13.W.237.169; 13.W.237.172; 13.W.237.175; 13.W.237.240;13.W.237.244; 13.W.238.228; 13.W.238.229; 13.W.238.230; 13.W.238.231;13.W.238.236; 13.W.238.237; 13.W.238.238; 13.W.238.239; 13.W.238.154;13.W.238.157; 13.W.238.166; 13.W.238.169; 13.W.238.172; 13.W.238.175;13.W.238.240; 13.W.238.244; 13.W.239.228; 13.W.239.229; 13.W.239.230;13.W.239.231; 13.W.239.236; 13.W.239.237; 13.W.239.238; 13.W.239.239;13.W.239.154; 13.W.239.157; 13.W.239.166; 13.W.239.169; 13.W.239.172;13.W.239.175; 13.W.239.240; 13.W.239.244; 13.W.154.228; 13.W.154.229;13.W.154.230; 13.W.154.231; 13.W.154.236; 13.W.154.237; 13.W.154.238;13.W.154.239; 13.W.154.154; 13.W.154.157; 13.W.154.166; 13.W.154.169; 13.W.154.172;13.W.154.175; 13.W.154.240; 13.W.154.244; 13.W.157.228; 13.W.157.229;13.W.157.230; 13.W.157.231; 13.W.157.236; 13.W.157.237; 13.W.157.238;13.W.157.239; 13.W.157.154; 13.W.157.157; 13.W.157.166; 13.W.157.169;13.W.157.172; 13.W.157.175; 13.W.157.240; 13.W.157.244; 13.W.166.228;13.W.166.229; 13.W.166.230; 13.W.166.231; 13.W.166.236; 13.W.166.237;13.W.166.238; 13.W.166.239; 13.W.166.154; 13.W.166.157; 13.W.166.166;13.W.166.169; 13.W.166.172; 13.W.166.175; 13.W.166.240; 13.W.166.244;13.W.169.228; 13.W.169.229; 13.W.169.230; 13.W.169.231; 13.W.169.236;13.W.169.237; 13.W.169.238; 13.W.169.239; 13.W.169.154; 13.W.169.157;13.W.169.166; 13.W.169.169; 13.W.169.172; 13.W.169.175; 13.W.169.240;13.W.169.244; 13.W.172.228; 13.W.172.229; 13.W.172.230; 13.W.172.231;13.W.172.236; 13.W.172.237; 13.W.172.238; 13.W.172.239; 13.W.172.154;13.W.172.157; 13.W.172.166; 13.W.172.169; 13.W.172.172; 13.W.172.175;13.W.172.240; 13.W.172.244; 13.W.175.228; 13.W.175.229; 13.W.175.230;13.W.175.231; 13.W.175.236; 13.W.175.237; 13.W.175.238; 13.W.175.239;13.W.175.154; 13.W.175.157; 13.W.175.166; 13.W.175.169; 13.W.175.172;13.W.175.175; 13.W.175.240; 13.W.175.244; 13.W.240.228; 13.W.240.229;13.W.240.230; 13.W.240.231; 13.W.240.236; 13.W.240.237; 13.W.240.238;13.W.240.239; 13.W.240.154; 13.W.240.157; 13.W.240.166; 13.W.240.169;13.W.240.172; 13.W.240.175; 13.W.240.240; 13.W.240.244; 13.W.244.228;13.W.244.229; 13.W.244.230; 13.W.244.231; 13.W.244.236; 13.W.244.237;13.W.244.238; 13.W.244.239; 13.W.244.154; 13.W.244.157; 13.W.244.166;13.W.244.169; 13.W.244.172; 13.W.244.175; 13.W.244.240; 13.W.244.244;

13.Yのプロドラッグ
13.Y.228.228; 13.Y.228.229; 13.Y.228.230; 13.Y.228.231; 13.Y.228.236;13.Y.228.237; 13.Y.228.238; 13.Y.228.239; 13.Y.228.154; 13.Y.228.157;13.Y.228.166; 13.Y.228.169; 13.Y.228.172; 13.Y.228.175; 13.Y.228.240;13.Y.228.244; 13.Y.229.228; 13.Y.229.229; 13.Y.229.230; 13.Y.229.231;13.Y.229.236; 13.Y.229.237; 13.Y.229.238; 13.Y.229.239; 13.Y.229.154;13.Y.229.157; 13.Y.229.166; 13.Y.229.169; 13.Y.229.172; 13.Y.229.175;13.Y.229.240; 13.Y.229.244; 13.Y.230.228; 13.Y.230.229; 13.Y.230.230;13.Y.230.231; 13.Y.230.236; 13.Y.230.237; 13.Y.230.238; 13.Y.230.239;13.Y.230.154; 13.Y.230.157; 13.Y.230.166; 13.Y.230.169; 13.Y.230.172;13.Y.230.175; 13.Y.230.240; 13.Y.230.244; 13.Y.231.228; 13.Y.231.229;13.Y.231.230; 13.Y.231.231; 13.Y.231.236; 13.Y.231.237; 13.Y.231.238;13.Y.231.239; 13.Y.231.154; 13.Y.231.157; 13.Y.231.166; 13.Y.231.169;13.Y.231.172; 13.Y.231.175; 13.Y.231.240; 13.Y.231.244; 13.Y.236.228;13.Y.236.229; 13.Y.236.230; 13.Y.236.231; 13.Y.236.236; 13.Y.236.237;13.Y.236.238; 13.Y.236.239; 13.Y.236.154; 13.Y.236.157; 13.Y.236.166;13.Y.236.169; 13.Y.236.172; 13.Y.236.175; 13.Y.236.240; 13.Y.236.244;13.Y.237.228; 13.Y.237.229; 13.Y.237.230; 13.Y.237.231; 13.Y.237.236;13.Y.237.237; 13.Y.237.238; 13.Y.237.239; 13.Y.237.154; 13.Y.237.157;13.Y.237.166; 13.Y.237.169; 13.Y.237.172; 13.Y.237.175; 13.Y.237.240;13.Y.237.244; 13.Y.238.228; 13.Y.238.229; 13.Y.238.230; 13.Y.238.231;13.Y.238.236; 13.Y.238.237; 13.Y.238.238; 13.Y.238.239; 13.Y.238.154;13.Y.238.157; 13.Y.238.166; 13.Y.238.169; 13.Y.238.172; 13.Y.238.175;13.Y.238.240; 13.Y.238.244; 13.Y.239.228; 13.Y.239.229; 13.Y.239.230;13.Y.239.231; 13.Y.239.236; 13.Y.239.237; 13.Y.239.238; 13.Y.239.239;13.Y.239.154; 13.Y.239.157; 13.Y.239.166; 13.Y.239.169; 13.Y.239.172;13.Y.239.175; 13.Y.239.240; 13.Y.239.244; 13.Y.154.228; 13.Y.154.229;13.Y.154.230; 13.Y.154.231; 13.Y.154.236; 13.Y.154.237; 13.Y.154.238;13.Y.154.239; 13.Y.154.154; 13.Y.154.157; 13.Y.154.166; 13.Y.154.169;13.Y.154.172; 13.Y.154.175; 13.Y.154.240; 13.Y.154.244; 13.Y.157.228;13.Y.157.229; 13.Y.157.230; 13.Y.157.231; 13.Y.157.236; 13.Y.157.237;13.Y.157.238; 13.Y.157.239; 13.Y.157.154; 13.Y.157.157; 13.Y.157.166;13.Y.157.169; 13.Y.157.172; 13.Y.157.175; 13.Y.157.240; 13.Y.157.244;13.Y.166.228; 13.Y.166.229; 13.Y.166.230; 13.Y.166.231; 13.Y.166.236;13.Y.166.237; 13.Y.166.238; 13.Y.166.239; 13.Y.166.154; 13.Y.166.157;13.Y.166.166; 13.Y.166.169; 13.Y.166.172; 13.Y.166.175; 13.Y.166.240;13.Y.166.244; 13.Y.169.228; 13.Y.169.229; 13.Y.169.230; 13.Y.169.231;13.Y.169.236; 13.Y.169.237; 13.Y.169.238; 13.Y.169.239; 13.Y.169.154;13.Y.169.157; 13.Y.169.166; 13.Y.169.169; 13.Y.169.172; 13.Y.169.175;13.Y.169.240; 13.Y.169.244; 13.Y.172.228; 13.Y.172.229; 13.Y.172.230;13.Y.172.231; 13.Y.172.236; 13.Y.172.237; 13.Y.172.238; 13.Y.172.239;13.Y.172.154; 13.Y.172.157; 13.Y.172.166; 13.Y.172.169; 13.Y.172.172;13.Y.172.175; 13.Y.172.240; 13.Y.172.244; 13.Y.175.228; 13.Y.175.229;13.Y.175.230; 13.Y.175.231; 13.Y.175.236; 13.Y.175.237; 13.Y.175.238;13.Y.175.239; 13.Y.175.154; 13.Y.175.157; 13.Y.175.166; 13.Y.175.169;13.Y.175.172; 13.Y.175.175; 13.Y.175.240; 13.Y.175.244; 13.Y.240.228;13.Y.240.229; 13.Y.240.230; 13.Y.240.231; 13.Y.240.236; 13.Y.240.237; 13.Y.240.238;13.Y.240.239; 13.Y.240.154; 13.Y.240.157; 13.Y.240.166; 13.Y.240.169;13.Y.240.172; 13.Y.240.175; 13.Y.240.240; 13.Y.240.244; 13.Y.244.228;13.Y.244.229; 13.Y.244.230; 13.Y.244.231; 13.Y.244.236; 13.Y.244.237;13.Y.244.238; 13.Y.244.239; 13.Y.244.154; 13.Y.244.157; 13.Y.244.166;13.Y.244.169; 13.Y.244.172; 13.Y.244.175; 13.Y.244.240; 13.Y.244.244;

14.AHのプロドラッグ
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のプロドラッグ
14.AJ.4.157; 14.AJ.4.158; 14.AJ.4.196; 14.AJ.4.223; 14.AJ.4.240; 14.AJ.4.244;14.AJ.4.243; 14.AJ.4.247; 14.AJ.5.157; 14.AJ.5.158; 14.AJ.5.196; 14.AJ.5.223;14.AJ.5.240; 14.AJ.5.244; 14.AJ.5.243; 14.AJ.5.247; 14.AJ.7.157; 14.AJ.7.158;14.AJ.7.196; 14.AJ.7.223; 14.AJ.7.240; 14.AJ.7.244; 14.AJ.7.243; 14.AJ.7.247;14.AJ.15.157; 14.AJ.15.158; 14.AJ.15.196; 14.AJ.15.223; 14.AJ.15.240;14.AJ.15.244; 14.AJ.15.243; 14.AJ.15.247; 14.AJ.16.157; 14.AJ.16.158;14.AJ.16.196; 14.AJ.16.223; 14.AJ.16.240; 14.AJ.16.244; 14.AJ.16.243;14.AJ.16.247; 14.AJ.18.157; 14.AJ.18.158; 14.AJ.18.196; 14.AJ.18.223;14.AJ.18.240; 14.AJ.18.244; 14.AJ.18.243; 14.AJ.18.247; 14.AJ.26.157;14.AJ.26.158; 14.AJ.26.196; 14.AJ.26.223; 14.AJ.26.240; 14.AJ.26.244;14.AJ.26.243; 14.AJ.26.247; 14.AJ.27.157; 14.AJ.27.158; 14.AJ.27.196;14.AJ.27.223; 14.AJ.27.240; 14.AJ.27.244; 14.AJ.27.243; 14.AJ.27.247; 14.AJ.29.157;14.AJ.29.158; 14.AJ.29.196; 14.AJ.29.223; 14.AJ.29.240; 14.AJ.29.244;14.AJ.29.243; 14.AJ.29.247; 14.AJ.54.157; 14.AJ.54.158; 14.AJ.54.196;14.AJ.54.223; 14.AJ.54.240; 14.AJ.54.244; 14.AJ.54.243; 14.AJ.54.247;14.AJ.55.157; 14.AJ.55.158; 14.AJ.55.196; 14.AJ.55.223; 14.AJ.55.240;14.AJ.55.244; 14.AJ.55.243; 14.AJ.55.247; 14.AJ.56.157; 14.AJ.56.158;14.AJ.56.196; 14.AJ.56.223; 14.AJ.56.240; 14.AJ.56.244; 14.AJ.56.243;14.AJ.56.247; 14.AJ.157.157; 14.AJ.157.158; 14.AJ.157.196; 14.AJ.157.223; 14.AJ.157.240;14.AJ.157.244; 14.AJ.157.243; 14.AJ.157.247; 14.AJ.196.157; 14.AJ.196.158;14.AJ.196.196; 14.AJ.196.223; 14.AJ.196.240; 14.AJ.196.244; 14.AJ.196.243;14.AJ.196.247; 14.AJ.223.157; 14.AJ.223.158; 14.AJ.223.196; 14.AJ.223.223;14.AJ.223.240; 14.AJ.223.244; 14.AJ.223.243; 14.AJ.223.247; 14.AJ.240.157;14.AJ.240.158; 14.AJ.240.196; 14.AJ.240.223; 14.AJ.240.240; 14.AJ.240.244;14.AJ.240.243; 14.AJ.240.247; 14.AJ.244.157; 14.AJ.244.158; 14.AJ.244.196;14.AJ.244.223; 14.AJ.244.240; 14.AJ.244.244; 14.AJ.244.243; 14.AJ.244.247;14.AJ.247.157; 14.AJ.247.158; 14.AJ.247.196; 14.AJ.247.223; 14.AJ.247.240;14.AJ.247.244; 14.AJ.247.243; 14.AJ.247.247;

14.ANのプロドラッグ
14.AN.4.157; 14.AN.4.158; 14.AN.4.196; 14.AN.4.223; 14.AN.4.240; 14.AN.4.244;14.AN.4.243; 14.AN.4.247; 14.AN.5.157; 14.AN.5.158; 14.AN.5.196; 14.AN.5.223;14.AN.5.240; 14.AN.5.244; 14.AN.5.243; 14.AN.5.247; 14.AN.7.157; 14.AN.7.158;14.AN.7.196; 14.AN.7.223; 14.AN.7.240; 14.AN.7.244; 14.AN.7.243; 14.AN.7.247;14.AN.15.157; 14.AN.15.158; 14.AN.15.196; 14.AN.15.223; 14.AN.15.240;14.AN.15.244; 14.AN.15.243; 14.AN.15.247; 14.AN.16.157; 14.AN.16.158;14.AN.16.196; 14.AN.16.223; 14.AN.16.240; 14.AN.16.244; 14.AN.16.243;14.AN.16.247; 14.AN.18.157; 14.AN.18.158; 14.AN.18.196; 14.AN.18.223; 14.AN.18.240;14.AN.18.244; 14.AN.18.243; 14.AN.18.247; 14.AN.26.157; 14.AN.26.158;14.AN.26.196; 14.AN.26.223; 14.AN.26.240; 14.AN.26.244; 14.AN.26.243;14.AN.26.247; 14.AN.27.157; 14.AN.27.158; 14.AN.27.196; 14.AN.27.223;14.AN.27.240; 14.AN.27.244; 14.AN.27.243; 14.AN.27.247; 14.AN.29.157;14.AN.29.158; 14.AN.29.196; 14.AN.29.223; 14.AN.29.240; 14.AN.29.244;14.AN.29.243; 14.AN.29.247; 14.AN.54.157; 14.AN.54.158; 14.AN.54.196;14.AN.54.223; 14.AN.54.240; 14.AN.54.244; 14.AN.54.243; 14.AN.54.247;14.AN.55.157; 14.AN.55.158; 14.AN.55.196; 14.AN.55.223; 14.AN.55.240;14.AN.55.244; 14.AN.55.243; 14.AN.55.247; 14.AN.56.157; 14.AN.56.158;14.AN.56.196; 14.AN.56.223; 14.AN.56.240; 14.AN.56.244; 14.AN.56.243;14.AN.56.247; 14.AN.157.157; 14.AN.157.158; 14.AN.157.196; 14.AN.157.223;14.AN.157.240; 14.AN.157.244; 14.AN.157.243; 14.AN.157.247; 14.AN.196.157;14.AN.196.158; 14.AN.196.196; 14.AN.196.223; 14.AN.196.240; 14.AN.196.244;14.AN.196.243; 14.AN.196.247; 14.AN.223.157; 14.AN.223.158; 14.AN.223.196;14.AN.223.223; 14.AN.223.240; 14.AN.223.244; 14.AN.223.243; 14.AN.223.247;14.AN.240.157; 14.AN.240.158; 14.AN.240.196; 14.AN.240.223; 14.AN.240.240;14.AN.240.244; 14.AN.240.243; 14.AN.240.247; 14.AN.244.157; 14.AN.244.158;14.AN.244.196; 14.AN.244.223; 14.AN.244.240; 14.AN.244.244; 14.AN.244.243;14.AN.244.247; 14.AN.247.157; 14.AN.247.158; 14.AN.247.196; 14.AN.247.223;14.AN.247.240; 14.AN.247.244; 14.AN.247.243; 14.AN.247.247;

14.APのプロドラッグ
14.AP.4.157; 14.AP.4.158; 14.AP.4.196; 14.AP.4.223; 14.AP.4.240; 14.AP.4.244; 14.AP.4.243;14.AP.4.247; 14.AP.5.157; 14.AP.5.158; 14.AP.5.196; 14.AP.5.223; 14.AP.5.240;14.AP.5.244; 14.AP.5.243; 14.AP.5.247; 14.AP.7.157; 14.AP.7.158; 14.AP.7.196;14.AP.7.223; 14.AP.7.240; 14.AP.7.244; 14.AP.7.243; 14.AP.7.247; 14.AP.15.157;14.AP.15.158; 14.AP.15.196; 14.AP.15.223; 14.AP.15.240; 14.AP.15.244;14.AP.15.243; 14.AP.15.247; 14.AP.16.157; 14.AP.16.158; 14.AP.16.196;14.AP.16.223; 14.AP.16.240; 14.AP.16.244; 14.AP.16.243; 14.AP.16.247;14.AP.18.157; 14.AP.18.158; 14.AP.18.196; 14.AP.18.223; 14.AP.18.240;14.AP.18.244; 14.AP.18.243; 14.AP.18.247; 14.AP.26.157; 14.AP.26.158;14.AP.26.196; 14.AP.26.223; 14.AP.26.240; 14.AP.26.244; 14.AP.26.243;14.AP.26.247; 14.AP.27.157; 14.AP.27.158; 14.AP.27.196; 14.AP.27.223;14.AP.27.240; 14.AP.27.244; 14.AP.27.243; 14.AP.27.247; 14.AP.29.157;14.AP.29.158; 14.AP.29.196; 14.AP.29.223; 14.AP.29.240; 14.AP.29.244;14.AP.29.243; 14.AP.29.247; 14.AP.54.157; 14.AP.54.158; 14.AP.54.196;14.AP.54.223; 14.AP.54.240; 14.AP.54.244; 14.AP.54.243; 14.AP.54.247; 14.AP.55.157;14.AP.55.158; 14.AP.55.196; 14.AP.55.223; 14.AP.55.240; 14.AP.55.244;14.AP.55.243; 14.AP.55.247; 14.AP.56.157; 14.AP.56.158; 14.AP.56.196;14.AP.56.223; 14.AP.56.240; 14.AP.56.244; 14.AP.56.243; 14.AP.56.247;14.AP.157.157; 14.AP.157.158; 14.AP.157.196; 14.AP.157.223; 14.AP.157.240;14.AP.157.244; 14.AP.157.243; 14.AP.157.247; 14.AP.196.157; 14.AP.196.158;14.AP.196.196; 14.AP.196.223; 14.AP.196.240; 14.AP.196.244; 14.AP.196.243;14.AP.196.247; 14.AP.223.157; 14.AP.223.158; 14.AP.223.196; 14.AP.223.223;14.AP.223.240; 14.AP.223.244; 14.AP.223.243; 14.AP.223.247; 14.AP.240.157;14.AP.240.158; 14.AP.240.196; 14.AP.240.223; 14.AP.240.240; 14.AP.240.244;14.AP.240.243; 14.AP.240.247; 14.AP.244.157; 14.AP.244.158; 14.AP.244.196;14.AP.244.223; 14.AP.244.240; 14.AP.244.244; 14.AP.244.243; 14.AP.244.247;14.AP.247.157; 14.AP.247.158; 14.AP.247.196; 14.AP.247.223; 14.AP.247.240;14.AP.247.244; 14.AP.247.243; 14.AP.247.247;

14.AZのプロドラッグ
14.AZ.4.157; 14.AZ.4.158; 14.AZ.4.196; 14.AZ.4.223; 14.AZ.4.240; 14.AZ.4.244;14.AZ.4.243; 14.AZ.4.247; 14.AZ.5.157; 14.AZ.5.158; 14.AZ.5.196; 14.AZ.5.223;14.AZ.5.240; 14.AZ.5.244; 14.AZ.5.243; 14.AZ.5.247; 14.AZ.7.157; 14.AZ.7.158;14.AZ.7.196; 14.AZ.7.223; 14.AZ.7.240; 14.AZ.7.244; 14.AZ.7.243; 14.AZ.7.247;14.AZ.15.157; 14.AZ.15.158; 14.AZ.15.196; 14.AZ.15.223; 14.AZ.15.240;14.AZ.15.244; 14.AZ.15.243; 14.AZ.15.247; 14.AZ.16.157; 14.AZ.16.158;14.AZ.16.196; 14.AZ.16.223; 14.AZ.16.240; 14.AZ.16.244; 14.AZ.16.243;14.AZ.16.247; 14.AZ.18.157; 14.AZ.18.158; 14.AZ.18.196; 14.AZ.18.223;14.AZ.18.240; 14.AZ.18.244; 14.AZ.18.243; 14.AZ.18.247; 14.AZ.26.157;14.AZ.26.158; 14.AZ.26.196; 14.AZ.26.223; 14.AZ.26.240; 14.AZ.26.244;14.AZ.26.243; 14.AZ.26.247; 14.AZ.27.157; 14.AZ.27.158; 14.AZ.27.196;14.AZ.27.223; 14.AZ.27.240; 14.AZ.27.244; 14.AZ.27.243; 14.AZ.27.247;14.AZ.29.157; 14.AZ.29.158; 14.AZ.29.196; 14.AZ.29.223; 14.AZ.29.240;14.AZ.29.244; 14.AZ.29.243; 14.AZ.29.247; 14.AZ.54.157; 14.AZ.54.158;14.AZ.54.196; 14.AZ.54.223; 14.AZ.54.240; 14.AZ.54.244; 14.AZ.54.243; 14.AZ.54.247;14.AZ.55.157; 14.AZ.55.158; 14.AZ.55.196; 14.AZ.55.223; 14.AZ.55.240;14.AZ.55.244; 14.AZ.55.243; 14.AZ.55.247; 14.AZ.56.157; 14.AZ.56.158;14.AZ.56.196; 14.AZ.56.223; 14.AZ.56.240; 14.AZ.56.244; 14.AZ.56.243;14.AZ.56.247; 14.AZ.157.157; 14.AZ.157.158; 14.AZ.157.196; 14.AZ.157.223;14.AZ.157.240; 14.AZ.157.244; 14.AZ.157.243; 14.AZ.157.247; 14.AZ.196.157;14.AZ.196.158; 14.AZ.196.196; 14.AZ.196.223; 14.AZ.196.240; 14.AZ.196.244;14.AZ.196.243; 14.AZ.196.247; 14.AZ.223.157; 14.AZ.223.158; 14.AZ.223.196;14.AZ.223.223; 14.AZ.223.240; 14.AZ.223.244; 14.AZ.223.243; 14.AZ.223.247;14.AZ.240.157; 14.AZ.240.158; 14.AZ.240.196; 14.AZ.240.223; 14.AZ.240.240;14.AZ.240.244; 14.AZ.240.243; 14.AZ.240.247; 14.AZ.244.157; 14.AZ.244.158;14.AZ.244.196; 14.AZ.244.223; 14.AZ.244.240; 14.AZ.244.244; 14.AZ.244.243;14.AZ.244.247; 14.AZ.247.157; 14.AZ.247.158; 14.AZ.247.196; 14.AZ.247.223;14.AZ.247.240; 14.AZ.247.244; 14.AZ.247.243; 14.AZ.247.247;

14.BFのプロドラッグ
14.BF.4.157; 14.BF.4.158; 14.BF.4.196; 14.BF.4.223; 14.BF.4.240; 14.BF.4.244;14.BF.4.243; 14.BF.4.247; 14.BF.5.157; 14.BF.5.158; 14.BF.5.196; 14.BF.5.223;14.BF.5.240; 14.BF.5.244; 14.BF.5.243; 14.BF.5.247; 14.BF.7.157; 14.BF.7.158;14.BF.7.196; 14.BF.7.223; 14.BF.7.240; 14.BF.7.244; 14.BF.7.243; 14.BF.7.247;14.BF.15.157; 14.BF.15.158; 14.BF.15.196; 14.BF.15.223; 14.BF.15.240;14.BF.15.244; 14.BF.15.243; 14.BF.15.247; 14.BF.16.157; 14.BF.16.158;14.BF.16.196; 14.BF.16.223; 14.BF.16.240; 14.BF.16.244; 14.BF.16.243;14.BF.16.247; 14.BF.18.157; 14.BF.18.158; 14.BF.18.196; 14.BF.18.223;14.BF.18.240; 14.BF.18.244; 14.BF.18.243; 14.BF.18.247; 14.BF.26.157;14.BF.26.158; 14.BF.26.196; 14.BF.26.223; 14.BF.26.240; 14.BF.26.244;14.BF.26.243; 14.BF.26.247; 14.BF.27.157; 14.BF.27.158; 14.BF.27.196;14.BF.27.223; 14.BF.27.240; 14.BF.27.244; 14.BF.27.243; 14.BF.27.247;14.BF.29.157; 14.BF.29.158; 14.BF.29.196; 14.BF.29.223; 14.BF.29.240;14.BF.29.244; 14.BF.29.243; 14.BF.29.247; 14.BF.54.157; 14.BF.54.158;14.BF.54.196; 14.BF.54.223; 14.BF.54.240; 14.BF.54.244; 14.BF.54.243;14.BF.54.247; 14.BF.55.157; 14.BF.55.158; 14.BF.55.196; 14.BF.55.223;14.BF.55.240; 14.BF.55.244; 14.BF.55.243; 14.BF.55.247; 14.BF.56.157;14.BF.56.158; 14.BF.56.196; 14.BF.56.223; 14.BF.56.240; 14.BF.56.244;14.BF.56.243; 14.BF.56.247; 14.BF.157.157; 14.BF.157.158; 14.BF.157.196;14.BF.157.223; 14.BF.157.240; 14.BF.157.244; 14.BF.157.243; 14.BF.157.247;14.BF.196.157; 14.BF.196.158; 14.BF.196.196; 14.BF.196.223; 14.BF.196.240;14.BF.196.244; 14.BF.196.243; 14.BF.196.247; 14.BF.223.157; 14.BF.223.158;14.BF.223.196; 14.BF.223.223; 14.BF.223.240; 14.BF.223.244; 14.BF.223.243;14.BF.223.247; 14.BF.240.157; 14.BF.240.158; 14.BF.240.196; 14.BF.240.223;14.BF.240.240; 14.BF.240.244; 14.BF.240.243; 14.BF.240.247; 14.BF.244.157;14.BF.244.158; 14.BF.244.196; 14.BF.244.223; 14.BF.244.240; 14.BF.244.244;14.BF.244.243; 14.BF.244.247; 14.BF.247.157; 14.BF.247.158; 14.BF.247.196;14.BF.247.223; 14.BF.247.240; 14.BF.247.244; 14.BF.247.243; 14.BF.247.247;

14.CIのプロドラッグ
14.CI.4.157; 14.CI.4.158; 14.CI.4.196; 14.CI.4.223; 14.CI.4.240; 14.CI.4.244;14.CI.4.243; 14.CI.4.247; 14.CI.5.157; 14.CI.5.158; 14.CI.5.196; 14.CI.5.223;14.CI.5.240; 14.CI.5.244; 14.CI.5.243; 14.CI.5.247; 14.CI.7.157; 14.CI.7.158;14.CI.7.196; 14.CI.7.223; 14.CI.7.240; 14.CI.7.244; 14.CI.7.243; 14.CI.7.247;14.CI.15.157; 14.CI.15.158; 14.CI.15.196; 14.CI.15.223; 14.CI.15.240;14.CI.15.244; 14.CI.15.243; 14.CI.15.247; 14.CI.16.157; 14.CI.16.158;14.CI.16.196; 14.CI.16.223; 14.CI.16.240; 14.CI.16.244; 14.CI.16.243;14.CI.16.247; 14.CI.18.157; 14.CI.18.158; 14.CI.18.196; 14.CI.18.223;14.CI.18.240; 14.CI.18.244; 14.CI.18.243; 14.CI.18.247; 14.CI.26.157;14.CI.26.158; 14.CI.26.196; 14.CI.26.223; 14.CI.26.240; 14.CI.26.244;14.CI.26.243; 14.CI.26.247; 14.CI.27.157; 14.CI.27.158; 14.CI.27.196; 14.CI.27.223;14.CI.27.240; 14.CI.27.244; 14.CI.27.243; 14.CI.27.247; 14.CI.29.157;14.CI.29.158; 14.CI.29.196; 14.CI.29.223; 14.CI.29.240; 14.CI.29.244;14.CI.29.243; 14.CI.29.247; 14.CI.54.157; 14.CI.54.158; 14.CI.54.196;14.CI.54.223; 14.CI.54.240; 14.CI.54.244; 14.CI.54.243; 14.CI.54.247;14.CI.55.157; 14.CI.55.158; 14.CI.55.196; 14.CI.55.223; 14.CI.55.240;14.CI.55.244; 14.CI.55.243; 14.CI.55.247; 14.CI.56.157; 14.CI.56.158;14.CI.56.196; 14.CI.56.223; 14.CI.56.240; 14.CI.56.244; 14.CI.56.243;14.CI.56.247; 14.CI.157.157; 14.CI.157.158; 14.CI.157.196; 14.CI.157.223;14.CI.157.240; 14.CI.157.244; 14.CI.157.243; 14.CI.157.247; 14.CI.196.157;14.CI.196.158; 14.CI.196.196; 14.CI.196.223; 14.CI.196.240; 14.CI.196.244;14.CI.196.243; 14.CI.196.247; 14.CI.223.157; 14.CI.223.158; 14.CI.223.196;14.CI.223.223; 14.CI.223.240; 14.CI.223.244; 14.CI.223.243; 14.CI.223.247;14.CI.240.157; 14.CI.240.158; 14.CI.240.196; 14.CI.240.223; 14.CI.240.240;14.CI.240.244; 14.CI.240.243; 14.CI.240.247; 14.CI.244.157; 14.CI.244.158; 14.CI.244.196;14.CI.244.223; 14.CI.244.240; 14.CI.244.244; 14.CI.244.243; 14.CI.244.247;14.CI.247.157; 14.CI.247.158; 14.CI.247.196; 14.CI.247.223; 14.CI.247.240;14.CI.247.244; 14.CI.247.243; 14.CI.247.247;

14.COのプロドラッグ
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。

(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. D.231.166; 1.D.231.169; 1.D.231.172; 1.D.231.175; 1.D.231.240; 1.D.231.244; 1.D.236.228; 1.D.236.229; 1.D. 236.230; 1.D.236.231; 1.D.236.236; 1.D.236.237; 1.D.236.238; 1.D.236.239; 1.D.236.154; 1.D.236.157; 1.D.236.166; 1.D.236.169; 1.D.236.172; 1.D.236.175; 1.D.236.240; 1.D.236.244; 1.D.237.228; 1.D.237.229; 1.D.237.230; 1.D.237.231; 1.D.237.236; 1.D.237.237; 1. D.237.238; 1.D.237.239; 1.D.237.154; 1.D.237.157; 1.D.237.166; 1.D.237.169; 1.D.237.172; 1.D.237.175; 1.D. 237.240; 1.D.237.244; 1.D.238.228; 1.D.238.229; 1.D.238.230; 1.D.238.231; 1.D.238.236; 1.D.238.237; 1.D.238.238; 1.D.238.239; 1.D.238.154; 1.D.238.157; 1.D.238.166; 1.D.238.169; 1.D.238.172; 1.D.238.175; 1.D.238.240; 1. D.238.244; 1.D.239.228; 1.D.239.229; 1.D.239.230; 1.D.239.231; 1.D.239.236; 1.D.239.237; 1.D.239.238; 1.D. 239.239; 1.D.239.154; 1.D.239.157; 1.D.239.166; 1.D.239.169; 1.D.239.172; 1.D.239.175; 1.D.239.240; 1.D.239.244; 1.D.154.228; 1.D.154.229; 1.D.154.230; 1.D.154.231; 1.D.154.236; 1.D.154.237; 1.D.154.238; 1.D.154.239; 1. D.154.154; 1.D.154.157; 1.D.154.166; 1.D.154.169; 1.D.154.172; 1.D.154.175; 1.D.154.240; 1.D.154.244; 1.D. 157.228; 1.D.157.229; 1.D.157.230; 1.D.157.231; 1.D.157.236; 1.D.157.237; 1.D.157.238; 1.D.157.239; 1.D.157.154; 1.D.157.157; 1.D.157.166; 1.D.157.169 1.D.157.172; 1.D.157.175; 1.D.157.240; 1.D.157.244; 1.D.166.228; 1.D.166.229; 1.D.166.230; 1.D.166.231; 1 .D.166.236; 1.D.166.237; 1.D.166.238; 1.D.166.239; 1.D.166.154; 1.D.166.157; 1.D.166.166; 1.D.166.169; 1.D 1.166.172; 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.240.15 7; 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. 1.E.230.230; 1.E.230.231; 1.E.230.236; 1.E.230.237; 1.E.230.238; 1.E.230.239; 1.E.230.154; 1.E. 230.157; 1.E.230.166; 1.E.230.169; 1.E.230.172; 1.E.230.175; 1.E.230.240; 1.E.230.244; 1.E.231.228; 1.E.231.229; 1.E.231.230; 1.E.231.231; 1.E.231.236; 1.E.231.237; 1.E.231.238; 1.E.231.239; 1.E.231.154; 1.E.231.157; 1. E.231.166; 1.E.231.169; 1.E.231.172; 1.E.231.175; 1.E.231.240; 1.E.231.244; 1.E.236.228; 1.E.236.229; 1.E. 236.230; 1.E.236.231; 1.E.236.236; 1.E.236.237; 1.E.236.238; 1.E.236.239; 1.E.236.154; 1.E.236.157; 1.E.236.166; 1.E.236.169; 1.E.236.172; 1.E.236.175 ; 1.E.236.240; 1.E.236.244; 1.E.237.228; 1.E.237.229; 1.E.237.230; 1.E.237.231; 1.E.237.236; 1.E.237.237; 1 .E.237.238; 1.E.237.239; 1.E.237.154; 1.E.237.157; 1.E.237.166; 1.E.237.169; 1.E.237.172; 1.E.237.175; 1.E .237.240; 1.E.237.244; 1.E.238.228; 1.E.238.229; 1.E.238.230; 1.E.238.231; 1.E.238.236; 1.E.238.237; 1.E.238.238 1.E.238.239; 1.E.238.154; 1.E.238.157; 1.E.238.166; 1.E.238.169; 1.E.238.172; 1.E.238.175; 1.E.238.240; 1 .E.238.244; 1.E.239.228; 1.E.239.229; 1.E.239.230; 1.E.239.231; 1.E.239.236; 1.E.239.237; 1.E.239.238; 1.E .239.239; 1.E.239.154; 1.E.239.157; 1.E.239.166; 1.E.239.169; 1.E.239.172; 1.E.239.175; 1.E.239.240; 1.E.239.244 1.E.154.228; 1.E.154.229; 1.E.154.230; 1.E.154.231; 1.E.154.236; 1.E.154.237; 1.E.154.238; 1.E.154.239; 1 .E.154.154; 1.E.154.157; 1.E.154.166; 1.E.154.169; 1.E.154.172; 1.E.154.175; 1.E.154.240; 1.E.154.244; 1.E .157.228; 1.E.157.229; 1.E.157.230; 1.E.157.231; 1.E.157.236; 1.E.157.237; 1.E.157.238; 1.E.157.239; 1.E.157.154 ; 1.E.157.157; 1.E.157.166; 1.E.157.16 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. 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 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 .I.238.244; 1.I.239.228; 1.I.239.229; 1.I.239.230; 1.I.239.231; 1.I.239.236; 1.I.239.237; 1.I.239.238; 1.I .239.239; 1.I.239.154; 1.I.239.157; 1.I.239.166; 1.I.239.169; 1.I.239.172; 1.I.239.175; 1.I.239.240; 1.I.239.244 1.I.154.228; 1.I.154.229; 1.I.154.230; 1.I.154.231; 1.I.154.236; 1.I.154.237; 1.I.154.238; 1.I.154.239; 1 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 1.157.228; 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.157.16 9; 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.240.1 57; 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. 1.U.228.157; 1.U.228.166; 1.U.228.169; 1.U.228.172; 1.U.228.175; 1.U.228.240; 1.U.228.244; 1.U. 229.228; 1.U.229.229; 1.U.229.230; 1.U.229.231; 1.U.229.236; 1.U.229.237; 1.U.229.238; 1.U.229.239; 1.U.229.154; 1.U.229.157; 1.U.229.166; 1.U.229.169; 1.U.229.172; 1.U.229.175; 1.U.229.240; 1.U.229.244; 1.U.230.228; 1. U.230.229; 1.U.230.230; 1.U.230.231; 1.U.230.236; 1.U.230.237; 1.U.230.238; 1.U.230.239; 1.U.230.154; 1.U. 230.157; 1.U.230.166; 1.U.230.169; 1.U.230.172; 1.U.230.175; 1.U.230.240; 1.U.230.244; 1.U.231.228; 1.U.231.229; 1.U.231.230; 1.U.231.231; 1.U.231.236; 1.U.231.237; 1.U.231.238; 1.U.231.239; 1.U.231.154; 1.U.231.157; 1. U.231.166; 1.U.231.169; 1.U.231.172; 1.U.231.175; 1.U.231.240; 1.U.231.244; 1.U.236.228; 1.U.236.229; 1.U. 236.230; 1.U.236.231; 1.U.236.236; 1.U.236.237; 1.U.236.238; 1.U.236.239; 1.U.236.154; 1.U.236.157; 1.U.236.166; 1.U.236.169; 1.U.236.172; 1.U.236.175; 1.U.236.240; 1.U.236.244; 1.U.237.228; 1.U.237.229; 1.U.237.230; 1.U.237.231; 1.U.237.236; 1.U.237.237; 1. U.237.238; 1.U.237.239; 1.U.237.154; 1.U.237.157; 1.U.237.166; 1.U.237.169; 1.U.237.172; 1.U.237.175; 1.U. 237.240; 1.U.237.244; 1.U.238.228; 1.U.238.229; 1.U.238.230; 1.U.238.231; 1.U.238.236; 1.U.238.237; 1.U.238.238; 1.U.238.239; 1.U.238.154; 1.U.238.157; 1.U.238.166; 1.U.238.169; 1.U.238.172; 1.U.238.175; 1.U.238.240; 1. U.238.244; 1.U.239.228; 1.U.239.229; 1.U.239.230; 1.U.239.231; 1.U.239.236; 1.U.239.237; 1.U.239.238; 1.U. 239.239; 1.U.239.154; 1.U.239.157; 1.U.239.166; 1.U.239.169; 1.U.239.172; 1.U.239.175; 1.U.239.240; 1.U.239.244; 1.U.154.228; 1.U.154.229; 1.U.154.230; 1.U.154.231; 1.U.154.236; 1.U.154.237; 1.U.154.238; 1.U.154.239; 1. U.154.154; 1.U.154.157; 1.U.154.166; 1.U.154.169; 1.U.154.172; 1.U.154.175; 1.U.154.240; 1.U.154.244; 1.U. 157.228; 1.U.157.229; 1.U.157.230; 1.U.157.231; 1.U.157.236; 1.U.157.237; 1.U.157.238; 1.U.157.239; 1.U.157.154; 1.U.157.157; 1.U.157.166; 1.U.157.169 1.U.157.172; 1.U.157.175; 1.U.157.240; 1.U.157.244; 1.U.166.228; 1.U.166.229; 1.U.166.230; 1.U.166.231; 1 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 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 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.240.15 7; 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. W.175.240; 1.W.175.244; 1.W.240.228; 1.W.240.229; 1.W.240.230; 1.W.240.231; 1.W.240.236; 1.W.240.237; 1.W. 240.238; 1.W.240.239; 1.W.240.154; 1.W.240.1 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 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 2.157.228; 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 .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.244.228; 3.E.244.229; 3.E.244.230; 3.E.244.231; 3.E.244.236; 3.E.244.237; 3.E.244.238; 3.E.244.239; 3.E.244.154; 3.E.244.157; 3. E.244.166; 3.E.244.169; 3.E.244.172; 3.E.244.175; 3.E.244.240; 3.E.244.244;

3.G prodrug
3.G.228.228; 3.G.228.229; 3.G.228.230; 3.G.228.231; 3.G.228.236; 3.G.228.237; 3.G.228.238; 3.G.228.239; 3. G.228.154; 3.G.228.157; 3.G.228.166; 3.G.228.169; 3.G.228.172; 3.G.228.175; 3.G.228.240; 3.G.228.244; 3.G. 229.228; 3.G.229.229; 3.G.229.230; 3.G.229.231; 3.G.229.236; 3.G.229.237; 3.G.229.238; 3.G.229.239; 3.G.229.154; 3.G.229.157; 3.G.229.166; 3.G.229.169; 3.G.229.172; 3.G.229.175; 3.G.229.240; 3.G.229.244; 3.G.230.228; 3. G.230.229; 3.G.230.230; 3.G.230.231; 3.G.230.236; 3.G.230.237; 3.G.230.238; 3.G.230.239; 3.G.230.154; 3.G. 230.157; 3.G.230.166; 3.G.230.169; 3.G.230.172; 3.G.230.175; 3.G.230.240; 3.G.230.244; 3.G.231.228; 3.G.231.229; 3.G.231.230; 3.G.231.231; 3.G.231.236; 3.G.231.237; 3.G.231.238; 3.G.231.239; 3.G.231.154; 3.G.231.157; 3. G.231.166; 3.G.231.169; 3.G.231.172; 3.G.231.175; 3.G.231.240; 3.G.231.244; 3.G.236.228; 3.G.236.229; 3.G. 236.230; 3.G.236.231; 3.G.236.236; 3.G.236.237; 3.G.236.238; 3.G.236.239; 3.G.236.154; 3.G.236.157; 3.G.236.166; 3.G.236.169; 3.G.236.172; 3.G.236.175 ; 3.G.236.240; 3.G.236.244; 3.G.237.228; 3.G.237.229; 3.G.237.230; 3.G.237.231; 3.G.237.236; 3.G.237.237; 3 .G.237.238; 3.G.237.239; 3.G.237.154; 3.G.237.157; 3.G.237.166; 3.G.237.169; 3.G.237.172; 3.G.237.175; 3.G .237.240; 3.G.237.244; 3.G.238.228; 3.G.238.229; 3.G.238.230; 3.G.238.231; 3.G.238.236; 3.G.238.237; 3.G.238.238 3.G.238.239; 3.G.238.154; 3.G.238.157; 3.G.238.166; 3.G.238.169; 3.G.238.172; 3.G.238.175; 3.G.238.240; 3 .G.238.244; 3.G.239.228; 3.G.239.229; 3.G.239.230; 3.G.239.231; 3.G.239.236; 3.G.239.237; 3.G.239.238; 3.G .239.239; 3.G.239.154; 3.G.239.157; 3.G.239.166; 3.G.239.169; 3.G.239.172; 3.G.239.175; 3.G.239.240; 3.G.239.244 ; 3.G.154.228; 3.G.154.229; 3.G.154.230; 3.G.154.231; 3.G.154.236; 3.G.154.237; 3.G.154.238; 3.G.154.239; 3 .G.154.154; 3.G.154.157; 3.G.154.166; 3.G.154.169; 3.G.154.172; 3.G.154.175; 3.G.154.240; 3.G.154.244; 3.G .157.228; 3.G.157.229; 3.G.157.230; 3.G.157.231; 3.G.157.236; 3.G.157.237; 3.G.157.238; 3.G.157.239; 3.G.157.154 ; 3.G.157.157; 3.G.157.166; 3.G.157.16 9; 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.240.1 57; 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. I.231.166; 3.I.231.169; 3.I.231.172; 3.I.231.175; 3.I.231.240; 3.I.231.244; 3.I.236.228; 3.I.236.229; 3.I. 236.230; 3.I.236.231; 3.I.236.236; 3.I.236.237; 3.I.236.238; 3.I.236.239; 3.I.236.154; 3.I.236.157; 3.I.236.166; 3.I.236.169; 3.I.236.172; 3.I.236.175; 3.I.236.240; 3.I.236.244; 3.I.237.228; 3.I.237.229; 3.I.237.230; 3.I.237.231; 3.I.237.236; 3.I.237.237; 3. I.237.238; 3.I.237.239; 3.I.237.154; 3.I.237.157; 3.I.237.166; 3.I.237.169; 3.I.237.172; 3.I.237.175; 3.I. 237.240; 3.I.237.244; 3.I.238.228; 3.I.238.229; 3.I.238.230; 3.I.238.231; 3.I.238.236; 3.I.238.237; 3.I.238.238; 3.I.238.239; 3.I.238.154; 3.I.238.157; 3.I.238.166; 3.I.238.169; 3.I.238.172; 3.I.238.175; 3.I.238.240; 3. I.238.244; 3.I.239.228; 3.I.239.229; 3.I.239.230; 3.I.239.231; 3.I.239.236; 3.I.239.237; 3.I.239.238; 3.I. 239.239; 3.I.239.154; 3.I.239.157; 3.I.239.166; 3.I.239.169; 3.I.239.172; 3.I.239.175; 3.I.239.240; 3.I.239.244; 3.I.154.228; 3.I.154.229; 3.I.154.230; 3.I.154.231; 3.I.154.236; 3.I.154.237; 3.I.154.238; 3.I.154.239; 3. I.154.154; 3.I.154.157; 3.I.154.166; 3.I.154.169; 3.I.154.172; 3.I.154.175; 3.I.154.240; 3.I.154.244; 3.I. 157.228; 3.I.157.229; 3.I.157.230; 3.I.157.231; 3.I.157.236; 3.I.157.237; 3.I.157.238; 3.I.157.239; 3.I.157.154; 3.I.157.157; 3.I.157.166; 3.I.157.169 ; 3.I.157.172; 3.I.157.175; 3.I.157.240; 3.I.157.244; 3.I.166.228; 3.I.166.229; 3.I.166.230; 3.I.166.231; 3 .I.166.236; 3.I.166.237; 3.I.166.238; 3.I.166.239; 3.I.166.154; 3.I.166.157; 3.I.166.166; 3.I.166.169; 3.I .166.172; 3.I.166.175; 3.I.166.240; 3.I.166.244; 3.I.169.228; 3.I.169.229; 3.I.169.230; 3.I.169.231; 3.I.169.236 ; 3.I.169.237; 3.I.169.238; 3.I.169.239; 3.I.169.154; 3.I.169.157; 3.I.169.166; 3.I.169.169; 3.I.169.172; 3 .I.169.175; 3.I.169.240; 3.I.169.244; 3.I.172.228; 3.I.172.229; 3.I.172.230; 3.I.172.231; 3.I.172.236; 3.I .172.237; 3.I.172.238; 3.I.172.239; 3.I.172.154; 3.I.172.157; 3.I.172.166; 3.I.172.169; 3.I.172.172; 3.I.172.175 3.I.172.240; 3.I.172.244; 3.I.175.228; 3.I.175.229; 3.I.175.230; 3.I.175.231; 3.I.175.236; 3.I.175.237; 3 .I.175.238; 3.I.175.239; 3.I.175.154; 3.I.175.157; 3.I.175.166; 3.I.175.169; 3.I.175.172; 3.I.175.175; 3.I .175.240; 3.I.175.244; 3.I.240.228; 3.I.240.229; 3.I.240.230; 3.I.240.231; 3.I.240.236; 3.I.240.237; 3.I.240.238 ; 3.I.240.239; 3.I.240.154; 3.I.240.15 7; 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.157.169 4.E.157.172; 4.E.157.175; 4.E.157.240; 4.E.157.244; 4.E.166.228; 4.E.166.229; 4.E.166.230; 4.E.166.231; 4 .E.166.236; 4.E.166.237; 4.E.166.238; 4.E.166.239; 4.E.166.154; 4.E.166.157; 4.E.166.166; 4.E.166.169; 4.E .166.172; 4.E.166.175; 4.E.166.240; 4.E.166.244; 4.E.169.228; 4.E.169.229; 4.E.169.230; 4.E.169.231; 4.E.169.236 ; 4.E.169.237; 4.E.169.238; 4.E.169.239; 4.E.169.154; 4.E.169.157; 4.E.169.166; 4.E.169.169; 4.E.169.172; 4 .E.169.175; 4.E.169.240; 4.E.169.244; 4.E.172.228; 4.E.172.229; 4.E.172.230; 4.E.172.231; 4.E.172.236; 4.E .172.237; 4.E.172.238; 4.E.172.239; 4.E.172.154; 4.E.172.157; 4.E.172.166; 4.E.172.169; 4.E.172.172; 4.E.172.175 4.E.172.240; 4.E.172.244; 4.E.175.228; 4.E.175.229; 4.E.175.230; 4.E.175.231; 4.E.175.236; 4.E.175.237; 4 .E.175.238; 4.E.175.239; 4.E.175.154; 4.E.175.157; 4.E.175.166; 4.E.175.169; 4.E.175.172; 4.E.175.175; 4.E .175.240; 4.E.175.244; 4.E.240.228; 4.E.240.229; 4.E.240.230; 4.E.240.231; 4.E.240.236; 4.E.240.237; 4.E.240.238 ; 4.E.240.239; 4.E.240.154; 4.E.240.15 7; 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.169.228; 4.O.169.229; 4.O.169.230; 4.O.169.231; 4.O. 169.236; 4.O.169.237; 4.O.169.238; 4.O.169.239; 4.O.169.154; 4.O.169.157; 4.O.169.166; 4.O.169.169; 4.O.169.172; 4.O.169.175; 4.O.169.240; 4.O.169.244; 4.O.172.228; 4.O.172.229; 4.O.172.230; 4.O.172.231; 4.O.172.236; 4. O.172.237; 4.O.172.238; 4.O.172.239; 4.O.172.154; 4.O.172.157; 4.O.172.166; 4.O.172.169; 4.O.172.172; 4.O. 172.175; 4.O.172.240; 4.O.172.244; 4.O.175.228; 4.O.175.229; 4.O.175.230; 4.O.175.231; 4.O.175.236; 4.O.175.237; 4.O.175.238; 4.O.175.239; 4.O.175.154; 4.O.175.157; 4.O.175.166; 4.O.175.169; 4.O.175.172; 4.O.175.175; 4. O.175.240; 4.O.175.244; 4.O.240.228; 4.O.240.229; 4.O.240.230; 4.O.240.231; 4.O.240.236; 4.O.240.237; 4.O. 240.238; 4.O.240.239; 4.O.240.154; 4.O.240.1 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.157.16 9; 5.P.157.172; 5.P.157.175; 5.P.157.240; 5.P.157.244; 5.P.166.228; 5.P.166.229; 5.P.166.230; 5.P.166.231; 5.P.166.236; 5.P.166.237; 5.P.166.238; 5.P.166.239; 5.P.166.154; 5.P.166.157; 5.P.166.166; 5.P.166.169; 5. P.166.172; 5.P.166.175; 5.P.166.240; 5.P.166.244; 5.P.169.228; 5.P.169.229; 5.P.169.230; 5.P.169.231; 5.P. 169.236; 5.P.169.237; 5.P.169.238; 5.P.169.239; 5.P.169.154; 5.P.169.157; 5.P.169.166; 5.P.169.169; 5.P.169.172; 5.P.169.175; 5.P.169.240; 5.P.169.244; 5.P.172.228; 5.P.172.229; 5.P.172.230; 5.P.172.231; 5.P.172.236; 5. P.172.237; 5.P.172.238; 5.P.172.239; 5.P.172.154; 5.P.172.157; 5.P.172.166; 5.P.172.169; 5.P.172.172; 5.P. 172.175; 5.P.172.240; 5.P.172.244; 5.P.175.228; 5.P.175.229; 5.P.175.230; 5.P.175.231; 5.P.175.236; 5.P.175.237; 5.P.175.238; 5.P.175.239; 5.P.175.154; 5.P.175.157; 5.P.175.166; 5.P.175.169; 5.P.175.172; 5.P.175.175; 5. P.175.240; 5.P.175.244; 5.P.240.228; 5.P.240.229; 5.P.240.230; 5.P.240.231; 5.P.240.236; 5.P.240.237; 5.P. 240.238; 5.P.240.239; 5.P.240.154; 5.P.240.1 57; 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; 5U.157.239; 5.U.157.154; 5.U.157.157; 5.U.157.166; 5.U.157.169 ; 5.U.157.172; 5.U.157.175; 5.U.157.240; 5.U.157.244; 5.U.166.228; 5.U.166.229; 5.U.166.230; 5.U.166.231; 5 .U.166.236; 5.U.166.237; 5.U.166.238; 5.U.166.239; 5.U.166.154; 5.U.166.157; 5.U.166.166; 5.U.166.169; 5.U .166.172; 5.U.166.175; 5.U.166.240; 5.U.166.244; 5.U.169.228; 5.U.169.229; 5.U.169.230; 5.U.169.231; 5.U.169.236 ; 5.U.169.237; 5.U.169.238; 5.U.169.239; 5.U.169.154; 5.U.169.157; 5.U.169.166; 5.U.169.169; 5.U.169.172; 5 .U.169.175; 5.U.169.240; 5.U.169.244; 5.U.172.228; 5.U.172.229; 5.U.172.230; 5.U.172.231; 5.U.172.236; 5.U .172.237; 5.U.172.238; 5.U.172.239; 5.U.172.154; 5.U.172.157; 5.U.172.166; 5.U.172.169; 5.U.172.172; 5.U.172.175 5.U.172.240; 5.U.172.244; 5.U.175.228; 5.U.175.229; 5.U.175.230; 5.U.175.231; 5.U.175.236; 5.U.175.237; 5 .U.175.238; 5.U.175.239; 5.U.175.154; 5.U.175.157; 5.U.175.166; 5.U.175.169; 5.U.175.172; 5.U.175.175; 5.U .175.240; 5.U.175.244; 5.U.240.228; 5.U.240.229; 5.U.240.230; 5.U.240.231; 5.U.240.236; 5.U.240.237; 5.U.240.238 ; 5.U.240.239; 5.U.240.154; 5.U.240.15 7; 5.U.240.166; 5.U.240.169; 5.U.240.172; 5.U.240.175; 5.U.240.240; 5.U.240.244; 5.U.244.228; 5.U.244.229; 5.U.244.230; 5.U.244.231; 5.U.244.236; 5.U.244.237; 5.U.244.238; 5.U.244.239; 5.U.244.154; 5.U.244.157; 5. U.244.166; 5.U.244.169; 5.U.244.172; 5.U.244.175; 5.U.244.240; 5.U.244.244;

5.W prodrug
5.W.228.228; 5.W.228.229; 5.W.228.230; 5.W.228.231; 5.W.228.236; 5.W.228.237; 5.W.228.238; 5.W.228.239; 5. W.228.154; 5.W.228.157; 5.W.228.166; 5.W.228.169; 5.W.228.172; 5.W.228.175; 5.W.228.240; 5.W.228.244; 5.W. 229.228; 5.W.229.229; 5.W.229.230; 5.W.229.231; 5.W.229.236; 5.W.229.237; 5.W.229.238; 5.W.229.239; 5.W.229.154; 5.W.229.157; 5.W.229.166; 5.W.229.169; 5.W.229.172; 5.W.229.175; 5.W.229.240; 5.W.229.244; 5.W.230.228; 5. W.230.229; 5.W.230.230; 5.W.230.231; 5.W.230.236; 5.W.230.237; 5.W.230.238; 5.W.230.239; 5.W.230.154; 5.W. 230.157; 5.W.230.166; 5.W.230.169; 5.W.230.172; 5.W.230.175; 5.W.230.240; 5.W.230.244; 5.W.231.228; 5.W.231.229; 5.W.231.230; 5.W.231.231; 5.W.231.236; 5.W.231.237; 5.W.231.238; 5.W.231.239; 5.W.231.154; 5.W.231.157; 5. W.231.166; 5.W.231.169; 5.W.231.172; 5.W.231.175; 5.W.231.240; 5.W.231.244; 5.W.236.228; 5.W.236.229; 5.W. 236.230; 5.W.236.231; 5.W.236.236; 5.W.236.237; 5.W.236.238; 5.W.236.239; 5.W.236.154; 5.W.236.157; 5.W.236.166; 5.W.236.169; 5.W.236.172; 5.W.236.175; 5.W.236.240; 5.W.236.244; 5.W.237.228; 5.W.237.229; 5.W.237.230; 5.W.237.231; 5.W.237.236; 5.W.237.237; 5. W.237.238; 5.W.237.239; 5.W.237.154; 5.W.237.157; 5.W.237.166; 5.W.237.169; 5.W.237.172; 5.W.237.175; 5.W. 237.240; 5.W.237.244; 5.W.238.228; 5.W.238.229; 5.W.238.230; 5.W.238.231; 5.W.238.236; 5.W.238.237; 5.W.238.238; 5.W.238.239; 5.W.238.154; 5.W.238.157; 5.W.238.166; 5.W.238.169; 5.W.238.172; 5.W.238.175; 5.W.238.240; 5. W.238.244; 5.W.239.228; 5.W.239.229; 5.W.239.230; 5.W.239.231; 5.W.239.236; 5.W.239.237; 5.W.239.238; 5.W. 239.239; 5.W.239.154; 5.W.239.157; 5.W.239.166; 5.W.239.169; 5.W.239.172; 5.W.239.175; 5.W.239.240; 5.W.239.244; 5.W.154.228; 5.W.154.229; 5.W.154.230; 5.W.154.231; 5.W.154.236; 5.W.154.237; 5.W.154.238; 5.W.154.239; 5. W.154.154; 5.W.154.157; 5.W.154.166; 5.W.154.169; 5.W.154.172; 5.W.154.175; 5.W.154.240; 5.W.154.244; 5.W. 157.228; 5.W.157.229; 5.W.157.230; 5.W.157.231; 5.W.157.236; 5.W.157.237; 5.W.157.238; 5.W.157.239; 5.W.157.154; 5.W.157.157; 5.W.157.166; 5.W.157.169 ; 5.W.157.172; 5.W.157.175; 5.W.157.240; 5.W.157.244; 5.W.166.228; 5.W.166.229; 5.W.166.230; 5.W.166.231; 5 .W.166.236; 5.W.166.237; 5.W.166.238; 5.W.166.239; 5.W.166.154; 5.W.166.157; 5.W.166.166; 5.W.166.169; 5.W .166.172; 5.W.166.175; 5.W.166.240; 5.W.166.244; 5.W.169.228; 5.W.169.229; 5.W.169.230; 5.W.169.231; 5.W.169.236 ; 5.W.169.237; 5.W.169.238; 5.W.169.239; 5.W.169.154; 5.W.169.157; 5.W.169.166; 5.W.169.169; 5.W.169.172; 5 .W.169.175; 5.W.169.240; 5.W.169.244; 5.W.172.228; 5.W.172.229; 5.W.172.230; 5.W.172.231; 5.W.172.236; 5.W .172.237; 5.W.172.238; 5.W.172.239; 5.W.172.154; 5.W.172.157; 5.W.172.166; 5.W.172.169; 5.W.172.172; 5.W.172.175 ; 5.W.172.240; 5.W.172.244; 5.W.175.228; 5.W.175.229; 5.W.175.230; 5.W.175.231; 5.W.175.236; 5.W.175.237; 5 .W.175.238; 5.W.175.239; 5.W.175.154; 5.W.175.157; 5.W.175.166; 5.W.175.169; 5.W.175.172; 5.W.175.175; 5.W .175.240; 5.W.175.244; 5.W.240.228; 5.W.240.229; 5.W.240.230; 5.W.240.231; 5.W.240.236; 5.W.240.237; 5.W.240.238 ; 5.W.240.239; 5.W.240.154; 5.W.240.15 7; 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. 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. 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.157.16 9; 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.240.1 57; 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.157.16 9; 6.L.157.172; 6.L.157.175; 6.L.157.240; 6.L.157.244; 6.L.166.228; 6.L.166.229; 6.L.166.230; 6.L.166.231; 6.L.166.236; 6.L.166.237; 6.L.166.238; 6.L.166.239; 6.L.166.154; 6.L.166.157; 6.L.166.166; 6.L.166.169; 6. L.166.172; 6.L.166.175; 6.L.166.240; 6.L.166.244; 6.L.169.228; 6.L.169.229; 6.L.169.230; 6.L.169.231; 6.L. 169.236; 6.L.169.237; 6.L.169.238; 6.L.169.239; 6.L.169.154; 6.L.169.157; 6.L.169.166; 6.L.169.169; 6.L.169.172; 6.L.169.175; 6.L.169.240; 6.L.169.244; 6.L.172.228; 6.L.172.229; 6.L.172.230; 6.L.172.231; 6.L.172.236; 6. L.172.237; 6.L.172.238; 6.L.172.239; 6.L.172.154; 6.L.172.157; 6.L.172.166; 6.L.172.169; 6.L.172.172; 6.L. 172.175; 6.L.172.240; 6.L.172.244; 6.L.175.228; 6.L.175.229; 6.L.175.230; 6.L.175.231; 6.L.175.236; 6.L.175.237; 6.L.175.238; 6.L.175.239; 6.L.175.154; 6.L.175.157; 6.L.175.166; 6.L.175.169; 6.L.175.172; 6.L.175.175; 6. L.175.240; 6.L.175.244; 6.L.240.228; 6.L.240.229; 6.L.240.230; 6.L.240.231; 6.L.240.236; 6.L.240.237; 6.L. 240.238; 6.L.240.239; 6.L.240.154; 6.L.240.1 57; 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.157.169 6.O.157.172; 6.O.157.175; 6.O.157.240; 6.O.157.244; 6.O.166.228; 6.O.166.229; 6.O.166.230; 6.O.166.231; 6 .O.166.236; 6.O.166.237; 6.O.166.238; 6.O.166.239; 6.O.166.154; 6.O.166.157; 6.O.166.166; 6.O.166.169; 6.O .166.172; 6.O.166.175; 6.O.166.240; 6.O.166.244; 6.O.169.228; 6.O.169.229; 6.O.169.230; 6.O.169.231; 6.O.169.236 ; 6.O.169.237; 6.O.169.238; 6.O.169.239; 6.O.169.154; 6.O.169.157; 6.O.169.166; 6.O.169.169; 6.O.169.172; 6 .O.169.175; 6.O.169.240; 6.O.169.244; 6.O.172.228; 6.O.172.229; 6.O.172.230; 6.O.172.231; 6.O.172.236; 6.O .172.237; 6.O.172.238; 6.O.172.239; 6.O.172.154; 6.O.172.157; 6.O.172.166; 6.O.172.169; 6.O.172.172; 6.O.172.175 6.O.172.240; 6.O.172.244; 6.O.175.228; 6.O.175.229; 6.O.175.230; 6.O.175.231; 6.O.175.236; 6.O.175.237; 6 .O.175.238; 6.O.175.239; 6.O.175.154; 6.O.175.157; 6.O.175.166; 6.O.175.169; 6.O.175.172; 6.O.175.175; 6.O .175.240; 6.O.175.244; 6.O.240.228; 6.O.240.229; 6.O.240.230; 6.O.240.231; 6.O.240.236; 6.O.240.237; 6.O.240.238 ; 6.O.240.239; 6.O.240.154; 6.O.240.15 7; 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. 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 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; 7AP.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. 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.54.24 7; 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. 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.54.24 7; 7.CO.55.157; 7.CO.55.158; 7.CO.55.196; 7.CO.55.223; 7.CO.55.240; 7.CO.55.244; 7.CO.55.243; 7.CO.55.247; 7.CO.56.157; 7.CO.56.158; 7.CO.56.196; 7.CO.56.223; 7.CO.56.240; 7.CO.56.244; 7.CO.56.243; 7.CO.56.247; 7. CO.157.157; 7.CO.157.158; 7.CO.157.196; 7.CO.157.223; 7.CO.157.240; 7.CO.157.244; 7.CO.157.243; 7.CO.157.247; 7.CO. 196.157; 7.CO.196.158; 7.CO.196.196; 7.CO.196.223; 7.CO.196.240; 7.CO.196.244; 7.CO.196.243; 7.CO.196.247; 7.CO.223.157; 7.CO.223.158; 7.CO.223.196; 7.CO.223.223; 7.CO.223.240; 7.CO.223.244; 7.CO.223.243; 7.CO.223.247; 7.CO.240.157; 7. CO.240.158; 7.CO.240.196; 7.CO.240.223; 7.CO.240.240; 7.CO.240.244; 7.CO.240.243; 7.CO.240.247; 7.CO.244.157; 7.CO. 244.158; 7.CO.244.196; 7.CO.244.223; 7.CO.244.240; 7.CO.244.244; 7.CO.244.243; 7.CO.244.247; 7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247;

8.AH prodrug
8.AH.4.157; 8.AH.4.158; 8.AH.4.196; 8.AH.4.223; 8.AH.4.240; 8.AH.4.244; 8.AH.4.243; 8.AH.4.247; 8. AH.5.157; 8.AH.5.158; 8.AH.5.196; 8.AH.5.223; 8.AH.5.240; 8.AH.5.244; 8.AH.5.243; 8.AH.5.247; 8.AH. 7.157; 8.AH.7.158; 8.AH.7.196; 8.AH.7.223; 8.AH.7.240; 8.AH.7.244; 8.AH.7.243; 8.AH.7.247; 8.AH.15.157; 8.AH.15.158; 8.AH.15.196; 8.AH.15.223; 8.AH.15.240; 8.AH.15.244; 8.AH.15.243; 8.AH.15.247; 8.AH.16.157; 8. AH.16.158; 8.AH.16.196; 8.AH.16.223; 8.AH.16.240; 8.AH.16.244; 8.AH.16.243; 8.AH.16.247; 8.AH.18.157; 8.AH. 18.158; 8.AH.18.196; 8.AH.18.223; 8.AH.18.240; 8.AH.18.244; 8.AH.18.243; 8.AH.18.247; 8.AH.26.157; 8.AH.26.158; 8.AH.26.196; 8.AH.26.223; 8.AH.26.240; 8.AH.26.244; 8.AH.26.243; 8.AH.26.247; 8.AH.27.157; 8.AH.27.158; 8. AH.27.196; 8.AH.27.223; 8.AH.27.240; 8.AH.27.244; 8.AH.27.243; 8.AH.27.247; 8.AH.29.157; 8.AH.29.158; 8.AH. 29.196; 8.AH.29.223; 8.AH.29.240; 8.AH.29.244; 8.AH.29.243; 8.AH.29.247; 8.AH.54.157; 8.AH.54.158; 8.AH.54.196; 8.AH.54.223; 8.AH.54.240; 8.AH.54.244; 8.AH.54.243; 8.AH.54.24 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. 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. 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. 244.158; 8.BF.244.196; 8.BF.244.223; 8.BF.244.240; 8.BF.244.244; 8.BF.244.243; 8.BF.244.247; 8.BF.247.157; 8.BF.247.158; 8.BF.247.196; 8.BF.247.223; 8.BF.247.240; 8.BF.247.244; 8.BF.247.243; 8.BF.247.247;

8.CI prodrug
8.CI.4.157; 8.CI.4.158; 8.CI.4.196; 8.CI.4.223; 8.CI.4.240; 8.CI.4.244; 8.CI.4.243; 8.CI.4.247; 8. CI.5.157; 8.CI.5.158; 8.CI.5.196; 8.CI.5.223; 8.CI.5.240; 8.CI.5.244; 8.CI.5.243; 8.CI.5.247; 8.CI. 7.157; 8.CI.7.158; 8.CI.7.196; 8.CI.7.223; 8.CI.7.240; 8.CI.7.244; 8.CI.7.243; 8.CI.7.247; 8.CI.15.157; 8.CI.15.158; 8.CI.15.196; 8.CI.15.223; 8.CI.15.240; 8.CI.15.244; 8.CI.15.243; 8.CI.15.247; 8.CI.16.157; 8. CI.16.158; 8.CI.16.196; 8.CI.16.223; 8.CI.16.240; 8.CI.16.244; 8.CI.16.243; 8.CI.16.247; 8.CI.18.157; 8.CI. 18.158; 8.CI.18.196; 8.CI.18.223; 8.CI.18.240; 8.CI.18.244; 8.CI.18.243; 8.CI.18.247; 8.CI.26.157; 8.CI.26.158; 8.CI.26.196; 8.CI.26.223; 8.CI.26.240; 8.CI.26.244; 8.CI.26.243; 8.CI.26.247; 8.CI.27.157; 8.CI.27.158; 8. CI.27.196; 8.CI.27.223; 8.CI.27.240; 8.CI.27.244; 8.CI.27.243; 8.CI.27.247; 8.CI.29.157; 8.CI.29.158; 8.CI. 29.196; 8.CI.29.223; 8.CI.29.240; 8.CI.29.244; 8.CI.29.243; 8.CI.29.247; 8.CI.54.157; 8.CI.54.158; 8.CI.54.196; 8.CI.54.223; 8.CI.54.240; 8.CI.54.244; 8.CI.54.243; 8.CI.54.24 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.54.24 7; 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.54.24 7; 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. 29.196; 9.BF.29.223; 9.BF.29.240; 9.BF.29.244; 9.BF.29.243; 9.BF.29.247; 9.BF.54.157; 9.BF.54.158; 9.BF.54.196; 9.BF.54.223; 9.BF.54.240; 9.BF.54.244; 9.BF.54.243; 9.BF.54.24 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. 244.158; 9.BF.244.196; 9.BF.244.223; 9.BF.244.240; 9.BF.244.244; 9.BF.244.243; 9.BF.244.247; 9.BF.247.157; 9.BF.247.158; 9.BF.247.196; 9.BF.247.223; 9.BF.247.240; 9.BF.247.244; 9.BF.247.243; 9.BF.247.247;

9.CI prodrug
9.CI.4.157; 9.CI.4.158; 9.CI.4.196; 9.CI.4.223; 9.CI.4.240; 9.CI.4.244; 9.CI.4.243; 9.CI.4.247; 9. CI.5.157; 9.CI.5.158; 9.CI.5.196; 9.CI.5.223; 9.CI.5.240; 9.CI.5.244; 9.CI.5.243; 9.CI.5.247; 9.CI. 7.157; 9.CI.7.158; 9.CI.7.196; 9.CI.7.223; 9.CI.7.240; 9.CI.7.244; 9.CI.7.243; 9.CI.7.247; 9.CI.15.157; 9.CI.15.158; 9.CI.15.196; 9.CI.15.223; 9.CI.15.240; 9.CI.15.244; 9.CI.15.243; 9.CI.15.247; 9.CI.16.157; 9. CI.16.158; 9.CI.16.196; 9.CI.16.223; 9.CI.16.240; 9.CI.16.244; 9.CI.16.243; 9.CI.16.247; 9.CI.18.157; 9.CI. 18.158; 9.CI.18.196; 9.CI.18.223; 9.CI.18.240; 9.CI.18.244; 9.CI.18.243; 9.CI.18.247; 9.CI.26.157; 9.CI.26.158; 9.CI.26.196; 9.CI.26.223; 9.CI.26.240; 9.CI.26.244; 9.CI.26.243; 9.CI.26.247; 9.CI.27.157; 9.CI.27.158; 9. CI.27.196; 9.CI.27.223; 9.CI.27.240; 9.CI.27.244; 9.CI.27.243; 9.CI.27.247; 9.CI.29.157; 9.CI.29.158; 9.CI. 29.196; 9.CI.29.223; 9.CI.29.240; 9.CI.29.244; 9.CI.29.243; 9.CI.29.247; 9.CI.54.157; 9.CI.54.158; 9.CI.54.196; 9.CI.54.223; 9.CI.54.240; 9.CI.54.244; 9.CI.54.243; 9.CI.54.24 7; 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. CO.157.157; 9.CO.157.158; 9.CO.157.196; 9.CO.157.223; 9.CO.157.240; 9.CO.157.244; 9.CO.157.243; 9.CO.157.247; 9.CO. 196.157; 9.CO.196.158; 9.CO.196.196; 9.CO.196.223; 9.CO.196.240; 9.CO.196.244; 9.CO.196.243; 9.CO.196.247; 9.CO.223.157; 9.CO.223.158; 9.CO.223.196; 9.CO.223.223; 9.CO.223.240; 9.CO.223.244; 9.CO.223.243; 9.CO.223.247; 9.CO.240.157; 9. CO.240.158; 9.CO.240.196; 9.CO.240.223; 9.CO.240.240; 9.CO.240.244; 9.CO.240.243; 9.CO.240.247; 9.CO.244.157; 9.CO. 244.158; 9.CO.244.196; 9.CO.244.223; 9.CO.244.240; 9.CO.244.244; 9.CO.244.243; 9.CO.244.247; 9.CO.247.157; 9.CO.247.158; 9.CO.247.196; 9.CO.247.223; 9.CO.247.240; 9.CO.247.244; 9.CO.247.243; 9.CO.247.247;

10.AH prodrug
10.AH.4.157; 10.AH.4.158; 10.AH.4.196; 10.AH.4.223; 10.AH.4.240; 10.AH.4.244; 10.AH.4.243; 10.AH.4.247; 10. AH.5.157; 10.AH.5.158; 10.AH.5.196; 10.AH.5.223; 10.AH.5.240; 10.AH.5.244; 10.AH.5.243; 10.AH.5.247; 10.AH. 7.157; 10.AH.7.158; 10.AH.7.196; 10.AH.7.223; 10.AH.7.240; 10.AH.7.244; 10.AH.7.243; 10.AH.7.247; 10.AH.15.157; 10.AH.15.158; 10.AH.15.196; 10.AH.15.223; 10.AH.15.240; 10.AH.15.244; 10.AH.15.243; 10.AH.15.247; 10.AH.16.157; 10. AH.16.158; 10.AH.16.196; 10.AH.16.223; 10.AH.16.240; 10.AH.16.244; 10.AH.16.243; 10.AH.16.247; 10.AH.18.157; 10.AH. 18.158; 10.AH.18.196; 10.AH.18.223; 10.AH.18.240; 10.AH.18.244; 10.AH.18.243; 10.AH.18.247; 10.AH.26.157; 10.AH.26.158; 10.AH.26.196; 10.AH.26.223; 10.AH.26.240; 10.AH.26.244; 10.AH.26.243; 10.AH.26.247; 10.AH.27.157; 10.AH.27.158; 10. AH.27.196; 10.AH.27.223; 10.AH.27.240; 10.AH.27.244; 10.AH.27.243; 10.AH.27.247; 10.AH.29.157; 10.AH.29.158; 10.AH. 29.196; 10.AH.29.223; 10.AH.29.240; 10.AH.29.244; 10.AH.29.243; 10.AH.29.247; 10.AH.54.157; 10.AH.54.158; 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; 1 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; 10 .CO.54.196; 10.CO.54.223; 10.CO.54.240; 10.CO.54.244; 10.CO.54.243; 10.CO.54.247; 10.CO.55.157; 10.CO.55.158; 10.CO .55.196; 10.CO.55.223; 10.CO.55.240; 10.CO.55.244; 10.CO.55.243; 10.CO.55.247; 10.CO.56.157; 10.CO.56.158; 10.CO.56.196 10.CO.56.223; 10.CO.56.240; 10.CO.56.244; 10.CO.56.243; 10.CO.56.247; 10.CO.157.157; 10.CO.157.158; 10.CO.157.196; 10 .CO.157.223; 10.CO.157.240; 10.CO.157.244; 10.CO.157.243; 10.CO.157.247; 10.CO.196.157; 10.CO.196.158; 10.CO.196.196; 10.CO .196.223; 10.CO.196.240; 10.CO.196.244; 10.CO.196.243; 10.CO.196.247; 10.CO.223.157; 10.CO.223.158; 10.CO.223.196; 10.CO.223.223 10.CO.223.240; 10.CO.223.244; 10.CO.223.243; 10.CO.223.247; 10.CO.240.157; 10.CO.240.158; 10.CO.240.196; 10.CO.240.223; 10 .CO.240.240; 10.CO.240.244; 10.CO.240.243; 10.CO.240.247; 10.CO.244.157; 10.CO.244.158; 10.CO.244.196; 10.CO.244.223; 10.CO .244.240; 10.CO.244.244; 10.CO.244.243; 10.CO.244.247; 10.CO.247.157; 10.CO.247.158; 10.CO.247.196; 10.CO.247.223; 10.CO.247.240 ; 10.CO.247.244; 10.CO.247.243; 10 .CO.247.247;

11.AH prodrug
11.AH.4.157; 11.AH.4.158; 11.AH.4.196; 11.AH.4.223; 11.AH.4.240; 11.AH.4.244; 11.AH.4.243; 11.AH.4.247; 11. AH.5.157; 11.AH.5.158; 11.AH.5.196; 11.AH.5.223; 11.AH.5.240; 11.AH.5.244; 11.AH.5.243; 11.AH.5.247; 11.AH. 7.157; 11.AH.7.158; 11.AH.7.196; 11.AH.7.223; 11.AH.7.240; 11.AH.7.244; 11.AH.7.243; 11.AH.7.247; 11.AH.15.157; 11.AH.15.158; 11.AH.15.196; 11.AH.15.223; 11.AH.15.240; 11..AH.15.244; 11.AH.15.243; 11.AH.15.247; 11.AH.16.157; 11. AH.16.158; 11.AH.16.196; 11.AH.16.223; 11.AH.16.240; 11.AH.16.244; 11.AH.16.243; 11.AH.16.247; 11.AH.18.157; 11.AH. 18.158; 11.AH.18.196; 11.AH.18.223; 11.AH.18.240; 11.AH.18.244; 11.AH.18.243; 11.AH.18.247; 11.AH.26.157; 11.AH.26.158; 11.AH.26.196; 11.AH.26.223; 11.AH.26.240; 11.AH.26.244; 11..AH.26.243; 11.AH.26.247; 11.AH.27.157; 11.AH.27.158; 11. AH.27.196; 11.AH.27.223; 11.AH.27.240; 11.AH.27.244; 11.AH.27.243; 11.AH.27.247; 11.AH.29.157; 11.AH.29.158; 11.AH. 29.196; 11.AH.29.223; 11.AH.29.240; 11.AH.29.244; 11.AH.29.243; 11.AH.29.247; 11.AH.54.157; 11.AH.54.158; 1 1.AH.54.196; 11.AH.54.223; 11.AH.54.240; 11.AH.54.244; 11.AH.54.243; 11.AH.54.247; 11.AH.55.157; 11.AH.55.158; 11. AH.55.196; 11.AH.55.223; 11.AH.55.240; 11.AH.55.244; 11.AH.55.243; 11.AH.55.247; 11.AH.56.157; 11.AH.56.158; 11.AH. 56.196; 11.AH.56.223; 11.AH.56.240; 11.AH.56.244; 11.AH.56.243; 11..AH.56.247; 11.AH.157.157; 11.AH.157.158; 11.AH.157.196; 11.AH.157.223; 11.AH.157.240; 11.AH.157.244; 11.AH.157.243; 11.AH.157.247; 11.AH.196.157; 11.AH.196.158; 11.AH.196.196; 11. AH.196.223; 11.AH.196.240; 11.AH.196.244; 11.AH.196.243; 11.AH.196.247; 11.AH.223.157; 11.AH.223.158; 11.AH.223.196; 11.AH. 223.223; 11.AH.223.240; 11.AH.223.244; 11.AH.223.243; 11.AH.223.247; 11.AH.240.157; 11.AH.240.158; 11.AH.240.196; 11.AH.240.223; 11.AH.240.240; 11.AH.240.244; 11.AH.240.243; 11.AH.240.247; 11.AH.244.157; 11.AH.244.158; 11.AH.244.196; 11.AH.244.223; 11. 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; 11 .AJ.54.196; 11.AJ.54.223; 11.AJ.54.240; 11.AJ.54.244; 11.AJ.54.243; 11.AJ.54.247; 11.AJ.55.157; 11.AJ.55.158; 11.AJ .55.196; 11.AJ.55.223; 11.AJ.55.240; 11.AJ.55.244; 11.AJ.55.243; 11.AJ.55.247; 11.AJ.56.157; 11.AJ.56.158; 11.AJ.56.196 11.AJ.56.223; 11.AJ.56.240; 11.AJ.56.244; 11.AJ.56.243; 11.AJ.56.247; 11.AJ.157.157; 11.AJ.157.158; 11.AJ.157.196; 11 .AJ.157.223; 11.AJ.157.240; 11.AJ.157.244; 11.AJ.157.243; 11.AJ.157.247; 11..AJ.196.157; 11.AJ.196.158; 11.AJ.196.196; 11.AJ .196.223; 11.AJ.196.240; 11.AJ.196.244; 11.AJ.196.243; 11.AJ.196.247; 11.AJ.223.157; 11.AJ.223.158; 11.AJ.223.196; 11.AJ.223.223 11.AJ.223.240; 11.AJ.223.244; 11.AJ.223.243; 11.AJ.223.247; 11.AJ.240.157; 11.AJ.240.158; 11.AJ.240.196; 11.AJ.240.223; 11 .AJ.240.240; 11.AJ.240.244; 11.AJ.240.243; 11.AJ.240.247; 11.AJ.244.157; 11.AJ.244.158; 11.AJ.244.196; 11.AJ.244.223; 11.AJ .244.240; 11.AJ.244.244; 11.AJ.244.243; 11.AJ.244.247; 11.AJ.247.157; 11.AJ.247.158; 11.AJ.247.196; 11.AJ.247.223; 11.AJ.247.240 ; 11.AJ.247.244; 11.AJ.247.243; 11 .AJ.247.247;

11.AN 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. 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; 1 1.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. 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. 11.158; 11.AP.18.196; 11.AP.18.223; 11.AP.18.240; 11.AP.18.244; 11.AP.18.243; 11.AP.18.247; 11.AP.26.157; 11.AP.26.158; 11.AP.26.196; 11.AP.26.223; 11.AP.26.240; 11.AP.26.244; 11.AP.26.243; 11.AP.26.247; 11.AP.27.157; 11.AP.27.158; 11. AP.27.196; 11.AP.27.223; 11.AP.27.240; 11.AP.27.244; 11.AP.27.243; 11.AP.27.247; 11.AP.29.157; 11.AP.29.158; 11.AP. 29.196; 11.AP.29.223; 11.AP.29.240; 11.AP.29.244; 11.AP.29.243; 11.AP.29.247; 11.AP.54.157; 11.AP.54.158; 11 .AP.54.196; 11.AP.54.223; 11.AP.54.240; 11.AP.54.244; 11.AP.54.243; 11.AP.54.247; 11.AP.55.157; 11.AP.55.158; 11.AP .55.196; 11.AP.55.223; 11.AP.55.240; 11.AP.55.244; 11.AP.55.243; 11.AP.55.247; 11.AP.56.157; 11.AP.56.158; 11.AP.56.196 11.AP.56.223; 11.AP.56.240; 11.AP.56.244; 11.AP.56.243; 11.AP.56.247; 11.AP.157.157; 11.AP.157.158; 11.AP.157.196; 11 .AP.157.223; 11.AP.157.240; 11.AP.157.244; 11.AP.157.243; 11.AP.157.247; 11.AP.196.157; 11.AP.196.158; 11.AP.196.196; 11.AP .196.223; 11.AP.196.240; 11.AP.196.244; 11.AP.196.243; 11.AP.196.247; 11.AP.223.157; 11.AP.223.158; 11.AP.223.196; 11.AP.223.223 11.AP.223.240; 11.AP.223.244; 11.AP.223.243; 11.AP.223.247; 11.AP.240.157; 11.AP.240.158; 11.AP.240.196; 11.AP.240.223; 11 .AP.240.240; 11.AP.240.244; 11.AP.240.243; 11.AP.240.247; 11.AP.244.157; 11.AP.244.158; 11.AP.244.196; 11.AP.244.223; 11.AP .244.240; 11.AP.244.244; 11.AP.244.243; 11.AP.244.247; 11.AP.247.157; 11.AP.247.158; 11.AP.247.196; 11.AP.247.223; 11.AP.247.240 ; 11.AP.247.244; 11.AP.247.243; 11 .AP.247.247;

11. AZ prodrug
11.AZ.4.157; 11.AZ.4.158; 11.AZ.4.196; 11.AZ.4.223; 11.AZ.4.240; 11.AZ.4.244; 11.AZ.4.243; 11.AZ.4.247; 11. 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; 1 1.BF.54.196; 11.BF.54.223; 11.BF.54.240; 11.BF.54.244; 11.BF.54.243; 11.BF.54.247; 11.BF.55.157; 11.BF.55.158; 11. BF.55.196; 11.BF.55.223; 11.BF.55.240; 11.BF.55.244; 11.BF.55.243; 11.BF.55.247; 11.BF.56.157; 11.BF.56.158; 11.BF. 11.BF.56.223; 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. 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. 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. 11.CO.27.196; 11.CO.27.223; 11.CO.27.240; 11.CO.27.244; 11.CO.27.243; 11.CO.27.247; 11.CO.29.157; 11.CO.29.158; 11.CO. 29.196; 11.CO.29.223; 11.CO.29.240; 11.CO.29.244; 11.CO.29.243; 11.CO.29.247; 11.CO.54.157; 11.CO.54.158; 1 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. 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. 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. 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; 12 .AN.54.196; 12.AN.54.223; 12.AN.54.240; 12.AN.54.244; 12.AN.54.243; 12.AN.54.247; 12.AN.55.157; 12.AN.55.158; 12.AN .55.196; 12.AN.55.223; 12.AN.55.240; 12.AN.55.244; 12.AN.55.243; 12.AN.55.247; 12.AN.56.157; 12.AN.56.158; 12.AN.56.196 ; 12.AN.56.223; 12.AN.56.240; 12.AN.56.244; 12.AN.56.243; 12.AN.56.247; 12.AN.157.157; 12.AN.157.158; 12.AN.157.196; 12 .AN.157.223; 12.AN.157.240; 12.AN.157.244; 12.AN.157.243; 12.AN.157.247; 12.AN.196.157; 12.AN.196.158; 12.AN.196.196; 12.AN .196.223; 12.AN.196.240; 12.AN.196.244; 12.AN.196.243; 12.AN.196.247; 12.AN.223.157; 12.AN.223.158; 12.AN.223.196; 12.AN.223.223 ; 12.AN.223.240; 12.AN.223.244; 12.AN.223.243; 12.AN.223.247; 12.AN.240.157; 12.AN.240.158; 12.AN.240.196; 12.AN.240.223; 12 .AN.240.240; 12.AN.240.244; 12.AN.240.243; 12.AN.240.247; 12.AN.244.157; 12.AN.244.158; 12.AN.244.196; 12.AN.244.223; 12.AN .244.240; 12.AN.244.244; 12.AN.244.243; 12.AN.244.247; 12.AN.247.157; 12.AN.247.158; 12.AN.247.196; 12.AN.247.223; 12.AN.247.240 ; 12.AN.247.244; 12.AN.247.243; 12 .AN.247.247;

12.AP prodrug
12.AP.4.157; 12.AP.4.158; 12.AP.4.196; 12.AP.4.223; 12.AP.4.240; 12.AP.4.244; 12.AP.4.243; 12.AP.4.247; 12. AP.5.157; 12.AP.5.158; 12.AP.5.196; 12.AP.5.223; 12.AP.5.240; 12.AP.5.244; 12.AP.5.243; 12.AP.5.247; 12.AP. 7.157; 12.AP.7.158; 12.AP.7.196; 12.AP.7.223; 12.AP.7.240; 12.AP.7.244; 12.AP.7.243; 12.AP.7.247; 12.AP.15.157; 12.AP.15.158; 12.AP.15.196; 12.AP.15.223; 12.AP.15.240; 12.AP.15.244; 12.AP.15.243; 12.AP.15.247; 12.AP.16.157; 12. AP.16.158; 12.AP.16.196; 12.AP.16.223; 12.AP.16.240; 12.AP.16.244; 12.AP.16.243; 12.AP.16.247; 12.AP.18.157; 12.AP. 18.158; 12.AP.18.196; 12.AP.18.223; 12.AP.18.240; 12.AP.18.244; 12.AP.18.243; 12.AP.18.247; 12.AP.26.157; 12.AP.26.158; 12.AP.26.196; 12.AP.26.223; 12.AP.26.240; 12.AP.26.244; 12.AP.26.243; 12.AP.26.247; 12.AP.27.157; 12.AP.27.158; 12. AP.27.196; 12.AP.27.223; 12.AP.27.240; 12.AP.27.244; 12.AP.27.243; 12.AP.27.247; 12.AP.29.157; 12.AP.29.158; 12.AP. 29.196; 12.AP.29.223; 12.AP.29.240; 12.AP.29.244; 12.AP.29.243; 12.AP.29.247; 12.AP.54.157; 12.AP.54.158; 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. AP.244.240; 12.AP.244.244; 12.AP.244.243; 12.AP.244.247; 12.AP.247.157; 12.AP.247.158; 12.AP.247.196; 12.AP.247.223; 12.AP. 247.240; 12.AP.247.244; 12.AP.247.243; 12 .AP.247.247;

12.AZ prodrug
12.AZ.4.157; 12.AZ.4.158; 12.AZ.4.196; 12.AZ.4.223; 12.AZ.4.240; 12.AZ.4.244; 12.AZ.4.243; 12.AZ.4.247; 12. AZ.5.157; 12.AZ.5.158; 12.AZ.5.196; 12.AZ.5.223; 12.AZ.5.240; 12.AZ.5.244; 12.AZ.5.243; 12.AZ.5.247; 12.AZ. 7.157; 12.AZ.7.158; 12.AZ.7.196; 12.AZ.7.223; 12.AZ.7.240; 12.AZ.7.244; 12.AZ.7.243; 12.AZ.7.247; 12.AZ.15.157; 12.AZ.15.158; 12.AZ.15.196; 12.AZ.15.223; 12.AZ.15.240; 12.AZ.15.244; 12.AZ.15.243; 12.AZ.15.247; 12.AZ.16.157; 12. AZ.16.158; 12.AZ.16.196; 12.AZ.16.223; 12.AZ.16.240; 12.AZ.16.244; 12.AZ.16.243; 12.AZ.16.247; 12.AZ.18.157; 12.AZ. 18.158; 12.AZ.18.196; 12.AZ.18.223; 12.AZ.18.240; 12.AZ.18.244; 12.AZ.18.243; 12.AZ.18.247; 12.AZ.26.157; 12.AZ.26.158; 12.AZ.26.196; 12.AZ.26.223; 12.AZ.26.240; 12.AZ.26.244; 12.AZ.26.243; 12.AZ.26.247; 12.AZ.27.157; 12.AZ.27.158; 12. AZ.27.196; 12.AZ.27.223; 12.AZ.27.240; 12.AZ.27.244; 12.AZ.27.243; 12.AZ.27.247; 12.AZ.29.157; 12.AZ.29.158; 12.AZ. 29.196; 12.AZ.29.223; 12.AZ.29.240; 12.AZ.29.244; 12.AZ.29.243; 12.AZ.29.247; 12.AZ.54.157; 12.AZ.54.158; 12 .AZ.54.196; 12.AZ.54.223; 12.AZ.54.240; 12.AZ.54.244; 12.AZ.54.243; 12.AZ.54.247; 12.AZ.55.157; 12.AZ.55.158; 12.AZ .55.196; 12.AZ.55.223; 12.AZ.55.240; 12.AZ.55.244; 12.AZ.55.243; 12.AZ.55.247; 12.AZ.56.157; 12.AZ.56.158; 12.AZ.56.196 ; 12.AZ.56.223; 12.AZ.56.240; 12.AZ.56.244; 12.AZ.56.243; 12.AZ.56.247; 12.AZ.157.157; 12.AZ.157.158; 12.AZ.157.196; 12 .AZ.157.223; 12.AZ.157.240; 12.AZ.157.244; 12.AZ.157.243; 12.AZ.157.247; 12.AZ.196.157; 12.AZ.196.158; 12.AZ.196.196; 12.AZ .196.223; 12.AZ.196.240; 12.AZ.196.244; 12.AZ.196.243; 12.AZ.196.247; 12.AZ.223.157; 12.AZ.223.158; 12.AZ.223.196; 12.AZ.223.223 ; 12.AZ.223.240; 12.AZ.223.244; 12.AZ.223.243; 12.AZ.223.247; 12.AZ.240.157; 12.AZ.240.158; 12.AZ.240.196; 12.AZ.240.223; 12 .AZ.240.240; 12.AZ.240.244; 12.AZ.240.243; 12.AZ.240.247; 12.AZ.244.157; 12.AZ.244.158; 12.AZ.244.196; 12.AZ.244.223; 12.AZ .244.240; 12.AZ.244.244; 12.AZ.244.243; 12.AZ.244.247; 12.AZ.247.157; 12.AZ.247.158; 12.AZ.247.196; 12.AZ.247.223; 12.AZ.247.240 ; 12.AZ.247.244; 12.AZ.247.243; 12. AZ.247.247;

12.BF 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. CI.244.240; 12.CI.244.244; 12.CI.244.243; 12.CI.244.247; 12.CI.247.157; 12.CI.247.158; 12.CI.247.196; 12.CI.247.223; 12.CI. 247.240; 12.CI.247.244; 12.CI.247.243; 12 .CI.247.247;

12.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.23 6.154; 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.1 75.157; 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; 13U.157.231; 13U.157.236; 13U.157.237; 13U.157.238; 13.U.157.239; 13U.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.2 36.154; 13.Y.236.157; 13.Y.236.166; 13.Y.236.169; 13.Y.236.172; 13.Y.236.175; 13.Y.236.240; 13.Y.236.244; 13.Y.237.228; 13.Y.237.229; 13.Y.237.230; 13.Y.237.231; 13.Y.237.236; 13.Y.237.237; 13.Y.237.238; 13.Y.237.239; 13.Y.237.154; 13. Y.237.157; 13.Y.237.166; 13.Y.237.169; 13.Y.237.172; 13.Y.237.175; 13.Y.237.240; 13.Y.237.244; 13.Y.238.228; 13.Y. 238.229; 13.Y.238.230; 13.Y.238.231; 13.Y.238.236; 13.Y.238.237; 13.Y.238.238; 13.Y.238.239; 13.Y.238.154; 13.Y.238.157; 13.Y.238.166; 13.Y.238.169; 13.Y.238.172; 13.Y.238.175; 13.Y.238.240; 13.Y.238.244; 13.Y.239.228; 13.Y.239.229; 13. Y.239.230; 13.Y.239.231; 13.Y.239.236; 13.Y.239.237; 13.Y.239.238; 13.Y.239.239; 13.Y.239.154; 13.Y.239.157; 13.Y. 239.166; 13.Y.239.169; 13.Y.239.172; 13.Y.239.175; 13.Y.239.240; 13.Y.239.244; 13.Y.154.228; 13.Y.154.229; 13.Y.154.230; 13.Y.154.231; 13.Y.154.236; 13.Y.154.237; 13.Y.154.238; 13.Y.154.239; 13.Y.154.154; 13.Y.154.157; 13.Y.154.166; 13. Y.154.169; 13.Y.154.172; 13.Y.154.175; 13.Y.154.240; 13.Y.154.244; 13.Y.157.228 ; 13.Y.157.229; 13.Y.157.230; 13.Y.157.231; 13.Y.157.236; 13.Y.157.237; 13.Y.157.238; 13.Y.157.239; 13.Y.157.154; 13 .Y.157.157; 13.Y.157.166; 13.Y.157.169; 13.Y.157.172; 13.Y.157.175; 13.Y.157.240; 13.Y.157.244; 13.Y.166.228; 13.Y .166.229; 13.Y.166.230; 13.Y.166.231; 13.Y.166.236; 13.Y.166.237; 13.Y.166.238; 13.Y.166.239; 13.Y.166.154; 13.Y.166.157 ; 13.Y.166.166; 13.Y.166.169; 13.Y.166.172; 13.Y.166.175; 13.Y.166.240; 13.Y.166.244; 13.Y.169.228; 13.Y.169.229; 13 .Y.169.230; 13.Y.169.231; 13.Y.169.236; 13.Y.169.237; 13.Y.169.238; 13.Y.169.239; 13.Y.169.154; 13.Y.169.157; 13.Y .169.166; 13.Y.169.169; 13.Y.169.172; 13.Y.169.175; 13.Y.169.240; 13.Y.169.244; 13.Y.172.228; 13.Y.172.229; 13.Y.172.230 ; 13.Y.172.231; 13.Y.172.236; 13.Y.172.237; 13.Y.172.238; 13.Y.172.239; 13.Y.172.154; 13.Y.172.157; 13.Y.172.166; 13 .Y.172.169; 13.Y.172.172; 13.Y.172.175; 13.Y.172.240; 13.Y.172.244; 13.Y.175.228; 13.Y.175.229; 13.Y.175.230; 13.Y .175.231; 13.Y.175.236; 13.Y.175.237; 13.Y.175.238; 13.Y.175.239; 13.Y.175.154; 13.Y. 175.157; 13.Y.175.166; 13.Y.175.169; 13.Y.175.172; 13.Y.175.175; 13.Y.175.240; 13.Y.175.244; 13.Y.240.228; 13.Y.240.229; 13.Y.240.230; 13.Y.240.231; 13.Y.240.236; 13.Y.240.237; 13.Y.240.238; 13.Y.240.239; 13.Y.240.154; 13.Y.240.157; 13. Y.240.166; 13.Y.240.169; 13.Y.240.172; 13.Y.240.175; 13.Y.240.240; 13.Y.240.244; 13.Y.244.228; 13.Y.244.229; 13.Y. 244.230; 13.Y.244.231; 13.Y.244.236; 13.Y.244.237; 13.Y.244.238; 13.Y.244.239; 13.Y.244.154; 13.Y.244.157; 13.Y.244.166; 13.Y.244.169; 13.Y.244.172; 13.Y.244.175; 13.Y.244.240; 13.Y.244.244;

14.AH prodrug
14.AH.4.157; 14.AH.4.158; 14.AH.4.196; 14.AH.4.223; 14.AH.4.240; 14.AH.4.244; 14.AH.4.243; 14.AH.4.247; 14. AH.5.157; 14.AH.5.158; 14.AH.5.196; 14.AH.5.223; 14.AH.5.240; 14.AH.5.244; 14.AH.5.243; 14.AH.5.247; 14.AH. 7.157; 14.AH.7.158; 14.AH.7.196; 14.AH.7.223; 14.AH.7.240; 14.AH.7.244; 14.AH.7.243; 14.AH.7.247; 14.AH.15.157; 14.AH.15.158; 14.AH.15.196; 14.AH.15.223; 14.AH.15.240; 14.AH.15.244; 14.AH.15.243; 14.AH.15.247; 14.AH.16.157; 14. AH.16.158; 14.AH.16.196; 14.AH.16.223; 14.AH.16.240; 14.AH.16.244; 14.AH.16.243; 14.AH.16.247; 14.AH.18.157; 14.AH. 18.158; 14.AH.18.196; 14.AH.18.223; 14.AH.18.240; 14.AH.18.244; 14.AH.18.243; 14.AH.18.247; 14.AH.26.157; 14.AH.26.158; 14.AH.26.196; 14.AH.26.223; 14.AH.26.240; 14.AH.26.244; 14.AH.26.243; 14.AH.26.247; 14.AH.27.157; 14.AH.27.158; 14. AH.27.196; 14.AH.27.223; 14.AH.27.240; 14.AH.27.244; 14.AH.27.243; 14.AH.27.247; 14.AH.29.157; 14.AH.29.158; 14.AH. 29.196; 14.AH.29.223; 14.AH.29.240; 14.AH.29.244; 14.AH.29.243; 14.AH.29.247; 14.AH.54.157; 14.AH.54.158; 14 .AH.54.196; 14.AH.54.223; 14.AH.54.240; 14.AH.54.244; 14.AH.54.243; 14.AH.54.247; 14.AH.55.157; 14.AH.55.158; 14.AH .55.196; 14.AH.55.223; 14.AH.55.240; 14.AH.55.244; 14.AH.55.243; 14.AH.55.247; 14.AH.56.157; 14.AH.56.158; 14.AH.56.196 ; 14.AH.56.223; 14.AH.56.240; 14.AH.56.244; 14.AH.56.243; 14.AH.56.247; 14.AH.157.157; 14.AH.157.158; 14.AH.157.196; 14 .AH.157.223; 14.AH.157.240; 14.AH.157.244; 14.AH.157.243; 14.AH.157.247; 14.AH.196.157; 14.AH.196.158; 14.AH.196.196; 14.AH .196.223; 14.AH.196.240; 14.AH.196.244; 14.AH.196.243; 14.AH.196.247; 14.AH.223.157; 14.AH.223.158; 14.AH.223.196; 14.AH.223.223 ; 14.AH.223.240; 14.AH.223.244; 14.AH.223.243; 14.AH.223.247; 14.AH.240.157; 14.AH.240.158; 14.AH.240.196; 14.AH.240.223; 14 .AH.240.240; 14.AH.240.244; 14.AH.240.243; 14.AH.240.247; 14.AH.244.157; 14.AH.244.158; 14.AH.244.196; 14.AH.244.223; 14.AH .244.240; 14.AH.244.244; 14.AH.244.243; 14.AH.244.247; 14.AH.247.157; 14.AH.247.158; 14.AH.247.196; 14.AH.247.223; 14.AH.247.240 ; 14.AH.247.244; 14.AH.247.243; 14 .AH.247.247;

14.AJ 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. 18.158; 14.AN.18.196; 14.AN.18.223; 14.AN.18.240; 14.AN.18.244; 14.AN.18.243; 14.AN.18.247; 14.AN.26.157; 14.AN.26.158; 14.AN.26.196; 14.AN.26.223; 14.AN.26.240; 14.AN.26.244; 14.AN.26.243; 14.AN.26.247; 14.AN.27.157; 14.AN.27.158; 14. AN.27.196; 14.AN.27.223; 14.AN.27.240; 14.AN.27.244; 14.AN.27.243; 14.AN.27.247; 14.AN.29.157; 14.AN.29.158; 14.AN. 29.196; 14.AN.29.223; 14.AN.29.240; 14.AN.29.244; 14.AN.29.243; 14.AN.29.247; 14.AN.54.157; 14.AN.54.158; 1 4.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. 54.196; 14.AN.56.223; 14.AN.56.240; 14.AN.56.244; 14.AN.56.243; 14.AN.56.247; 14.AN.157.157; 14.AN.157.158; 14.AN.157.196; 14.AN.157.223; 14.AN.157.240; 14.AN.157.244; 14.AN.157.243; 14.AN.157.247; 14.AN.196.157; 14.AN.196.158; 14.AN.196.196; 14. AN.196.223; 14.AN.196.240; 14.AN.196.244; 14.AN.196.243; 14.AN.196.247; 14.AN.223.157; 14.AN.223.158; 14.AN.223.196; 14.AN. 223.223; 14.AN.223.240; 14.AN.223.244; 14.AN.223.243; 14.AN.223.247; 14.AN.240.157; 14.AN.240.158; 14.AN.240.196; 14.AN.240.223; 14.AN.240.240; 14.AN.240.244; 14.AN.240.243; 14.AN.240.247; 14.AN.244.157; 14.AN.244.158; 14.AN.244.196; 14.AN.244.223; 14. AN.244.240; 14.AN.244.244; 14.AN.244.243; 14.AN.244.247; 14.AN.247.157; 14.AN.247.158; 14.AN.247.196; 14.AN.247.223; 14.AN. 247.240; 14.AN.247.244; 14.AN.247.243; 14 .AN.247.247;

14.AP prodrug
14.AP.4.157; 14.AP.4.158; 14.AP.4.196; 14.AP.4.223; 14.AP.4.240; 14.AP.4.244; 14.AP.4.243; 14.AP.4.247; 14. AP.5.157; 14.AP.5.158; 14.AP.5.196; 14.AP.5.223; 14.AP.5.240; 14.AP.5.244; 14.AP.5.243; 14.AP.5.247; 14.AP. 7.157; 14.AP.7.158; 14.AP.7.196; 14.AP.7.223; 14.AP.7.240; 14.AP.7.244; 14.AP.7.243; 14.AP.7.247; 14.AP.15.157; 14.AP.15.158; 14.AP.15.196; 14.AP.15.223; 14.AP.15.240; 14.AP.15.244; 14.AP.15.243; 14.AP.15.247; 14.AP.16.157; 14. AP.16.158; 14.AP.16.196; 14.AP.16.223; 14.AP.16.240; 14.AP.16.244; 14.AP.16.243; 14.AP.16.247; 14.AP.18.157; 14.AP. 18.158; 14.AP.18.196; 14.AP.18.223; 14.AP.18.240; 14.AP.18.244; 14.AP.18.243; 14.AP.18.247; 14.AP.26.157; 14.AP.26.158; 14.AP.26.196; 14.AP.26.223; 14.AP.26.240; 14.AP.26.244; 14.AP.26.243; 14.AP.26.247; 14.AP.27.157; 14.AP.27.158; 14. AP.27.196; 14.AP.27.223; 14.AP.27.240; 14.AP.27.244; 14.AP.27.243; 14.AP.27.247; 14.AP.29.157; 14.AP.29.158; 14.AP. 29.196; 14.AP.29.223; 14.AP.29.240; 14.AP.29.244; 14.AP.29.243; 14.AP.29.247; 14.AP.54.157; 14.AP.54.158; 1 4.AP.54.196; 14.AP.54.223; 14.AP.54.240; 14.AP.54.244; 14.AP.54.243; 14.AP.54.247; 14.AP.55.157; 14.AP.55.158; 14. AP.55.196; 14.AP.55.223; 14.AP.55.240; 14.AP.55.244; 14.AP.55.243; 14.AP.55.247; 14.AP.56.157; 14.AP.56.158; 14.AP. 56.196; 14.AP.56.223; 14.AP.56.240; 14.AP.56.244; 14.AP.56.243; 14.AP.56.247; 14.AP.157.157; 14.AP.157.158; 14.AP.157.196; 14.AP.157.223; 14.AP.157.240; 14.AP.157.244; 14.AP.157.243; 14.AP.157.247; 14.AP.196.157; 14.AP.196.158; 14.AP.196.196; 14. AP.196.223; 14.AP.196.240; 14.AP.196.244; 14.AP.196.243; 14.AP.196.247; 14.AP.223.157; 14.AP.223.158; 14.AP.223.196; 14.AP. 223.223; 14.AP.223.240; 14.AP.223.244; 14.AP.223.243; 14.AP.223.247; 14.AP.240.157; 14.AP.240.158; 14.AP.240.196; 14.AP.240.223; 14.AP.240.240; 14.AP.240.244; 14.AP.240.243; 14.AP.240.247; 14.AP.244.157; 14.AP.244.158; 14.AP.244.196; 14.AP.244.223; 14. AP.244.240; 14.AP.244.244; 14.AP.244.243; 14.AP.244.247; 14.AP.247.157; 14.AP.247.158; 14.AP.247.196; 14.AP.247.223; 14.AP. 247.240; 14.AP.247.244; 14.AP.247.243; 14 .AP.247.247;

14. AZ prodrug
14.AZ.4.157; 14.AZ.4.158; 14.AZ.4.196; 14.AZ.4.223; 14.AZ.4.240; 14.AZ.4.244; 14.AZ.4.243; 14.AZ.4.247; 14. AZ.5.157; 14.AZ.5.158; 14.AZ.5.196; 14.AZ.5.223; 14.AZ.5.240; 14.AZ.5.244; 14.AZ.5.243; 14.AZ.5.247; 14.AZ. 7.157; 14.AZ.7.158; 14.AZ.7.196; 14.AZ.7.223; 14.AZ.7.240; 14.AZ.7.244; 14.AZ.7.243; 14.AZ.7.247; 14.AZ.15.157; 14.AZ.15.158; 14.AZ.15.196; 14.AZ.15.223; 14.AZ.15.240; 14.AZ.15.244; 14.AZ.15.243; 14.AZ.15.247; 14.AZ.16.157; 14. AZ.16.158; 14.AZ.16.196; 14.AZ.16.223; 14.AZ.16.240; 14.AZ.16.244; 14.AZ.16.243; 14.AZ.16.247; 14.AZ.18.157; 14.AZ. 18.158; 14.AZ.18.196; 14.AZ.18.223; 14.AZ.18.240; 14.AZ.18.244; 14.AZ.18.243; 14.AZ.18.247; 14.AZ.26.157; 14.AZ.26.158; 14.AZ.26.196; 14.AZ.26.223; 14.AZ.26.240; 14.AZ.26.244; 14.AZ.26.243; 14.AZ.26.247; 14.AZ.27.157; 14.AZ.27.158; 14. AZ.27.196; 14.AZ.27.223; 14.AZ.27.240; 14.AZ.27.244; 14.AZ.27.243; 14.AZ.27.247; 14.AZ.29.157; 14.AZ.29.158; 14.AZ. 29.196; 14.AZ.29.223; 14.AZ.29.240; 14.AZ.29.244; 14.AZ.29.243; 14.AZ.29.247; 14.AZ.54.157; 14.AZ.54.158; 14 .AZ.54.196; 14.AZ.54.223; 14.AZ.54.240; 14.AZ.54.244; 14.AZ.54.243; 14.AZ.54.247; 14.AZ.55.157; 14.AZ.55.158; 14.AZ .55.196; 14.AZ.55.223; 14.AZ.55.240; 14.AZ.55.244; 14.AZ.55.243; 14.AZ.55.247; 14.AZ.56.157; 14.AZ.56.158; 14.AZ.56.196 ; 14.AZ.56.223; 14.AZ.56.240; 14.AZ.56.244; 14.AZ.56.243; 14.AZ.56.247; 14.AZ.157.157; 14.AZ.157.158; 14.AZ.157.196; 14 .AZ.157.223; 14.AZ.157.240; 14.AZ.157.244; 14.AZ.157.243; 14.AZ.157.247; 14.AZ.196.157; 14.AZ.196.158; 14.AZ.196.196; 14.AZ .196.223; 14.AZ.196.240; 14.AZ.196.244; 14.AZ.196.243; 14.AZ.196.247; 14.AZ.223.157; 14.AZ.223.158; 14.AZ.223.196; 14.AZ.223.223 ; 14.AZ.223.240; 14.AZ.223.244; 14.AZ.223.243; 14.AZ.223.247; 14.AZ.240.157; 14.AZ.240.158; 14.AZ.240.196; 14.AZ.240.223; 14 .AZ.240.240; 14.AZ.240.244; 14.AZ.240.243; 14.AZ.240.247; 14.AZ.244.157; 14.AZ.244.158; 14.AZ.244.196; 14.AZ.244.223; 14.AZ .244.240; 14.AZ.244.244; 14.AZ.244.243; 14.AZ.244.247; 14.AZ.247.157; 14.AZ.247.158; 14.AZ.247.196; 14.AZ.247.223; 14.AZ.247.240 ; 14.AZ.247.244; 14.AZ.247.243; 14 .AZ.247.247;

14.BF 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.

  The contents of all the above references and patent citations are hereby incorporated by reference at the location of those citations. The contents of the cited part or page of the above cited reference are specifically incorporated herein by reference. The present invention has been described in sufficient detail to enable those skilled in the art to make and use the contents of the above claims. It will be apparent that certain modifications of the claimed methods and compositions may be within the scope and spirit of the invention.

In the above claims, the subscript and superscript of the predetermined variable are different. For example, R ₁ is different from R ¹ .

Claims (118)

Conjugates containing immunomodulatory compounds linked to one or more phosphonate groups, or pharmaceutically acceptable salts or solvates thereof. One or more of a compound of any one of formulas 500-547 substituted with A ⁰ groups, conjugate according to claim 1 or a pharmaceutically acceptable salt or solvate thereof:
here:
A ⁰ is A ¹ , A ² or W ³ provided that the conjugate comprises at least one A ¹ ;
A ¹ is the following:

Is:
A ² is the following:

Is:
A ³ include the following:

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 is; and ^{when Y 2} is bonded to two phosphorus atoms, ^{Y 2} also, C (R ²⁾ may be a ^{(R 2);}
R ^x is independently H, R ¹ , R ² , W ³ , a protecting group or the following formula:

Is:
here:
R ^y is independently H, W ³ , R ² or a protecting group;
R ¹ is independently H or alkyl having 1 to 18 carbon atoms;
R ² is independently H, R ¹ , R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups or 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, or alkynyl having 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO _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.
Conjugate. The conjugate of claim 2 having the formula: or a pharmaceutically acceptable salt or solvate thereof:
[DRUG]-(A ⁰ ) _nn
here:
DRUG is any one compound of Formula 500-547; and nn is 1, 2, or 3.
Conjugate. 13. A conjugate according to claim 2 having any one of formulas 1-151, wherein:
One A ⁰ is A ¹ ; each X ⁵⁰ is independently hydrogen, F, Cl, CF ₃ , CN, methyl or tertiary butyl;
X ⁵¹ is hydrogen, halo, trifluoromethyl, (C1-C3) alkyl, cyano or (C1-C3) alkoxy;
X ⁵² is hydrogen, fluoro, chloro, bromo, methyl or trifluoromethyl;
X ⁵³ is —O— or —S—;
X ⁵⁴ and X ⁵⁵ are independently selected from hydrogen or C ₁ -C ₁₈ acyl;
X ⁵⁶ is hydrogen, C ₁ -C ₁₈ acyl or

Or X ⁵⁴ is hydrogen and X ⁵⁵ and X ⁵⁶ are taken together,

Is
X ⁵⁷ is H, amino, hydroxy or halogen, wherein the halogen is selected from Cl and Br;
X ⁵⁸ is hydrogen, F, Cl, CF _3, cyano, is methyl or t- butyl;
X ⁵⁹ is hydrogen, CH ₂ OH;
X ⁶⁰ is CO (CH ₂ ) ₆ CONMe (CH ₂ ) ₂ SO ₃ H;
^X62 is methyl, chloro or trifluoromethyl;
X ⁶³ is H, methyl, ethyl, cyclopropyl, vinyl or trifluoromethyl;
^X64 is H, methyl, ethyl, cyclopropyl, chloro, vinyl, allyl, 3-methyl-1-buten-1-yl;
^X65 is hydrogen or F; and Ar is aryl or heteroaryl,
Conjugate. Each ^{A 1} is, the following formula:

The conjugate according to any one of claims 2 to 4, which is Each ^{A 1} is, the following formula:

The conjugate according to any one of claims 2 to 4, which is Each ^{A 1} is, the following formula:

The conjugate according to any one of claims 2 to 4, which is Each ^{A 1} is, the following formula:

The conjugate according to any one of claims 2 to 4, which is Each ^{A 1} is, the following formula:

A conjugate according to any one of claims 2 to 4, wherein:
Where W ^5a is a carbocycle or heterocycle, wherein W ^5a is independently substituted with 0 or 1 R ² groups,
Conjugate. The conjugate according to any one of claims 2 to 4, wherein M12a is 1. Each ^{A 1} is, the following formula:

The conjugate according to any one of claims 2 to 4, which is Each ^{A 1} is, the following formula:

The conjugate according to any one of claims 2 to 4, which is Each ^{A 1} is, the following formula:

A conjugate according to any one of claims 2 to 4, wherein:
Wherein W ^5a is a carbocycle, which is separately substituted with 0 or 1 R ² groups,
Conjugate. Each ^{A 1} is, the following formula:

A conjugate according to any one of claims 2 to 4, wherein:
here:
Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Conjugate. Each ^{A 1} is, the following formula:

A conjugate according to any one of claims 2 to 4, wherein:
Where: W ^5a is a carbocycle, which is separately substituted with 0 or 1 R ² groups,
Conjugate. Each ^{A 1} is, the following formula:

A conjugate according to any one of claims 2 to 4, wherein:
Where: W ^5a is a carbocycle or heterocycle, wherein W ^5a is independently substituted with 0 or 1 R ² groups,
Conjugate. Each ^{A 1} is, the following formula:

A conjugate according to any one of claims 2 to 4, wherein:
here:
Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Conjugate. Each ^{A 2} is, the following equation:

The conjugate according to any one of claims 2 to 17, which is Each ^{A 2} is, the following equation:

The conjugate according to any one of claims 2 to 17, which is The conjugate according to any one of claims 2 to 17, wherein each M12b is 1. M12b is a 0, ^{Y 2} is a bond and ^{W 5} is a carbocycle or heterocycle, wherein, ^{W 5} is optionally independently substituted with 1, 2 or 3 21. A conjugate according to claim 20, substituted with ² R2 groups. Each ^{A 2} is, the following equation:

A conjugate according to any one of claims 2 to 17, wherein:
Wherein W ^5a is a carbocyclic or heterocyclic ring, wherein W ^5a is optionally substituted separately with one, two or three R ² groups,
Conjugate. 23. The conjugate according to claim 22, wherein M12a 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} is, the following equation:

The conjugate according to any one of claims 2 to 17, which is Each ^{A 2} is, the following equation:

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} is, the following equation:

The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} is, the following equation:

The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
Y ^1a is O or S; and Y ^2a is O, N (R ^x ) or S.
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
Here, Y ^2b is O or N (R ^x ),
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Conjugate. 34. The conjugate according to claim 33, wherein M12d is 1. Each ^{A 3} is, the following equation:

The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} is, the following equation:

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} is, the following equation:

The conjugate according to any one of claims 2 to 27, wherein W ⁵ is phenyl conjugate of claim 38. 40. The conjugate of claim 39, wherein M12b is 1. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
Y ^1a is O or S; and Y ^2a is O, N (R ^x ) or S.
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
Here, Y ^2b is O or N (R ^x ),
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Conjugate. R ¹ is H, conjugate of claim 43. 45. The conjugate of claim 44, wherein M12d is 1. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
Wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups,
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
Wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups,
Conjugate. Each ^{A 3} is, the following equation:

The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} is, the following equation:

The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} is, the following equation:

The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
Y ^1a is O or S; and Y ^2a is O, N (R ² ) or S.
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
Y ^1a is O or S;
Y ^2b is O or N (R ² ); and Y ^2c is O, N (R ^y ) or S.
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
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.
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
Here, Y ^2b is O or N (R ² ),
Conjugate. Each ^{A 3} is, the following equation:

The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} is, the following equation:

The conjugate according to any one of claims 2 to 27, wherein Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
Y ^1a is O or S; and Y ^2a is O, N (R ² ) or S.
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
Y ^1a is O or S;
Y ^2b is O or N (R ² ); and Y ^2c is O, N (R ^y ) or S.
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
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.
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
here:
Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Conjugate. Each ^{A 3} is, the following equation:

28. A conjugate according to any one of claims 2 to 27, wherein:
Here, Y ^2b is O or N (R ² ),
Conjugate. A ⁰ is the following formula:

A conjugate according to claim 3, wherein:
Where each R is independently alkyl.
Conjugate. The following formula:

A conjugate according to claim 1, 2, 3 or 4, or a pharmaceutically acceptable salt or solvate thereof, having:
here:
DRUG is an immunomodulatory 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 - is;
R ^x is independently H, R ² , W ³ , a protecting group or the following 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 , wherein each R ⁴ is independently 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, or alkynyl having 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
M2 is 1, 2 or 3;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
nn is 1, 2 or 3; and L is a direct bond or linking group,
Conjugates, or pharmaceutically acceptable salts or solvates thereof. Each R ^x has the following formula:

66. The conjugate of claim 64, wherein:
Y ^1a is O or S; and Y ^2c is O, N (R ^y ) or S.
Conjugate. Each R ^x has the following formula:

66. The conjugate of claim 64, wherein:
Y ^1a is O or S; and Y ^2d is O or N (R ^y ),
Conjugate. Each R ^x has the following formula:

66. A conjugate according to claim 64, wherein Each ^{R y} is, independently, is H or alkyl with 1 to 10 carbons, conjugate according to any one of claims 65 to 67. Each R ^x has the following formula:

66. A conjugate according to claim 64, wherein Each R ^x has the following formula:

66. A conjugate according to claim 64, wherein Each R ^x has the following formula:

66. A conjugate according to claim 64, wherein Each ^{Y 1} is O or S, conjugate of claim 64. Each ^{Y 2} is an O, N ^{(R y)} or S, conjugate of claim 64. The conjugate according to any one of claims 64 to 73, wherein nn is 1. 74. The conjugate according to any one of claims 64-73, wherein nn is 2. 74. The conjugate according to any one of claims 64-73, wherein nn is 3. 65. The conjugate according to claim 64, wherein the kinase inhibitor compound is a compound of any one of formulas 500-547. 78. The conjugate of claim 77, wherein each L has a molecular weight of about 20 daltons to about 400 daltons. 78. The conjugate of claim 77, wherein each L has a length of about 5 angstroms to about 300 angstroms. 78. The conjugate of claim 77, wherein each L separates any one compound of formula 500-547 and the phosphorus of the phosphonate group by about 5 angstroms to about 200 angstroms (inclusive). Each L is a divalent branched or unbranched saturated or unsaturated hydrocarbon chain, the hydrocarbon chain having 2 to 25 carbon atoms, wherein one of the carbon atoms Or more are optionally replaced with (-O-), wherein the chain is optionally substituted on the carbon with one or more substituents; the substituent _{is, (C} 1 _{~C 6) alkoxy, (C} 3 _{~C 6) cycloalkyl, (C} 1 _{~C 6) alkanoyl, (C} 1 _{~C 6) alkanoyloxy, (C} 1 _~C 6) _{alkoxycarbonyl, (C} 1 _{~C 6)} alkylthio, azido, cyano, nitro, halo, hydroxy, oxo (= O), carboxy, aryl, aryloxy, heteroaryl and heteroaryloxy, to claim 77 The conjugates described. Each L is a formula W-A, 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 combinations thereof, wherein 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 78. The conjugate of claim 77, wherein (R) -S (O) _M2- or a direct bond; wherein each R is independently H or alkyl having 1-10 carbons. 83. The conjugate of claim 82, wherein each A is an alkylene having 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 , where n is between about 1 and about 10; and 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; wherein each R is an independently, H or _(C 1 _{~C 6)} alkyl, wherein Item 80. The conjugate according to Item 77. 78. A conjugate according to claim 77, wherein each L is methylene, ethylene or propylene. 78. The conjugate of claim 77, wherein each L is a carbon atom of L and is linked to P. 90. A conjugate according to any one of claims 1 to 89, isolated and purified. The conjugate according to any one of claims 1 to 90, which is not an anti-inflammatory compound. 92. A conjugate according to any one of claims 1 to 91 which is not an anti-infective agent. 93. The conjugate according to any one of claims 1 to 92, which is not a compound that is not a kinase inhibitor. 94. The conjugate according to any one of claims 1 to 93, wherein the conjugate is not a compound that is active against metabolic diseases. 95. The conjugate according to any one of claims 1 to 94, wherein the conjugate is not an antiviral agent. 96. The conjugate according to any one of claims 1 to 95, wherein the conjugate is not a nucleoside. 99. The conjugate according to any one of claims 1 to 96, wherein the conjugate is not an IMPDH inhibitor. 98. The conjugate of any one of claims 1 to 97, wherein the conjugate is not an antimetabolite. 99. The conjugate according to any one of claims 1 to 98, wherein the conjugate is not a PNP inhibitor. 101. A conjugate according to any one of claims 2 to 99, which is not a substituted compound of any one of formulas 500-533, 535-541 or 543-547. 101. A conjugate according to any one of claims 2 to 100 which is not a substituted compound of formula 534 or 542. 102. A conjugate according to any one of claims 4 to 101 which is not a compound of any one of formulas 1 to 104, 107 to 124 or 128 to 151. 103. A conjugate according to any one of claims 4 to 102 which is not a compound of formula 105-106 or 125-127. Kinase inhibitor conjugates as described herein. A compound of formula MBF. 106. The compound of claim 105, selected from Table 100. 105. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the conjugate of any one of claims 1-89 and 91-104 or the compound of claim 105 or 106. 105. A unit dosage form containing the conjugate of any one of claims 1-89 and 91-104 or the compound of claim 105 or 106 and a pharmaceutically acceptable excipient. 109. A method of inhibiting an immune response in vitro or in vivo, wherein an analyte in need of such treatment is a conjugate according to any one of claims 1-89 and 91-104 or claim 105 or 106. A method comprising the step of contacting with a compound described in 1. 110. The method of claim 109, wherein the contacting is made in vivo. 105. A method of modulating an immune response in a mammal comprising administering to said mammal a conjugate according to any one of claims 1 to 89 and 91 to 104 or a compound according to claim 105 or 106. A method comprising the steps. 112. The method of claim 111, wherein the compound is formulated with a pharmaceutically acceptable carrier. 113. The method of claim 112, wherein the formulation further comprises a second active ingredient. 113. The method of claim 111 or 112, wherein the immune response is suppressed. 109. A conjugate according to any one of claims 1 to 89 and 91 to 104 or a compound according to claim 105 or 106 for use in medical therapy. 107. Use of a conjugate according to any one of claims 1 to 89 and 91 to 104 or a compound according to claim 105 or 106 for the preparation of a medicament for modulating an immune response in an animal. The phosphate-substituted immunomodulatory conjugates described herein. Methods for preparing the conjugates described in the schemes and examples herein.