JP2007529421A - Kinase inhibitor phosphonate conjugate - Google Patents

Abstract

The present invention relates to phosphorus-substituted kinase inhibitory compounds, compositions containing such compounds and conjugates, and therapeutic methods comprising administering such compounds and conjugates, as well as such compounds and conjugates. It relates to processes and intermediates useful for preparing bodies. Furthermore, the present invention provides compositions and methods useful for inhibiting at least one kinase that may have therapeutic activity against diseases associated with kinase activity (eg, cancer).

Description

(Priority of invention)
This application claims priority benefit under 35 USC 119 (e) for US Provisional Patent Application No. 60 / 622,962, filed October 26, 2004, Claims priority benefit under 35 USC 119 (e) for US Provisional Patent Application No. 60/531932, filed December 22, 2003, and this application also Both claim the benefit of priority to US patent application no. 10/832811 and PCT application no. PCT / US2004 / 013062, filed April 26, 2004. Each of the above is hereby incorporated by reference in its entirety.

(Field of Invention)
The present invention relates generally to phosphonate-containing compounds having kinase inhibitory activity (ie, compounds that inhibit at least one kinase).

(Background of the Invention)
Improving the delivery of drugs and other drugs to target cells and tissues has been the focus of all research for many years. Many attempts have been made to develop effective methods for transporting biologically active molecules into cells both in vivo and in vitro, but overall satisfaction is that Not yet proven. It is often difficult and inefficient to minimize the intracellular redistribution of the drug (eg, relative to neighboring cells) while optimizing the association of the inhibitor with its intracellular target It is.

  Currently, most drugs that are administered parenterally to patients are not targeted, thereby leading to systemic delivery of the drug to the cells and tissues of the body, where the drug is not necessary and often undesirable . This systemic delivery can result in side effects and often limits the dose of drugs (eg, glucocorticoids and other anti-inflammatory drugs) that can be administered. In comparison, oral administration of drugs is generally recognized as a traditional and economical method of administration. However, oral administration of a drug may result in (a) ingestion of drugs through cell and tissue barriers (eg, blood brain barrier, endothelial cells, or cell membranes) and / or (b) Can result in a temporary retention of the drug in the tube. Thus, the main goal was to develop methods for agents that specifically target cells and tissues. The benefits of such treatment include avoiding the overall physiological effects of improper delivery of such agents to other cells and tissues (eg, non-infected cells).

  Thus, therapeutic agents (eg, agents that inhibit at least one kinase with improved pharmacological properties, improved kinase inhibitory activity and pharmacokinetic properties (improved oral bioavailability, greater efficacy) And a drug with a) that has an extended effective half-life in vivo. Such inhibitors have therapeutic uses (eg, anticancer agents). Thus, novel kinase inhibitors should have fewer side effects, have a simpler dosing schedule, and be orally active. In particular, there is a need for less cumbersome dosing regimens (eg, one pill once a day).

  Assay methods that can determine the presence, absence, or amount of kinase inhibition are practically useful in the search for kinase inhibitors as well as to diagnose the presence of conditions associated with kinase activity.

(Summary of the Invention)
Intracellular targeting can be achieved by methods and compositions that allow biologically active agents to accumulate and retain inside the cell. The present invention provides novel analogs of kinase inhibitory compounds (ie, compounds that inhibit the activity of at least one kinase). Such novel kinase inhibitory analogs have the utility of kinase inhibitory compounds and provide intracellular accumulation as needed. Furthermore, the present invention provides compositions and methods useful for inhibiting at least one kinase that may have therapeutic activity against diseases associated with kinase activity (eg, cancer).

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

  The compounds of the present invention include kinase inhibitor compounds having at least one phosphonate group. Accordingly, in one embodiment, the present invention provides a conjugate comprising a kinase inhibitor compound linked to one or more phosphonate groups.

  In another embodiment, the present invention provides one or more phosphonates and formula I:

の下部構造を含む化合物、またはその薬学的に受容可能な塩を提供し、ここで、Ｌ^１およびＬ^２は、−Ｎ−または−ＣＲ^ａ−であり；そしてＲ^ａは、水素、アルキル、置換アルキル、アリール、または置換アリールである。

Or a pharmaceutically acceptable salt thereof, wherein L ¹ and L ² are —N— or —CR ^a —; and R ^a is hydrogen, alkyl, Substituted alkyl, aryl, or substituted aryl.

  In another embodiment, the present invention provides one or more phosphonates and Formula II:

の下部構造を含む化合物を提供する。

A compound comprising the substructure of

  In another embodiment, the invention provides for one or more phosphonates and Formula IIIa, Formula IVa, or Formula Va:

の下部構造を含む化合物を提供する。

A compound comprising the substructure of

  In another embodiment, the present invention relates to one or more phosphonates and Formula III, Formula IV, or Formula V:

の下部構造を含む化合物を提供する。

A compound comprising the substructure of

  In another embodiment, the present invention provides compounds of formulas 1-4:

のいずれか１つの化合物を提供し、ここで：
Ａ^０は、Ａ^１であり；
Ａ^１は：

Provide one of the compounds where:
A ⁰ is A ¹ ;
A ¹ is:

であり；
Ａ^３は：

Is;
A ³ is:

であり、
Ｙ^１は、独立してＯ、Ｓ、Ｎ（Ｒ^Ｘ）、Ｎ（ＯＲ^Ｘ）、またはＮ（Ｎ（Ｒ^Ｘ）（Ｒ^Ｘ））であり；
Ｙ^２は、独立して結合、Ｏ、Ｎ（Ｒ^Ｘ）、Ｎ（ＯＲ^Ｘ）、Ｎ（Ｎ（Ｒ^Ｘ）（Ｒ^Ｘ））、または−Ｓ（Ｏ）_Ｍ２−であり；そして、Ｙ^２は、２つのリン原子に結合する場合、Ｙ^２はまた、Ｃ（Ｒ^２）（Ｒ^２）であり得；
Ｒ^Ｘは、独立してＨ、Ｒ^２、Ｗ^３、保護基、または次式：

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

であり；
Ｒ^ｙは、独立してＨ、Ｗ^３、Ｒ^２、または保護基であり；
Ｒ^２は、独立してＨ、Ｒ^３、またはＲ^４であって、ここで、各々のＲ^４は、独立して、０〜３個のＲ^３基で置換され；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃ、またはＲ^３ｄであるが、ただし、Ｒ^３がヘテロ原子に結合される場合、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄであり；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３、または−ＮＯ_２であり；
Ｒ^３ｂは、Ｙ^１であり；
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））であり；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^Ｘ、−Ｃ（Ｙ^１）ＯＲ^Ｘ、または−Ｃ（Ｙ^１）（Ｎ（Ｒ^Ｘ）（Ｒ^Ｘ））であり；
Ｒ^４は、１〜１８個の炭素原子からなるアルキル、２〜１８個の炭素原子からなるアルケニル、または２〜１８個の炭素原子からなるアルキニルであり；
Ｒ^５は、Ｒ^４であって、各々のＲ^４は、０〜３個のＲ^３基で置換され；
Ｗ^３は、Ｗ^４またはＷ^５であり；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５または-ＳＯ_２Ｗ^５であり；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、独立して０個〜３個のＲ^２基で置換され；
Ｗ^６は、独立して１個、２個または３個のＡ^３基で置換されるＷ^３であり；
Ｍ２は、０、１または２であり；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、独立して０または１であり；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｌ^１およびＬ^２は、独立して−Ｎ−または−ＣＲ^ａ−であるが、ただし、Ｌ^１またはＬ^２の一方のみが窒素原子であり；
Ｒ^ａは、水素、アルキル、アリール、または置換アリールであり
Ｒ^２０は、水素、アルキル、置換アルキル、シクロアルキル、置換シクロアルキルアリール、シクロアルキル、置換アリール、または−ＮＲ^ｂＲ^ｃであり；
Ｒ^ｂおよびＲ^ｃは、独立して、水素、アルキル、置換アルキル、アリール、置換アリール、またはアラルキルであり；
Ｒ^２１は、水素、アルキル、シクロアルキル、置換シクロアルキル、置換アルキル、アリール、置換アリール、アラルキルまたは置換アラルキルであり；そして
Ｒ^２２およびＲ^２３は、独立して、水素、アルキル、置換アリール、またはアラルキルである。

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 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , provided that when R ³ is attached to a heteroatom, R ³ is R ^3c or R ^3d ;
R ^3a is F, Cl, Br, I, —CN, N ₃ , or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^X , —N (R ^X ) (R ^X ), —SR ^X , —S (O) R ^X , —S (O) ₂ R ^X , —S (O) (OR ^X ), —S (O) ₂ (OR ^X ), —OC (Y ¹ ) R ^X , —OC (Y ¹ ) OR ^X , —OC (Y ¹ ) (N (R ^X ) (R ^X )), —SC ( Y ¹ ) R ^X , —SC (Y ¹ ) OR ^X , —SC (Y ¹ ) (N (R ^X ) (R ^X )), —N (R ^X ) C (Y ¹ ) R ^X , —N ( R ^X ) C (Y ¹ ) OR ^X , or —N (R ^X ) C (Y ¹ ) (N (R ^X ) (R ^X ));
R ^3d is —C (Y ¹ ) R ^X , —C (Y ¹ ) OR ^X , or —C (Y ¹ ) (N (R ^X ) (R ^X ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , each R ⁴ is substituted with 0-3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0-3 R ² groups;
W ⁶ being one independently a ^{W 3} is substituted with two or three ^{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;
L ¹ and L ² are independently —N— or —CR ^a — provided that only ^one of L ¹ or L ² is a nitrogen atom;
R ^a is hydrogen, alkyl, aryl, or substituted aryl and R ²⁰ is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkylaryl, cycloalkyl, substituted aryl, or —NR ^b R ^c ;
R ^b and R ^c are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or aralkyl;
R ²¹ is hydrogen, alkyl, cycloalkyl, substituted cycloalkyl, substituted alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; and R ²² and R ²³ are independently hydrogen, alkyl, substituted aryl, or Aralkyl.

  In another embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excipient.

  In another embodiment, the present invention provides a method of increasing the accumulation and retention of a drug compound in cells, thus improving its therapeutic and diagnostic value, which method comprises one or more ( For example, it includes the step of linking the above compound to the phosphonate group of 1, 2, 3 or 4).

  In another embodiment, the invention provides a method of inhibiting the activity of at least one kinase in an animal (eg, a mammal), the method comprising administering to the animal an effective amount of a compound of the invention. Is included.

  In another embodiment, the present invention provides a unit dosage form comprising a compound of the present invention and a pharmaceutically acceptable excipient.

  In another embodiment, the invention provides a method for inhibiting a kinase in vitro or in vivo, wherein the method comprises contacting a sample in need of such treatment with a compound of the invention. Is included.

  In another embodiment, the invention provides a method of treating cancer in an animal (eg, mammal) in need of treating cancer, wherein the method comprises administering an effective amount of a compound of the invention to the animal. The step of administering to.

  In another embodiment, the present invention relates to compounds of the invention for use in medicine, preferably for use in the treatment of conditions associated with kinase activity (eg, increased kinase activity), as well as kinase activity. There is provided the use of a compound of the invention for the manufacture of a medicament useful for the treatment of a condition (eg, associated with increased kinase activity).

  In another embodiment, the invention provides the use of a compound according to any one of claims 1 to 55 for the preparation of a medicament for inhibiting a kinase in an animal (eg a mammal). To do.

  In another embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating cancer in an animal (eg, a mammal).

  In another embodiment, the present invention provides a method for preparing the compounds of the invention, as described in the schemes and examples herein.

  In another embodiment, the present invention provides a method of preparing a pharmaceutical composition, comprising combining a pharmaceutically acceptable excipient with a compound of the present invention.

  In another embodiment, the present invention provides the processes and novel intermediates disclosed herein. This process and intermediates are useful for preparing the compounds of the invention. Some compounds of the present invention are useful for preparing other compounds of the present invention.

  In another aspect of the invention, the activity of the kinase is inhibited by a method comprising treating a sample suspected of containing the kinase with a compound or composition of the invention.

(Detailed description of the invention)
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it is not intended that the invention be limited to these embodiments. 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 embodiments.

  Many of the current treatment regimens for cell proliferative disorders (eg, psoriasis and cancer) utilize compounds that inhibit DNA synthesis. Such compounds are toxic to whole cells, but their toxic effects on rapidly dividing cells (eg, tumor cells) can be beneficial. Alternative approaches to antiproliferative drugs that act by mechanisms other than inhibition of DNA synthesis have the potential to show increased selectivity of action.

  Recently, it has been discovered that conversion of a portion of DNA into an oncogene (ie, a gene that induces the formation of malignant tumor cells upon activation) can cause the cell to become cancerous (Bradshaw, Mutagenesis 1986). , 1, 91). Some such oncogenes cause the production of peptides that are receptors for growth factors. The growth factor receptor complex then leads to an increase in cell proliferation. For example, it is known that some oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes (Yarden et al., Ann. Rev. Biochem., 1988, 57, 443; Larsen et al., Ann. Reports in Med. Chem. 1989, Chpt. 13).

  Receptor tyrosine kinases are important in the transmission of biochemical signals that initiate cell replication. Tyrosine kinases are large enzymes that span cell membranes, including extracellular binding domains for growth factors (eg, epidermal growth factor (EGF)) and intracellular portions that function as kinases that phosphorylate tyrosine amino acids in proteins. And therefore affect cell proliferation. Different classes of receptor tyrosine kinases are known based on a family of growth factors that bind to different receptor tyrosine kinases (Wilks, Advances in Cancer Research, 1993, 60, 43-73). The classification includes class I receptor tyrosine kinases, including the EGF family of receptor tyrosine kinases (eg, EGF, TGFα, NEU, erbB, Xmrk, HER and let23 receptors), the insulin family of receptor tyrosine kinases (eg, insulin, IGFI and Class II receptor tyrosine kinases, including insulin-related receptors (IRR receptors), and class III receptors, including the platelet derived growth factor (PDGF) family of receptor tyrosine kinases (eg, PDGFα, PDGFβ and colony-stimulating factor 1 (CSF1) receptors) Examples include tyrosine kinases.

  Class I kinases (eg, the EGF family of receptor tyrosine kinases) are known to occur at high frequency in common human cancers such as: Breast cancer (Sainsbury et al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21 and Klijin et al., Breast Cancer Res. Treat., 1994, 29, 73), non-small cell lung cancer (NSCLC) (adenocarcinoma (Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al., Int. J. Cancer, 1990, 45, 269; and Rusch et al., Cancer Research, 1993, 53, 2379), and squamous cell carcinoma of the lung (Hendle) Cancer Cells, 1989, 7, 347)), bladder cancer (Neal et al., Lancet, 1985, 366), esophageal cancer (Mukaida et al., Cancer, 1991, 68, 142), gastrointestinal cancer (eg, colon , Rectum) or gastric cancer (Bolen et al., Oncogene Res., 1987, 1, 149), prostate cancer (Visakorpi et al., Histochem. J., 1992, 24, 481), leukemia (Konaka et al., Cell, 1984, 37, 1035), as well as ovarian, bronchial or pancreatic cancer (European Patent Specification No. 0400466). Furthermore, as human tumor tissues are tested for the EGF family of receptor tyrosine kinases, it is expected that their broad presence will be demonstrated in additional cancers (eg, thyroid cancer and uterine cancer). It is also known that EGF-type tyrosine kinase activity is detected more frequently in malignant cells while it is rarely detected in normal cells (Hunter, Cell, 1987, 50, 823). EGF receptors with tyrosine kinase activity are found in many human cancers (eg, brain tumors, lung squamous cell tumors, bladder tumors, stomach tumors, breast tumors, head and neck tumors, esophageal tumors, gynecological tumors and Thyroid tumor) (WJ Gullick, Brit. Med. Bull., 1991147, 87).

  Thus, inhibitors of receptor tyrosine kinases are valuable as selective inhibitors of the growth of mammalian cancer cells (Yaish et al., Science, 1988, 242, 933). Support for this concept is that Erubstatin, an EGF receptor tyrosine kinase inhibitor, specifically attenuates the growth of transplanted human breast cancer that expresses EGF receptor tyrosine kinase in athymic nude mice, but does not express EGF receptor tyrosine kinase. Provided by demonstration that it does not affect the growth of carcinomas (Toi et al., Eur. J. Cancer Clin. Oncol., 1990, 26, 722). Various derivatives of styrene are also stated to have tyrosine kinase inhibitory properties (European Patent Application Nos. 0 211 363, 0 304 43 and 0 322 738) and serve as antitumor agents. In vitro inhibitory effects of two such styrene derivatives that are EGF receptor tyrosine kinase inhibitors have been shown to grow human squamous cell carcinoma inoculated in nude mice (Yoneda et al., Cancer Research, 1991, 51). 4430). A variety of known tyrosine kinase inhibitors are described in T.W. R. Burke Jr. In a more recent review (Drugs of the Future, 1992, 17, 119).

  Kinase inhibitors have valuable pharmacological properties and can be used, for example, as anti-tumor drugs and as drugs against atherosclerosis. Protein phosphorylation has long been known as an important step in cell differentiation and proliferation. Phosphorylation is catalyzed by protein kinases, which are divided into serine / threonine kinases and tyrosine kinases. Serine / threonine kinases include protein kinase C, and tyrosine kinases include PDGF (platelet derived growth factor) receptor tyrosine kinase and Bcr-Abl kinase.

  Chronic myelogenous leukemia (CML) is a hematologic stem cell disorder associated with a specific chromosomal translocation known as the Philadelphia chromosome. The Philadelphia chromosome is detected in 95% of patients with CML and 20% of acute lymphocytic leukemia (ALL). The result of the molecular translocation is the fusion of the abl pre-oncogene to the bcr gene, resulting in the production of an activated form of Abl tyrosine protein kinase. The Bcr-Abl protein is capable of inducing leukemia in mice and is therefore related to the protein responsible for these diseases. Thus, a kinase inhibitor inhibits a cellular kinase (eg, Bcr-Abl) for a disease state. Inhibitors are useful treatments for these disorders because the tyrosine kinase activity of the Bcr-Abl protein is essential for its ability to transform.

  In addition, kinase inhibitors prevent the development of resistance (multidrug resistance) or remove existing resistance to other chemotherapeutic drugs in the treatment of cancer with other chemotherapeutic drugs.

  Two processes, the formation of new blood vessels from the differentiation of endothelial and hemangioblasts during embryo development (vasculogenesis), and the growth of new capillaries from existing blood vessels (angiogenesis ( angiogenesis)) relates to the development of the vasculature of animal organs and tissues. A transition phase of new blood vessel formation (neovascularization) also occurs in adults (eg, during the menstrual cycle, pregnancy, and wound healing). On the other hand, many diseases (eg, retinopathy, psoriasis, hemangioblastoma, hemangiomas and neoplastic diseases (eg, solid tumors)) are known to be associated with deregulation of angiogenesis. The combined process of angiogenesis and angiogenesis relates to a full range of molecules, in particular angiogenic growth factors and endothelial receptors, and cell adhesion molecules.

  Recent discoveries are at the heart of the network that regulates the growth and differentiation of the vasculature and its components, and during the development and normal growth of the embryo, as well as cell receptors along with cellular receptors, both during numerous pathological malformations and diseases Shows the presence of angiogenic factors known as endothelial cell growth factor (VEGF) (see Breier, G. et al., Trends in Cell Biology 6,454-6 (1996) and references cited therein). )

  VEGF is a dimeric, disulfide-linked 46 kDa glycoprotein and is related to platelet-derived growth factor (PDGF). VEGF is produced by normal and tumor cell lines, is an endothelial cell-specific mitogen, exhibits angiogenic activity in in vivo test systems (eg, rabbit cornea), and is chemotactic for endothelial cells and monocytes. It induces plasminogen activator in endothelial cells, which in turn is associated with proteolytic degradation of the extracellular matrix during capillary formation. Many isoforms of VEGF show comparable biological activity, but are known to differ in the type of cells secreting the isoform and the ability of the isoform to bind to heparin. In addition, there are other members of the VEGF family, such as placental growth factor (PLGF) and VEGF-C.

  The VEGF receptor is a transmembrane receptor tyrosine kinase. They are characterized by an extracellular domain that includes seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptors (eg, VEGFR-1, VEGFR-2 and VEGFR-3) are known.

  Many human tumors, particularly gliomas and carcinomas, express high levels of VEGF and its receptors. This led to the hypothesis that VEGF released by tumor cells stimulates capillary growth and tumor endothelium growth in a paracrine manner, thus accelerating tumor growth through improved blood supply. Increased VEGF expression may explain the occurrence of cerebral edema in patients with glioma. Direct evidence of the role of VEGF as a tumor angiogenesis factor in vivo comes from studies where VEGF expression or VEGF activity was inhibited. This was achieved through the use of antibodies that inhibit VEGF activity, dominant negative VEGFR-2 mutants with inhibited signal transduction, or antisense VEGF RNA technology. All approaches resulted in decreased proliferation of glioma cell lines or other tumor cell lines in vivo as a result of inhibited tumor angiogenesis.

  In addition, hypoxia, a number of growth factors and cytokines (eg, epidermal growth factor, transforming growth factor a, transforming growth factor A, interleukin 1, and interleukin 6) can cause VEGF expression in cell experiments. Induce. Angiogenesis is considered a requirement for tumors that grow beyond a maximum diameter of about 1-2 mm; up to this limit, oxygen and nutrients can be supplied to tumor cells by diffusion. Thus, any tumor, regardless of its origin and cause, relies on angiogenesis for its growth after reaching a certain size.

  Three major mechanisms play an important part in the activity of angiogenesis inhibitors against tumors: 1) inhibits proliferation into vascular (especially capillary) avascular resting cells and consequently Net tumor growth is lost due to the balance achieved between apoptosis and growth as; 2) migration of tumor cells is prevented due to the absence of blood flow to and from the tumor; and 3 ) Endothelial cell proliferation is inhibited, thus avoiding the paracrine growth stimulating effect normally exerted on the surrounding tissue by endothelial cells lining the vessel.

  Inhibitors of cyclin-dependent kinases such as Alvocidiv (US Pat. No. 4,900,727; also known as flavopiridol) are found in various cancers (gastrointestinal and colon tumors, leukemias and myeloma). (For example, Intl. J. Oncol., 1996, 9, 1143).

  Inhibitors of tyrosine kinases, including Bcr-Abl (eg, Gleevec) are useful in the treatment of chronic myeloid leukemia (CML) and other cancers that express these kinases (acute lymphocytic leukemia (ALL) and certain Potentially useful for the treatment of solid tumors). Gleevec has been approved for the treatment of inoperable and / or metastatic malignant gastrointestinal stromal tumors (GIST).

  Inhibitors of Flt3 tyrosine kinase (eg, CEP-701 (US Pat. No. 4,923,986) and Midostaurin (US Pat. No. 5,093,330)) have potential utility in the treatment of various cancers. (Cancer Res., 1999, 59, 10).

  Inhibitors of MAP Erk kinase, such as PD-184352 (US Pat. No. 6,251,943), have potential for a variety of oncological disorders, including colon cancer, breast cancer, pancreatic cancer and non-small cell lung cancer. (See, for example, Proc. Am. Soc. Clin. Oncol., 2003, 22, summary 816).

  Other kinase inhibitors, such as dramapimod (US Pat. No. 6,319,921), are potentially useful therapeutics for the treatment of inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn's disease. Has been identified as

  Other kinase inhibitors such as BAY-43-9006 (US Publication No. 2002/0165394) are potentially useful therapeutic agents for various cancers, including gastrointestinal and colon tumors, leukemias and carcinomas. (Curr. Pharm. Design, 2002, 8, 2269).

  Cytokine receptors are important for immune cell development and homeostasis. All of these receptors require the cytoplasmic tyrosine kinase JAK3 for signal transduction (Changelian, PS et al., Science, 2003, 302, 875). CP-690,550 (WO 02,096,909) is an orally available Janus kinase (JAK) -3 inhibitor for potential treatment of transplant rejection and psoriasis.

  Thus, therapeutic agents that are kinase inhibitors with improved pharmacological properties (eg, improved kinase inhibitory activity as well as drug kinetic properties (improved oral bioavailability, higher potency, and extended There is a need for drugs) having an effective half-life in vivo. Such inhibitors have therapeutic potential, for example as anticancer agents. This kinase inhibitor compound is provided herein and fulfills such a need, such as breast cancer, non-small cell lung cancer (NSCLC), adenocarcinoma, lung squamous cell carcinoma, esophageal cancer, gastrointestinal cancer, colon cancer, Rectal cancer, stomach cancer, prostate cancer, leukemia, ovarian cancer, bronchial cancer, pancreatic cancer, thyroid cancer, uterine cancer, brain cancer, lung squamous cell carcinoma, bladder cancer, stomach cancer, head and neck cancer, gynecological tumor And to treat thyroid tumors, to prevent the development of resistance (multi-drug resistance) in cancer treatment with other chemotherapeutic agents, or to eliminate existing resistance to other chemotherapeutic agents, retinopathy, hemangioblasts Tumor angiogenesis, myeloma, chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), inoperable and / or metastases for the treatment of cytomas, hemangiomas, and neoplastic diseases, gliomas Malignant gastrointestinal stromal tumor (G To inhibit ST), inflammatory diseases (e.g., rheumatoid arthritis, treatment of Crohn's disease), the treatment of cellular proliferative diseases, and may be used for the treatment of transplant rejection and psoriasis.

(Definition)
Unless otherwise stated, the following terms and phrases as used herein are to be interpreted as having the following meanings:
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 comprises a functional group or moiety in the molecule containing The terms “phosphonate” and “phosphonate group” are also separated from a compound so that the compound contains phosphorus having the above properties, 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 phosphonic acid, phosphonic monoester, phosphonic 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 So that the compound contains phosphorus having the above properties, as well as functional groups or moieties in the molecule containing a) single bond to oxygen and 4) single bond to another oxygen) It contains a functional group or functional moiety that contains a prodrug moiety that can be separated from the compound. 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) single-bonded to oxygen or nitrogen and 4) single-bonded to another oxygen or nitrogen) as well as the functional group or moiety in the molecule, the compound has the above properties It contains a functional group or moiety that contains a prodrug moiety that can be separated from the compound to contain phosphorus.

  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 an unstable 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. Krogsgard, H., B. Bloggaard, Hans, “Design and Application of Prodrugs. 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. A prodrug moiety may include an active metabolite or drug itself.

Exemplary prodrug moieties include hydrolysis sensitive or unstable 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 the cell membrane to enhance oral bioavailability. Alkoxycarbonyloxyalkyl esters (carbonates) can also enhance oral bioavailability as a prodrug moiety in the combination of compounds of the present invention. A representative acyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH ₂ OC (═O) C (CH ₃ ) ₃ . A representative 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. Benzyl analogs with acylated or alkylated phenols can yield this phenolic compound by the action of enzymes (eg, esterases, oxidases, etc.), which in turn undergo 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. II2345; 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 other thiol groups to form disulfides. 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. 39:25 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 used 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, planned manner. The 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 chelate formation). 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, acid or base salts 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.

As used herein, the term “substructure” refers to the removal of any hydrogen atom or substitutable group to provide an open valence for substitution of a group that includes a phosphonate group. Refers to a residue that can be removed. For example, the lower structure is a skeleton in which a substituent, -bond P (O) (OR ¹ ) ₂ is bonded. The substructure can have additional linked groups. For kinase inhibitor compounds that include at least one phosphonate group and a substructure, it is understood that the compound includes the substructure as at least part of the overall structure of the compound.

“Alkyl” is a C ₁ -C ₁₈ hydrocarbon containing normal, secondary, or tertiary 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).

“Alkylene” is a saturated branched or straight chain or cyclic hydrocarbon radical of C _{1 to} C ₁₈ carbon atoms that removes two hydrogen atoms from the same or two different carbon atoms of the parent alkane. And having 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.

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

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

“Arylalkyl” means an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal carbon atom or an sp ³ carbon atom) is replaced with an aryl radical. Typical arylalkyl groups include benzyl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 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, the alkyl portion (including alkanyl, alkenyl or alkynyl groups of arylalkyl groups) 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, arylalkyl and cycloalkyl, respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. To do. 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, An 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, Chapters 1, 3, 4, 6, 7 and 9; "The Chemistry of Heterocyclic Met" Wiley & Sons, New York, 1950-present), in particular, 13, 14, 16, 19 and 28; Am. Chem. Soc. (1960) 82: 5566. In one particular embodiment of the invention, a “heterocycle” includes a “carbocycle” as defined herein, where one or more (eg, one, two, three, or Four carbon atoms are replaced with heteroatoms (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, carbon-attached heterocycles include 2, 3, 4, 5 or 6 positions of pyridine, 3, 4, 5 or 6 positions of pyridazine, 2, 4, 5 or 6 positions of pyrimidine, pyrazine 2, 3, 5 or 6 position, furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole 2, 3, 4 or 5 position, oxazole, imidazole or thiazole 2, 4 or 5 position, 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, of isoquinoline Joined at 4, 5, 6, 7 or 8 positions. Even more typically, carbon-attached 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. Even 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. Monocyclic carbocycles have 3 to 6 ring atoms, still 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.

  The term “cycloalkyl” refers to a C1-C18 hydrocarbon containing one or more rings.

  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 mirror-image compounds that are not superimposable with each other.

  The term “treatment” or “treating” to the extent related to a disease or condition prevents the occurrence of the disease or condition, stops 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 the 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 the sign of rotation of plane polarized light 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 lack 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 can be optionally combined with the protecting group during synthetic procedures (ie, pathways or methods for preparing the compounds of the invention). Used to prevent side reactions. 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 more than one PG. 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”. The ether-forming group or ester-forming group can function as a chemical protecting group 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 discussed 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 incorporated herein by reference. In particular, Chapter 1, Protecting Groups: An Overview, 1-20, Chapter 2, Hydroxy Protecting Groups, 21-94, Chapter 3, Diol Protecting Groups, 95-117, Chapter 118, Chapter 154 Page, 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, hydrazines, and the like.

(Ether forming protecting group and ester forming protecting group)
Ester forming groups include: (1) phosphonate ester forming 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 cleavage or enzymatic cleavage or modification. Certain phosphonate moieties are stable under almost or almost all metabolic conditions. For example, a dialkyl phosphonate (again, the alkyl group is 2 or more carbons) may have adequate stability in vivo due to the slow rate of hydrolysis.

In connection with the phosphonate prodrug moiety, a number of structurally diverse prodrugs have been described for phosphonic acids (Freeman and Ross, 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、そしてそのフェニル炭素環は、０個〜３個のＲ_２基で置換されている。また、Ｙ_１がＯである場合、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, when Y ₁ is O, a lactic acid ester is formed, and when Y ₁ is N (R ₂ ), N (OR ₂ ), or N (N (R ₂ ) ₂ , a phosphonamidate ester is obtained. .

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 described 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 the included), 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-halo Rukirubenjiru (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 Including)), 2,2′-sihydroxybiphenyl, 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；および置換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）］；置換アルキルであって、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）；

; _C 4 -C ₈ esters of 2-carboxyphenyl; and substituted _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 the aryl moiety is substituted with 3 to five halogen atoms or one to 2 atoms or groups selected from: halogen, including C ₁ -C ₁₂ alkoxy (methoxy and ethoxy ), cyano, nitro, _OH, C 1 _{-C 12} haloalkyl (1 to 6 halogen atoms); _- CH 2 CCl ₃ ), C ₁ -C ₁₂ alkyl (including methyl and ethyl), C ₂ -C ₁₂ alkenyl or C ₂ -C ₁₂ alkynyl; alkoxyethyl [C ₁ -C ₆ alkyl (—CH ₂ —CH ₂ -O-CH 3, including _{(methoxyethyl));} a substituted alkyl, this is one of the groups indicated above for aryl, especially substituted by OH or 1 to 3 halo atoms has been is _{(-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、グリセリド脂質を含む脂肪酸は、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、本明細書における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、その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 (eg, α-D-β-diglycerides) (wherein fatty acids including glyceride lipids are generally naturally occurring saturated or unsaturated C _6-26 , C _6-18, or C _6-10 fatty acids (eg, Fatty acids such as linoleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoyl acid, linolenic acid), which are referred to herein via the glyceryl oxygen of their triglycerides Bound to the acyl of the parent compound;
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, a —C (O) O— or —P (O) (O—) ₂ group 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 compound to be protected is a phosphonate, the esters of structures 5-7, 11, 12, 21 and 23-26 are the corresponding amines in the case of compounds such as the alcohols or alkoxide salts (or 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もしくはＷ^５）Ｏ（（ＣＯ）Ｒ^３７）または−ＣＨ（Ｒ^１もしくは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）。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号を参照）。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、ピバロイルメチル基がある。これらは、経口投与のためのプロドラッグによる特定の用途を有する。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) An alkyl- or aryl-acyloxyalkyl group of R ³⁸ ) which is bound to the oxygen of the acidic group. Here, R ³⁷ and R ³⁸ are alkyl, aryl or alkylaryl groups (see US 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 pivaloylmethyl group. They have particular use with prodrugs for oral administration. Examples of such useful protecting groups include alkylacyloxymethyl esters and their derivatives, 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 embodiments, the protected acidic group is an ester of the acidic group and is the residue of a hydroxy-containing functional group. In other embodiments, amino compounds are used to protect this acid functionality. Suitable hydroxyl or amino-containing functional group residues are indicated above or can be found in WO 95/07920. Amino acids, amino acid esters, polypeptides or aryl alcohols are particularly important residues. 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 acidic functional groups are also described in WO 95/07920, and again, like the phosphonates of this' 920 publication, the acidic esters in this specification can be used to produce the same esters. It can be seen that it can be formed. Exemplary ester groups are defined at least as 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 acidic 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 yield the free acid.

  One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl 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-butoxy Methyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3- Bromotetrahydropyranyl, tetrahydropthiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydropthiopyranyl S, S-di Xoxide, 1-[(2-chloro-4-methyl) phenyl] -4-methoxypiperidin-4-yl, 1,4-dioxan-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- Fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl,
-P-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl);
Substituted benzyl ether (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-methoxyphenyldiphenyl Methyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4′-bromophenacyloxy) phenyldiphenylmethyl, 4,4 ′, 4 ″ -tris (4,5- Dichlorophthalimidophenyl) methyl, 4,4 ', 4 "-tris (levulinoylio) Ciphenyl) methyl, 4,4 ′, 4 ″ -tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4 ′, 4 ″ -dimethoxyphenyl) methyl, 1,1-bis (4- Methoxyphenyl) -1′-pyrenylmethyl, 9-anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S, S-dioxide);
Silyl ether (trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenyl Silyl, diphenylmethylsilyl, t-butylmethoxyphenylsilyl);
Esters (formic acid, benzoyl formate, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methoxyacetic acid, triphenylmethoxyacetic acid, phenoxyacetic acid, p-chlorophenoxyacetic acid, p-polyphenylacetic acid Phenylpropionic acid, 4-oxopentanoic acid (levulinic acid), 4,4- (ethylenedithio) pentanoic acid, pivalic acid, adamantate, crotonic acid, 4-methoxycrotonic acid, benzoic acid, p-phenyl benzoate, benzoic acid Acid 2,4,6-trimethyl (mesitoate));
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 in cleavage (2-iodobenzoate, 4-azide butyrate, 4-nitro-4-methyl pentanoate, o- (dibromomethyl) 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- Tetramethylbutyl) phenoxyacetate, 2,4-bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E) -2-methyl-2-butenoate (tigroate), o- (methoxy Carbonyl) benzoate, p-poly-vinyl Zoate, α-naphthoate, nitrate, alkyl N, N, N ′, N′-tetramethyl phosphorodiamidate, N-phenylcarbamate, boric acid, 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 acetals.

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- Butylphenyl) -1-methylethyl, 2- (2′- and 4′-pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropyl Allyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobe Jill, p- bromobenzyl, p- chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinyl benzyl, 9-anthrylmethyl, diphenylmethyl);
Groups that aid cleavage: (2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, 4-methylthiophenyl, 2,4- Dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (dihydroxybonyl) benzyl, 5-benzisoxazolyl Methyl, 2- (trifluoromethyl) -6-chromonylmethyl);
A group capable of photolytic cleavage: (m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl (o-nitrophenyl) methyl); urea derivative ( Phenothiazinyl- (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-dimethylcarboxamide) 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) Til, l-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);
Amides: (N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, 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-diphenyl maleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldi Silylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3-5-triazacyclohexane-2 -One, 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 -Cyclohexylidene);
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);
N-N 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-methoxybenzenesulfo , N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethyl Chroman-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 include carbamates and amides, even more typically —NHC (O) R ¹ or —N═CR ¹ N (R ¹ ) ₂ . 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 alkyl phosphate. R ¹⁰ is also taken together with the amino acid αN to form a proline residue (R ¹⁰ = —CH ₂ ) ₃ —). However, R ¹⁶ 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.

Another set of protecting groups includes amino-containing compounds, particularly amino acids, polypeptides, residues of protecting groups, —NHSO ₂ R, NHC (O) R, —N (R) ₂ , NH ₂ or —NH ( R) (H), whereby, for example, the carboxylic acid reacts (ie, couples) with the amine to form an amide, such as C (O) NR ₂ . Phosphonic acid is 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. Non-gene-encoded amino acids commonly encountered 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. , Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, B .; Edited 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 the compounds of the present invention. These conjugates are 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, conjugates between the amino group of R ³ and amino acid or polypeptide, is formed. 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 group or α-carboxyl group of the amino acid or the terminal amino group 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 an amide bond with this parent compound (but these groups may need to be protected during the synthesis of these conjugates, as further described below).

With respect to the carboxy-containing side chain of an amino acid or polypeptide, it can be seen that the carboxyl group is blocked, for example, 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 bonds or amide bonds with side chain amino groups or carboxyl groups are optionally under acidic (pH <3) conditions or basic (pH>), as the ester or amide with its parent molecule. 10) It is hydrolysable under conditions, 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 free base of the parent compound is readily formed from an ester or amino acid or polypeptide conjugate of the invention, for example, by conventional hydrolysis procedures.

  When the amino acid residue contains one or more chiral centers, any of its D, L, meso, threo or erythro (when appropriate) racemates, scalemate compounds or mixtures thereof can be used. In general, the D isomer is useful if these intermediates are hydrolyzed non-enzymatically (as when using their amides 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 (eg, glutamine and asparagine);
Polyamino-monocarboxylic acids 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-alkyl 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-aminoiso Butyric acid, α-aminodiethylacetic acid, α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid, α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid, α-aminoethylisopropylacetic acid, α-amino-n -Propylacetic acid, α-aminoisoamylacetic acid, α-methylaspartic acid, α-methylgluta Phosphate, 1-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-hydroxy acid, β-hydroxy acid, γ-hydroxy acid or ε-hydroxy acid (eg, homoserine, δ-hydroxynorvaline, γ-hydroxynorvaline and ε-hydroxynorleucine residues); canabin And canalin; γ-hydroxyornithine;
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 ether of cysteine or homocysteine);
Phenylalanine, tryptophan and ring-substituted α-amino acids (eg, phenylamino acids or cyclohexyl amino acids, α-aminophenylacetic acid, α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionic acid); phenylalanine analogs and derivatives Containing aryl, lower alkyl, hydroxy, guanidino, oxyalkyl ether, nitro, sulfur or halo-substituted phenyl (eg tyrosine, methyltyrosine and o-chloro-phenylalanine, p-chloro-phenylalanine, 3,4-dichloro) Phenylalanine, o-methyl-phenylalanine, m-methyl-phenylalanine or p-methyl-phenylalanine, 2,4,6-trimethyl-phenylalanine, 2-ethoxy-5-ni Tro-phenylalanine, 2-hydroxy-5-nitro-phenylalanine and p-nitro-phenylalanine); furyl-alanine, thienyl-alanine, pyridyl-alanine, pyrimidinyl-alanine, purinyl-alanine or naphthyl-alanine; and tryptophan analogues 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 amino acids 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 diheptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. The protein optionally contains 3, 5, 10, 50, 75, 100 or more residues, and suitably 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 that is desired to enhance the immune response. The nature and identity of this polypeptide can vary widely.

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

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

Peptide lytic enzymes for cleaving the polypeptide conjugates of the present invention are well known and include, in particular, carboxypeptidases. Carboxypeptidases that digest polypeptides by removing C-terminal residues are often specific for a particular C-terminal sequence. Such enzymes and their substrate requirements are generally 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 an embodiment where W ₁ is a phosphonate, the peptide is cleaved by an appropriate peptide lytic enzyme, eliminating the carboxyl of the proximal amino acid residue and predicting that the phosphonoamidate bond is autocatalytically cleaved. Is done.

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

Tripeptide residues are also useful as protecting groups. 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 substrate for aminopeptidase A and is N-terminal to hydrophobic amino acids (leu, tyr, phe, val, trp). A dipeptide or tripeptide lacking amino acid residues 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)
Certain values recited for radicals, substitutions, and ranges, and certain embodiments described herein are for illustrative purposes only; these are other defined values or are defined. Do not exclude other values within the specified range.

In one particular embodiment of the invention, A ¹ has the formula:

である。

It is.

In another specific embodiment of the invention, A ¹ has the formula:

である。

It is.

In another specific embodiment of the invention, A ¹ has the formula:

である。

It is.

In another specific embodiment of the invention, A ¹ has the formula:

である。

It is.

In another specific embodiment of the invention, A ¹ has the formula:

であり、Ｗ^５ａは炭素環または複素環であり、ここでＷ^５ａは、独立して０または１個のＲ^２基で置換される。Ｍ１２ａについての特定の値は、１である。

And W ^5a is a carbocyclic or heterocyclic ring, wherein W ^5a is independently substituted with 0 or 1 R ² group. A specific value for M12a is 1.

In another specific embodiment of the invention, A ¹ has the formula:

である。

It is.

In another specific embodiment of the invention, A ¹ has the formula:

である。

It is.

In another specific embodiment of the invention, A ¹ has the formula:

であり、Ｗ^５ａは、０または１個のＲ^２基で独立して置換される炭素環である。

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

In another specific embodiment of the invention, A ¹ has the formula:

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

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

In another specific embodiment of the invention, A ¹ has the formula:

であり、Ｗ^５ａは、０または１個のＲ^２基で独立して置換される炭素環である。

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

In another specific embodiment of the invention, A ¹ has the formula:

であり、Ｗ^５ａは炭素環または複素環であり、ここでＷ^５ａは、独立して０または１個のＲ^２基で置換される。

And W ^5a is a carbocyclic or heterocyclic ring, wherein W ^5a is independently substituted with 0 or 1 R ² group.

In another specific embodiment of the invention, A ¹ has the formula:

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

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

In one particular embodiment of the invention, A ³ is of the formula:

である。

It is.

In another specific embodiment of the invention A ³ is of the formula:

である。

It is.

In another specific embodiment of the invention A ³ is of the formula:

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

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

In another specific embodiment of the invention A ³ is of the formula:

であり、Ｙ^２ｂは、Ｏ、またはＮ（Ｒ^Ｘ）である。

And Y ^2b is O or N (R ^X ).

In another specific embodiment of the invention A ³ is of the formula:

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

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 A ³ is of the formula:

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

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 specific embodiment of the invention A ³ is of the formula:

である。

It is.

In another specific embodiment of the invention A ³ is of the formula:

である。

It is.

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

In another specific embodiment of the invention A ³ is of the formula:

である。

It is.

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

In another specific embodiment of the invention A ³ is of the formula:

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

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

In another specific embodiment of the invention A ³ is of the formula:

であり、Ｙ^２ｂは、ＯまたはＮ（Ｒ^Ｘ）である。

And Y ^2b is O or N (R ^X ).

In another specific embodiment of the invention A ³ is of the formula:

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

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 specific embodiment of the invention A ³ is of the formula:

であり、フェニル炭素環は、０、１、２、または３個のＲ^２基で置換される。

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

In another specific embodiment of the invention A ³ is of the formula:

である。

It is.

In another specific embodiment of the invention A ³ is of the formula:

である。

It is.

In another specific embodiment of the invention A ³ is of the formula:

である。

It is.

In another specific embodiment of the invention A ³ is of the formula:

である。

It is.

In another specific embodiment of the invention A ³ is of the formula:

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

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

In another specific embodiment of the invention A ³ is of the formula:

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

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

In another specific embodiment of the invention A ³ is of the formula:

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

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 specific embodiment of the invention A ³ is of the formula:

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

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

In another specific embodiment of the invention A ³ is of the formula:

であり、Ｙ^２ｂは、Ｏ、またはＮ（Ｒ^２）である。

Y ^2b is O or N (R ² ).

In another specific embodiment of the invention A ³ is of the formula:

である。

It is.

In another specific embodiment of the invention A ³ is of the formula:

である。

It is.

In another specific embodiment of the invention A ³ is of the formula:

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

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

In another specific embodiment of the invention A ³ is of the formula:

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

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

In another specific embodiment of the invention A ³ is of the formula:

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

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 specific embodiment of the invention A ³ is of the formula:

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

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

In another specific embodiment of the invention A ³ is of the formula:

であり、Ｙ^２ｂは、Ｏ、またはＮ（Ｒ^２）である。

Y ^2b is O or N (R ² ).

In another specific embodiment of the invention A ³ is of the formula:

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

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 A ³ is of the formula:

であり、フェニル炭素環は、０、１、２、または３個のＲ^２基で置換される。

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

In another specific embodiment of the invention A ³ is of the formula:

であり、フェニル炭素環は、０、１、２、または３個のＲ^２基で置換される。

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

In another specific embodiment of the invention A ³ is of the formula:

である。

It is.

In another specific embodiment of the invention A ³ is of the formula:

であり、各々のＲは，独立して（Ｃ_１〜Ｃ_６）アルキルである。

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

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

であり、
ここで：
Ｒ^ｙは、独立してＨ、Ｗ^３、Ｒ^２、または保護基であり；
Ｒ^１は、独立してＨまたは１〜１８個の炭素原子からなるアルキルであり；
Ｒ^２は、独立してＨ、Ｒ^１、Ｒ^３またはＲ^４であって、ここで、各々のＲ^４は、独立して、０〜３個のＲ^３基で置換されるか、または炭素原子において一緒になり、２個のＲ^２基は、３〜８個の炭素からなる環を形成し、そしてこの環は、０〜３個のＲ^３基で置換される。

And
here:
R ^y is independently H, W ³ , R ² , or a protecting group;
R ¹ is independently H or alkyl consisting of 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 0-3 R ³ groups or carbon Together at the atom, the two R ² groups form a ring of 3-8 carbons, and the ring is substituted with 0-3 R ³ groups.

In certain embodiments of the invention, R ^x is:

であり、ここでＹ^１ａは、Ｏ、またはＳであり；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 certain embodiments of the invention, R ^x is:

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

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

In certain embodiments of the invention, R ^x is:

である。

It is.

In certain embodiments of the invention R ^y is hydrogen or alkyl consisting of 1 to 10 carbon atoms.

In certain embodiments of the invention, R ^x is:

である。

It is.

In certain embodiments of the invention, R ^x is:

である。

It is.

In certain embodiments of the invention, R ^x is:

である。

It is.

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

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

In certain embodiments of the invention, R ^x is:

であり、ここで：
ｍ１ａ、ｍ１ｂ、ｍ１ｃ、ｍ１ｄおよびｍ１ｅは、独立して０または１であり；
ｍ１２ｃは、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｒ^ｙは、独立してＨ、Ｗ^３、Ｒ^２、または保護基であるが；
ただし：
ｍ１ａ、ｍ１２ｃおよびｍ１ｄが０である場合、ｍ１ｂ、ｍ１ｃ、およびｍ１ｅは、０であり；
ｍ１ａおよびｍ１２ｃが０であり、かつｍ１ｄが０でない場合、ｍ１ｂおよびｍ１ｃは０であり；
ｍ１ａおよびｍ１ｄが０であり、かつｍ１２ｃが０でない場合、ｍ１ｂおよびｍ１ｃおよびｍ１ｅの少なくとも１つは、０であり；
ｍ１ａが０であり、かつｍ１２ｃおよびｍ１ｄが０でない場合、ｍ１ｂは０であり；
ｍ１２ｃおよびｍ１ｄが０であり、かつｍ１ａが０でない場合、ｍ１ｂ、ｍ１ｃ、およびｍ１ｅの少なくとも２つは、０であり；
ｍ１２ｃが０であり、ｍ１ａおよびｍ１ｄが０でない場合、ｍ１ｂおよびｍ１ｃの少なくとも１つは０ではなく；そして
ｍ１ｄが０であり、かつｍ１ａおよびｍ１２ｃが０でない場合、ｍ１ｃおよびｍ１ｅの少なくとも１つは０である。

And here:
m1a, m1b, m1c, m1d and m1e are independently 0 or 1;
m12c is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
R ^y is independently H, W ³ , R ² , or a protecting group;
However:
when 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;
when m1a and m1d are 0 and m12c is not 0, at least one of m1b and m1c and m1e is 0;
if m1a is 0 and m12c and m1d are not 0, m1b is 0;
when 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 not 0; and if m1d is 0 and m1a and m12c are not 0, at least one of m1c and m1e is 0.

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 seven to ten ring members (four to nine carbon atoms and one to three heteroatoms, which are selected from N, O, P and S) It can be a ring. W ⁵ heterocycle is a ring of 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms, which are selected from N, O, P 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、０個〜３個のＲ^２基（上で定義した通りのもの）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：

The W ⁵ carbocycle and heterocycle 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）を介してのいずれかで、１個またはそれ以上のホスホネート基に連結されたキナーゼ阻害化合物を含有する結合体を提供する。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このリンカーは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任意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が実行可能な位置で、この化合物（例えば、１００〜１０３の化合物）に連結できる。

(Linking group and linker)
The present invention relates to conjugates comprising a kinase inhibitor compound linked to one or more phosphonate groups, either directly (eg, via a covalent bond) or via a linking group (ie, a linker). I will provide a. The nature of the linker is not critical provided that the linker does not interfere with the ability of the phosphonate-containing compound to function as a therapeutic agent. The phosphonate or linker is removed at a position where any synthesis on the compound is feasible by removing the hydrogen or any portion of the compound to provide an open valence for attachment of the phosphonate or linker. It can be linked to this compound (eg 100 to 103 compounds).

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 the linking group or linker is a divalent branched or unbranched saturated or unsaturated hydrocarbon chain, the hydrocarbon chain having 2 to 25 carbon atoms. Where one or more of the carbon atoms (eg, 1, 2, 3 or 4) is 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, Oki (= 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 , 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) — or a direct bond; where 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.

(Intracellular targeting)
The phosphonate groups of the compounds of the invention can be cleaved stepwise in vivo after they reach the desired site of action (ie, 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 group in the compounds of the 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 by appropriate changes in other physical properties. 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 not to be construed as exhaustive, but merely as exemplary.

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

  The term “kinase-inhibiting compound” includes compounds that inhibit the activity of at least one kinase. In particular, these compounds include CP-690, 550, AP23464, A-420983 and roscovitine.

  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 present invention provides a compound having a log D of less than about 4; in other embodiments, the present invention provides a compound having a log D of less than about 3; The invention provides compounds having a log D higher than about −5; in other embodiments, the invention provides compounds having a log D higher than about −3; and in other embodiments, the invention provides: Compounds having a log D greater than about 0 and less than about 3 are provided.

Selected substituents within the compounds of the invention are present to a recursive extent. In this context, “recursive substituent” means that one substituent may naturally enumerate the other. Due to the recursive nature of such substituents, in theory there can be many in any given embodiment. 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 certain embodiments, W ³ , R ^y and R ³ are all recursive substituents. Typically, each of these is separately, in certain embodiments, 20 times, 19 times, 18 times, 17 times, 16 times, 15 times, 14 times, 13 times, 12 times, 11 times, 10 times, May be present 9, 9, 8, 7, 6, 4, 3, 2, 1 or 0 times. More typically, each of these may be present separately, in a given embodiment, 12 or fewer times. More typically, in certain embodiments, W ³ is present 0 to 8 times, R ^y is present 0 to 6 times, and R ³ is present 0 to 10 times. Even more typically, in certain embodiments, 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 pluripotency of such substituents. To the extent that recursive substituents are present in embodiments of the present 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 group It can be seen that are selected separately. Wavy lines indicate sites of covalent bonding to adjacent groups, moieties or atoms.

  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, tissue, cells, etc.). In one particular embodiment of the invention, the term means that the compound or conjugate of the invention contains no biological material at least about 50% by weight; in other particular embodiments, the term Means that a compound or conjugate of the invention is free of at least about 75% biological material; in other specific embodiments, the term refers to a compound or conjugate of the invention containing at least about 90% biological material. In other embodiments, the term means that the compound or conjugate of the invention is free of at least about 98% by weight of biological material; in other embodiments, the term It means that the compound or conjugate of the invention is free of at least about 99% by weight of biological material. In other specific embodiments, the invention provides compounds or conjugates of the invention that are synthetically prepared (eg, ex vivo).

  In one embodiment of the invention, the compound is not an anti-inflammatory compound; in other embodiments, the compound is not anti-infective; in other embodiments, the compound is in an immune-mediated state. In other embodiments, the compound is not a compound active against metabolic disease; in other embodiments, the compound is not an antiviral agent; another embodiment The compound is not a nucleoside; in other embodiments, the compound is not an IMPDH inhibitor; in other embodiments, the compound is not an antimetabolite; in other embodiments, the compound is In other embodiments, the compound is a serine / threonine kinase, a tyrosine kinase, a Bcr-Ab1 kinase, a cyclin-dependent kinase. Inhibiting Fase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase, or EGF receptor tyrosine kinase; , Gefitinib, Imatinib, Erlotinib, Batalanib, Alvocidiv, CEP-701, GLEVEC, Midosturain, Midosturain (Midostalin) Not BAY-43-9006 or CP-690, 550; other In an embodiment, the compound is not a substituted compound of any one of formulas 1-4.

  In one embodiment, the invention provides a kinase inhibitor compound linked to one or more phosphonate groups; or a pharmaceutically acceptable salt or solvate thereof, wherein the kinase inhibitor compound is gefitinib , Imatinib, vatalanib, albocinib, CEP-701, GLEEVEC, midostaurin, MLN-518, PD-184352, dramapimod, BAY-43-9006 and CP-690,550.

  In another embodiment, the present invention provides compounds of formula 500 to formula 511:

のいずれか１つの化合物を提供し、この化合物は、１つ以上の基Ａ^０で置換され、
ここで：
Ａ^０は、Ａ^１、Ａ^２またはＷ^３であるが、ただし、結合体は、少なくとも１つのＡ^１を含み；
Ａ^１は：

^Which is substituted with one or more groups A ⁰ ,
here:
A ⁰ is A ¹ , A ² or W ³ provided that the conjugate comprises at least one A ¹ ;
A ¹ is:

であり；
Ａ^２は：

Is;
A ² is:

であり；
Ａ^３は：

Is;
A ³ is:

であり；
Ｙ^１は、独立して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））であり；
Ｙ^２は、独立して結合、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−であり；そしてここで、Ｙ^２は、２つのリン原子に結合する場合、Ｙ^２は、また、Ｃ（Ｒ^２）（Ｒ^２）であり得；
Ｒ^Ｘは、独立してＨ、Ｒ^１、Ｒ^２、Ｗ^３、保護基、または次式：

Is;
Y ¹ is independently O, S, N (R ^X ), N (O) (R ^X ), N (OR ^X ), N (O) (OR ^X ), or N (N (R ^X ) ( R ^X ));
Y ² is independently a bond, O, N (R ^X ), N (O) (R ^X ), N (OR ^X ), N (O) (OR ^X ), N (N (R ^X ) (R _{^{X)), - S (O}} ) M2 - , or _{-S (O) M2 -S (O} ) M2 - a and; and wherein, ^{Y 2} is, when bound to two phosphorus atoms, ^{Y 2} is also , C (R ² ) (R ² );
R ^X is independently H, R ¹ , R ² , W ³ , a protecting group, or

であり；
Ｒ^ｙは、独立してＨ、Ｗ^３、Ｒ^２、または保護基であり；
Ｒ^１は、独立してＨ、または１〜１８個の炭素原子からなるアルキルであり；
Ｒ^２は、独立してＨ、Ｒ^１、Ｒ^３、またはＲ^４であって、ここで、各々のＲ^４は、独立して、０〜３個のＲ^３基で置換されるか、炭素原子において一緒になり、２個のＲ^２基は、３〜８個の炭素からなる環を形成し、そしてこの環は、０〜３個のＲ^３基で置換され；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃ、またはＲ^３ｄであるが、ただし、Ｒ^３がヘテロ原子に結合される場合、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄであり；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３、または−ＮＯ_２であり；
Ｒ^３ｂは、Ｙ^１であり；
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））であり；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^Ｘ、−Ｃ（Ｙ^１）ＯＲ^Ｘ、または−Ｃ（Ｙ^１）（Ｎ（Ｒ^Ｘ）（Ｒ^Ｘ））であり；
Ｒ^４は、１〜１８個の炭素原子からなるアルキル、２〜１８個の炭素原子からなるアルケニル、または２〜１８個の炭素原子からなるアルキニルであり；
Ｒ^５は、Ｒ^４であって、各々のＲ^４は、０〜３個のＲ^３基で置換され；
Ｗ^３は、Ｗ^４またはＷ^５であり；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_Ｍ２Ｒ^５または−ＳＯ_Ｍ２Ｗ^５であり；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、独立して０個〜３個のＲ^２基で置換され；
Ｗ^６は、独立して１個、２個または３個のＡ^３基で置換されるＷ^３であり；
Ｍ２は、０、１または２であり；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、独立して０または１であり；そして
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。さらに別の実施形態において、本発明は、このような化合物を除くキナーゼ阻害結合体を提供する。

Is;
R ^y is independently H, W ³ , R ² , or a protecting group;
R ¹ is independently H or alkyl consisting of 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 0-3 R ³ groups or carbon Taken together at an atom, two R ² groups form a ring of 3-8 carbons, and the ring is substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , provided that when R ³ is attached to a heteroatom, R ³ is R ^3c or R ^3d ;
R ^3a is F, Cl, Br, I, —CN, N ₃ , or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^X , —N (R ^X ) (R ^X ), —SR ^X , —S (O) R ^X , —S (O) ₂ R ^X , —S (O) (OR ^X ), —S (O) ₂ (OR ^X ), —OC (Y ¹ ) R ^X , —OC (Y ¹ ) OR ^X , —OC (Y ¹ ) (N (R ^X ) (R ^X )), —SC ( Y ¹ ) R ^X , —SC (Y ¹ ) OR ^X , —SC (Y ¹ ) (N (R ^X ) (R ^X )), —N (R ^X ) C (Y ¹ ) R ^X , —N ( R ^X ) C (Y ¹ ) OR ^X , or —N (R ^X ) C (Y ¹ ) (N (R ^X ) (R ^X ));
R ^3d is —C (Y ¹ ) R ^X , —C (Y ¹ ) OR ^X , or —C (Y ¹ ) (N (R ^X ) (R ^X ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , each R ⁴ is substituted with 0-3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO _M2 R ⁵ or —SO _M2 W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0-3 R ² groups;
W ⁶ being one independently a ^{W 3} is substituted with two or three ^{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 yet another embodiment, the invention provides kinase inhibitor conjugates that exclude such compounds.

In another embodiment, the present invention provides a compound of formula: [DRUG]-(A ⁰ ) _nn , or a pharmaceutically acceptable salt or solvate thereof, wherein
DRUG is any one compound of Formula 500 to Formula 511 (exemplified above);
nn is 1, 2 or 3;
A ⁰ is A ¹ , A ² or W ³ provided that the conjugate comprises at least one A ¹ ;
A ¹ is:

であり；
Ａ^２は：

Is;
A ² is:

であり；
Ａ^３は：

Is;
A ³ is:

であり；
Ｙ^１は、独立して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））であり；
Ｙ^２は、独立して結合、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−であり；そしてここで、Ｙ^２は、２つのリン原子に結合する場合、Ｙ^２は、また、Ｃ（Ｒ^２）（Ｒ^２）であり得；
Ｒ^Ｘは、独立してＨ、Ｒ^１、Ｒ^２、Ｗ^３、保護基、または次式：

Is;
Y ¹ is independently O, S, N (R ^X ), N (O) (R ^X ), N (OR ^X ), N (O) (OR ^X ), or N (N (R ^X ) ( R ^X ));
Y ² is independently a bond, O, N (R ^X ), N (O) (R ^X ), N (OR ^X ), N (O) (OR ^X ), N (N (R ^X ) (R _{^{X)), - S (O}} ) M2 - , or _{-S (O) M2 -S (O} ) M2 - a and; and wherein, ^{Y 2} is, when bound to two phosphorus atoms, ^{Y 2} is also , C (R ² ) (R ² );
R ^X is independently H, R ¹ , R ² , W ³ , a protecting group, or

であり；
Ｒ^ｙは、独立してＨ、Ｗ^３、Ｒ^２、または保護基であり；
Ｒ^１は、独立してＨ、または１〜１８個の炭素原子からなるアルキルであり；
Ｒ^２は、独立してＨ、Ｒ^１、Ｒ^３、またはＲ^４であって、ここで、各々のＲ^４は、独立して、０〜３個のＲ^３基で置換されるか、炭素原子において一緒になり、２個のＲ^２基は、３〜８個の炭素からなる環を形成し、そしてこの環は、０〜３個のＲ^３基で置換され；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃ、またはＲ^３ｄであるが、ただし、Ｒ^３がヘテロ原子に結合される場合、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄであり；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３、または−ＮＯ_２であり；
Ｒ^３ｂは、Ｙ^１であり；
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））であり；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^Ｘ、−Ｃ（Ｙ^１）ＯＲ^Ｘ、または−Ｃ（Ｙ^１）（Ｎ（Ｒ^Ｘ）（Ｒ^Ｘ））であり；
Ｒ^４は、１〜１８個の炭素原子からなるアルキル、２〜１８個の炭素原子からなるアルケニル、または２〜１８個の炭素原子からなるアルキニルであり；
Ｒ^５は、Ｒ^４であって、各々のＲ^４は、０〜３個のＲ^３基で置換され；
Ｗ^３は、Ｗ^４またはＷ^５であり；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_Ｍ２Ｒ^５または−ＳＯ_Ｍ２Ｗ^５であり；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、独立して０個〜３個のＲ_２基で置換され；
Ｗ^６は、独立して１個、２個または３個のＡ^３基で置換されるＷ^３であり；
Ｍ２は、０、１または２であり；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、独立して０または１であり；そして
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。 別の実施形態において、本発明は、式１〜３６：

Is;
R ^y is independently H, W ³ , R ² , or a protecting group;
R ¹ is independently H or alkyl consisting of 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 0-3 R ³ groups or carbon Taken together at an atom, two R ² groups form a ring of 3-8 carbons, and the ring is substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , provided that when R ³ is attached to a heteroatom, R ³ is R ^3c or R ^3d ;
R ^3a is F, Cl, Br, I, —CN, N ₃ , or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^X , —N (R ^X ) (R ^X ), —SR ^X , —S (O) R ^X , —S (O) ₂ R ^X , —S (O) (OR ^X ), —S (O) ₂ (OR ^X ), —OC (Y ¹ ) R ^X , —OC (Y ¹ ) OR ^X , —OC (Y ¹ ) (N (R ^X ) (R ^X )), —SC ( Y ¹ ) R ^X , —SC (Y ¹ ) OR ^X , —SC (Y ¹ ) (N (R ^X ) (R ^X )), —N (R ^X ) C (Y ¹ ) R ^X , —N ( R ^X ) C (Y ¹ ) OR ^X , or —N (R ^X ) C (Y ¹ ) (N (R ^X ) (R ^X ));
R ^3d is —C (Y ¹ ) R ^X , —C (Y ¹ ) OR ^X , or —C (Y ¹ ) (N (R ^X ) (R ^X ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , each R ⁴ is substituted with 0-3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO _M2 R ⁵ or —SO _M2 W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0-3 R ₂ groups;
W ⁶ being one independently a ^{W 3} is substituted with two or three ^{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 compounds of formulas 1-36:

のいずれか１つの化合物を提供し、
ここで：
Ａ^０はＡ^１であり、
Ａ^１は：

A compound of any one of
here:
A ⁰ is A ¹
A ¹ is:

であり；
Ａ^３は：

Is;
A ³ is:

であり；
Ｙ^１は、独立して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））であり；
Ｙ^２は、独立して結合、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−であり；そしてここで、Ｙ^２は、２つのリン原子に結合する場合、Ｙ^２は、また、Ｃ（Ｒ^２）（Ｒ^２）であり得；
Ｒ^Ｘは、独立してＨ、Ｒ^２、Ｗ^３、保護基、または次式：

Is;
Y ¹ is independently O, S, N (R ^X ), N (O) (R ^X ), N (OR ^X ), N (O) (OR ^X ), or N (N (R ^X ) ( R ^X ));
Y ² is independently a bond, O, N (R ^X ), N (O) (R ^X ), N (OR ^X ), N (O) (OR ^X ), N (N (R ^X ) (R _{^{X)), - S (O}} ) M2 - , or _{-S (O) M2 -S (O} ) M2 - a and; and wherein, ^{Y 2} is, when bound to two phosphorus atoms, ^{Y 2} is also , C (R ² ) (R ² );
R ^X is independently H, R ² , W ³ , a protecting group, or the following formula:

であり；
Ｒ^ｙは、独立してＨ、Ｗ^３、Ｒ^２、または保護基であり；
Ｒ^１は、独立してＨ、または１〜１８個の炭素原子からなるアルキルであり；
Ｒ^２は、独立してＨ、Ｒ^３、またはＲ^４であって、ここで、各々のＲ^４は、独立して、０〜３個のＲ^３基で置換され；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃ、またはＲ^３ｄであるが、ただし、Ｒ^３がヘテロ原子に結合される場合、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄであり；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３、または−ＮＯ_２であり；
Ｒ^３ｂは、Ｙ^１であり；
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））であり；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^Ｘ、−Ｃ（Ｙ^１）ＯＲ^Ｘ、または−Ｃ（Ｙ^１）（Ｎ（Ｒ^Ｘ）（Ｒ^Ｘ））であり；
Ｒ^４は、１〜１８個の炭素原子からなるアルキル、２〜１８個の炭素原子からなるアルケニル、または２〜１８個の炭素原子からなるアルキニルであり；
Ｒ^５は、Ｒ^４であって、各々のＲ^４は、０〜３個のＲ^３基で置換され；
Ｒ^５ａは、独立して１〜１８個の炭素原子からなるアルキレン、２〜１８個の炭素原子からなるアルケニレン、２〜１８個の炭素原子からな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、０〜３個のＲ^３基で置換され；
Ｗ^３は、Ｗ^４またはＷ^５であり；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５または−ＳＯ_２Ｗ^５であり；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、独立して０個〜３個のＲ^２基で置換され；
Ｗ^６は、独立して１個、２個または３個のＡ^３基で置換されるＷ^３であり；
Ｍ２は、０、１または２であり；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、独立して０または１であり；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｘ^５０は、Ｈ、ＦまたはＣｌであり；そして
Ｘ^５１は、ＨまたはＣｌである。さらに別の実施形態において、本発明は、このような化合物を除くキナーゼ阻害結合体を提供する。

Is;
R ^y is independently H, W ³ , R ² , or a protecting group;
R ¹ is independently H or alkyl consisting of 1 to 18 carbon atoms;
R ² is independently H, R ³ , or R ⁴ , wherein each R ⁴ is independently substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , provided that when R ³ is attached to a heteroatom, R ³ is R ^3c or R ^3d ;
R ^3a is F, Cl, Br, I, —CN, N ₃ , or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^X , —N (R ^X ) (R ^X ), —SR ^X , —S (O) R ^X , —S (O) ₂ R ^X , —S (O) (OR ^X ), —S (O) ₂ (OR ^X ), —OC (Y ¹ ) R ^X , —OC (Y ¹ ) OR ^X , —OC (Y ¹ ) (N (R ^X ) (R ^X )), —SC ( Y ¹ ) R ^X , —SC (Y ¹ ) OR ^X , —SC (Y ¹ ) (N (R ^X ) (R ^X )), —N (R ^X ) C (Y ¹ ) R ^X , —N ( R ^X ) C (Y ¹ ) OR ^X , or —N (R ^X ) C (Y ¹ ) (N (R ^X ) (R ^X ));
R ^3d is —C (Y ¹ ) R ^X , —C (Y ¹ ) OR ^X , or —C (Y ¹ ) (N (R ^X ) (R ^X ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , each R ⁴ is substituted with 0-3 R ³ groups;
R ^5a is independently alkylene consisting of 1 to 18 carbon atoms, alkenylene consisting of 2 to 18 carbon atoms, alkynylene consisting of 2 to 18 carbon atoms, and either alkylene, alkenylene or alkynylene. One 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 0-3 R ² groups;
W ⁶ being one independently a ^{W 3} is substituted with two or three ^{A 3} groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
X ⁵⁰ is H, F or Cl; and X ⁵¹ is H or Cl. In yet another embodiment, the invention provides kinase inhibitor conjugates that exclude such compounds.

  In another embodiment, the present invention provides compounds of formula 500a to formula 511a:

のいずれか１つの化合物を提供し、この化合物は、１つ以上のＡ^０で置換され；
ここで：
Ａ^０は、Ａ^１、Ａ^２またはＷ^３であるが、ただし、結合体は、少なくとも１つのＡ^１を含み；
Ａ^１は：

Wherein one compound is substituted with one or more A ⁰ ;
here:
A ⁰ is A ¹ , A ² or W ³ provided that the conjugate comprises at least one A ¹ ;
A ¹ is:

であり；
Ａ^２は：

Is;
A ² is:

であり；
Ａ^３は：

Is;
A ³ is:

であり；
Ｙ^１は、独立して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））であり；
Ｙ^２は、独立して結合、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−であり；そしてここで、Ｙ^２は、２つのリン原子に結合する場合、Ｙ^２は、また、Ｃ（Ｒ^２）（Ｒ^２）であり得；
Ｒ^Ｘは、独立してＨ、Ｒ^１、Ｒ^２、Ｗ^３、保護基、または次式：

Is;
Y ¹ is independently O, S, N (R ^X ), N (O) (R ^X ), N (OR ^X ), N (O) (OR ^X ), or N (N (R ^X ) ( R ^X ));
Y ² is independently a bond, O, N (R ^X ), N (O) (R ^X ), N (OR ^X ), N (O) (OR ^X ), N (N (R ^X ) (R _{^{X)), - S (O}} ) M2 - , or _{-S (O) M2 -S (O} ) M2 - a and; and wherein, ^{Y 2} is, when bound to two phosphorus atoms, ^{Y 2} is also , C (R ² ) (R ² );
R ^X is independently H, R ¹ , R ² , W ³ , a protecting group, or

であり；
Ｒ^ｙは、独立してＨ、Ｗ^３、Ｒ^２、または保護基であり；
Ｒ^１は、独立してＨ、または１〜１８個の炭素原子からなるアルキルであり；
Ｒ^２は、独立してＨ、Ｒ^１、Ｒ^３、またはＲ^４であって、ここで、各々のＲ^４は、独立して、０〜３個のＲ^３基で置換されるか、炭素原子において一緒になり、２個のＲ^２基は、３〜８個の炭素からなる環を形成し、そしてこの環は、０〜３個のＲ^３基で置換され；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃ、またはＲ^３ｄであるが、ただし、Ｒ^３がヘテロ原子に結合される場合、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄであり；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３、または−ＮＯ_２であり；
Ｒ^３ｂは、Ｙ^１であり；
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））であり；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^Ｘ、−Ｃ（Ｙ^１）ＯＲ^Ｘ、または−Ｃ（Ｙ^１）（Ｎ（Ｒ^Ｘ）（Ｒ^Ｘ））であり；
Ｒ^４は、１〜１８個の炭素原子からなるアルキル、２〜１８個の炭素原子からなるアルケニル、または２〜１８個の炭素原子からなるアルキニルであり；
Ｒ^５は、Ｒ^４であって、各々のＲ^４は、０〜３個のＲ^３基で置換され；
Ｗ^３は、Ｗ^４またはＷ^５であり；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_Ｍ２Ｒ^５または−ＳＯ_Ｍ２Ｗ^５であり；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、独立して０個〜３個のＲ^２基で置換され；
Ｗ^６は、独立して１個、２個または３個のＡ^３基で置換されるＷ^３であり；
Ｍ２は、０、１または２であり；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、独立して０または１であり；そして
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２である。さらに別の実施形態において、本発明は、このような化合物を除くキナーゼ阻害結合体を提供する。

Is;
R ^y is independently H, W ³ , R ² , or a protecting group;
R ¹ is independently H or alkyl consisting of 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 0-3 R ³ groups or carbon Taken together at an atom, two R ² groups form a ring of 3-8 carbons, and the ring is substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , provided that when R ³ is attached to a heteroatom, R ³ is R ^3c or R ^3d ;
R ^3a is F, Cl, Br, I, —CN, N ₃ , or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^X , —N (R ^X ) (R ^X ), —SR ^X , —S (O) R ^X , —S (O) ₂ R ^X , —S (O) (OR ^X ), —S (O) ₂ (OR ^X ), —OC (Y ¹ ) R ^X , —OC (Y ¹ ) OR ^X , —OC (Y ¹ ) (N (R ^X ) (R ^X )), —SC ( Y ¹ ) R ^X , —SC (Y ¹ ) OR ^X , —SC (Y ¹ ) (N (R ^X ) (R ^X )), —N (R ^X ) C (Y ¹ ) R ^X , —N ( R ^X ) C (Y ¹ ) OR ^X , or —N (R ^X ) C (Y ¹ ) (N (R ^X ) (R ^X ));
R ^3d is —C (Y ¹ ) R ^X , —C (Y ¹ ) OR ^X , or —C (Y ¹ ) (N (R ^X ) (R ^X ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , each R ⁴ is substituted with 0-3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO _M2 R ⁵ or —SO _M2 W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0-3 R ² groups;
W ⁶ being one independently a ^{W 3} is substituted with two or three ^{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 yet another embodiment, the invention provides kinase inhibitor conjugates that exclude such compounds.

  In another embodiment, the present invention provides compounds of formula 1a to formula 36a:

のいずれか１つの化合物を提供し；
Ａ^０はＡ^１であり、
Ａ^１は：

A compound of any one of
A ⁰ is A ¹
A ¹ is:

であり；
Ａ^３は：

Is;
A ³ is:

であり；
Ｙ^１は、独立して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））であり；
Ｙ^２は、独立して結合、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−であり；そしてここで、Ｙ^２は、２つのリン原子に結合する場合、Ｙ^２は、また、Ｃ（Ｒ^２）（Ｒ^２）であり得；
Ｒ^Ｘは、独立してＨ、Ｒ^２、Ｗ^３、保護基、または次式：

Is;
Y ¹ is independently O, S, N (R ^X ), N (O) (R ^X ), N (OR ^X ), N (O) (OR ^X ), or N (N (R ^X ) ( R ^X ));
Y ² is independently a bond, O, N (R ^X ), N (O) (R ^X ), N (OR ^X ), N (O) (OR ^X ), N (N (R ^X ) (R _{^{X)), - S (O}} ) M2 - , or _{-S (O) M2 -S (O} ) M2 - a and; and wherein, ^{Y 2} is, when bound to two phosphorus atoms, ^{Y 2} is also , C (R ² ) (R ² );
R ^X is independently H, R ² , W ³ , a protecting group, or the following formula:

であり；
Ｒ^ｙは、独立してＨ、Ｗ^３、Ｒ^２、または保護基であり；
Ｒ^１は、独立してＨ、または１〜１８個の炭素原子からなるアルキルであり；
Ｒ^２は、独立してＨ、Ｒ^３、またはＲ^４であって、ここで、各々のＲ^４は、独立して、０〜３個のＲ^３基で置換され；
Ｒ^３は、Ｒ^３ａ、Ｒ^３ｂ、Ｒ^３ｃ、またはＲ^３ｄであるが、ただし、Ｒ^３がヘテロ原子に結合される場合、Ｒ^３は、Ｒ^３ｃまたはＲ^３ｄであり；
Ｒ^３ａは、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＮ、Ｎ_３、または−ＮＯ_２であり；
Ｒ^３ｂは、Ｙ^１であり；
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））であり；
Ｒ^３ｄは、−Ｃ（Ｙ^１）Ｒ^Ｘ、−Ｃ（Ｙ^１）ＯＲ^Ｘ、または−Ｃ（Ｙ^１）（Ｎ（Ｒ^Ｘ）（Ｒ^Ｘ））であり；
Ｒ^４は、１〜１８個の炭素原子からなるアルキル、２〜１８個の炭素原子からなるアルケニル、または２〜１８個の炭素原子からなるアルキニルであり；
Ｒ^５は、Ｒ^４であって、各々のＲ^４は、０〜３個のＲ^３基で置換され；
Ｒ^５ａは、独立して１〜１８個の炭素原子からなるアルキレン、２〜１８個の炭素原子からなるアルケニレン、２〜１８個の炭素原子からな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、０〜３個のＲ^３基で置換され；
Ｗ^３は、Ｗ^４またはＷ^５であり；
Ｗ^４は、Ｒ^５、−Ｃ（Ｙ^１）Ｒ^５、−Ｃ（Ｙ^１）Ｗ^５、−ＳＯ_２Ｒ^５または−ＳＯ_２Ｗ^５であり；
Ｗ^５は、炭素環または複素環であり、ここで、Ｗ^５は、独立して０個〜３個のＲ^２基で置換され；
Ｗ^６は、独立して１個、２個または３個のＡ^３基で置換されるＷ^３であり；
Ｍ２は、０、１または２であり；
Ｍ１２ａは、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１２ｂは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｍ１ａ、Ｍ１ｃおよびＭ１ｄは、独立して０または１であり；
Ｍ１２ｃは、０、１、２、３、４、５、６、７、８、９、１０、１１または１２であり；
Ｘ^５０は、Ｈ、ＦまたはＣｌであり；そして
Ｘ^５１は、ＨまたはＣｌである。さらに別の実施形態において、本発明は、このような化合物を除くキナーゼ阻害結合体を提供する。

Is;
R ^y is independently H, W ³ , R ² , or a protecting group;
R ¹ is independently H or alkyl consisting of 1 to 18 carbon atoms;
R ² is independently H, R ³ , or R ⁴ , wherein each R ⁴ is independently substituted with 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , provided that when R ³ is attached to a heteroatom, R ³ is R ^3c or R ^3d ;
R ^3a is F, Cl, Br, I, —CN, N ₃ , or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^X , —N (R ^X ) (R ^X ), —SR ^X , —S (O) R ^X , —S (O) ₂ R ^X , —S (O) (OR ^X ), —S (O) ₂ (OR ^X ), —OC (Y ¹ ) R ^X , —OC (Y ¹ ) OR ^X , —OC (Y ¹ ) (N (R ^X ) (R ^X )), —SC ( Y ¹ ) R ^X , —SC (Y ¹ ) OR ^X , —SC (Y ¹ ) (N (R ^X ) (R ^X )), —N (R ^X ) C (Y ¹ ) R ^X , —N ( R ^X ) C (Y ¹ ) OR ^X , or —N (R ^X ) C (Y ¹ ) (N (R ^X ) (R ^X ));
R ^3d is —C (Y ¹ ) R ^X , —C (Y ¹ ) OR ^X , or —C (Y ¹ ) (N (R ^X ) (R ^X ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , each R ⁴ is substituted with 0-3 R ³ groups;
R ^5a is independently alkylene consisting of 1 to 18 carbon atoms, alkenylene consisting of 2 to 18 carbon atoms, alkynylene consisting of 2 to 18 carbon atoms, and either alkylene, alkenylene or alkynylene. One 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 0-3 R ² groups;
W ⁶ being one independently a ^{W 3} is substituted with two or three ^{A 3} groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
X ⁵⁰ is H, F or Cl; and X ⁵¹ is H or Cl. In yet another embodiment, the invention provides kinase inhibitor conjugates that exclude such compounds.

(Cell accumulation)
In one embodiment, the present invention provides compounds that can accumulate in human PBMC (peripheral blood mononuclear cells). PBMC refers to blood cells having round white blood cells and monocytes. Physiologically, PBMC is an important component with respect to the mechanism for infection. PBMC can be isolated from heparinized whole blood or buffy coats of normal healthy donors by standard density gradient centrifugation and collected from the interface, washed (eg, with phosphate buffered saline), It is then stored in a freezing medium. PBMC can be cultured in multi-well plates. At various times in culture, the supernatant can either be removed for evaluation or the cells can be collected and analyzed (Smith R. et al. (2003) Blood 102 (7): 2532 -2540). The compound of this embodiment may further comprise a phosphonate or phosphonate prodrug. More typically, the phosphonate or phosphonate prodrug, as described herein, may have the structure A ^3.

  Typically, a compound of the present invention has an intracellular half-life of the compound in human PBMC, or an intracellular metabolite of the compound when compared to a phosphonate or an analog of the compound without a phosphonate prodrug. Show improvement. Typically, the half-life is at least up to about 50%, more typically in the range of at least 50-100%, even more typically at least about 100%, more typically still less than about 100%. Greatly improved.

  In one embodiment of the invention, the intracellular half-life of a compound metabolite in human PBMC is improved when compared to a phosphonate or an analog of the compound without a phosphonate prodrug. In such embodiments, metabolites can be produced intracellularly (eg, can be produced in human PBMC). The metabolite may be a cleavage product of a phosphonate prodrug within human PBMC. A phosphonate prodrug can be cleaved to form a metabolite having at least a monovalent negative charge at physiological pH. Phosphonate prodrugs can be enzymatically cleaved in human PBMC to form phosphonates having at least one active hydrogen atom in the P-OH form.

(Stereoisomers)
The compounds of the present invention may have chiral centers (eg, chiral carbon or phosphorus atoms). Thus, the compounds of the present invention include 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 are obtained by well-known techniques (eg, separation of diastereomeric salts formed using optically active auxiliary agents (eg, acids or bases, followed by conversion back to their optically active materials)). 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 are within the scope of the present invention.

(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). Things. 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 less soluble metal salt can be precipitated from a more soluble salt solution by adding an appropriate 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. Can be formed from the addition. Finally, the compositions herein contain the compounds of the invention in their zwitterionic form as well as in their non-ionized form, and formulated with stoichiometric amounts of water, such as hydrates. You should be able to understand what to do.

  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 the amino acids typically have 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 for inhibiting kinases)
Another aspect of the invention relates to a method of inhibiting the activity of at least one kinase, the method comprising contacting a sample suspected of containing a kinase with a composition of the invention.

  The compositions of the present invention can act as kinase inhibitors, intermediates for such inhibitors, or have other utilities as described below. These inhibitors bind to at least one kinase. Compositions that bind kinases 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 kinases. Accordingly, the present invention relates to a method for detecting at least one kinase in a sample suspected of containing a kinase, the method comprising the steps of: labeling a sample suspected of containing a kinase with a label. Treating with a composition containing bound compound of the invention; and observing the effect of the sample 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).

  Within the context of the present invention, samples suspected of containing at least one kinase include natural or artificial substances (eg, biological organisms; tissues or cell cultures); biological samples (eg, biomaterials). 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) Recombinant cells that synthesize glycoproteins))), etc. Typically, this sample is suspected of containing kinases, including any water and organic solvent / water mixtures. Samples can include biological organisms (eg, humans) and man-made materials (eg, cell cultures).

  The processing steps of the present invention include adding a composition of the present invention to the sample or adding a precursor of the composition to the sample. This addition step constitutes any of the above administration methods.

  If desired, the activity of the kinase after application of the composition can be observed by any method, including direct and indirect methods of detecting kinase activity. Quantitative, qualitative and semi-quantitative methods for determining kinase 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.

  Many organisms contain kinases. The compounds of the present invention are useful in the treatment or prevention of conditions associated with kinase activity in animals or humans.

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

(Screening for kinase inhibitors)
The compositions of the invention are screened for inhibitory activity against kinases by any of the usual techniques for assessing enzyme activity. Within the context of the present invention, typically compositions are first screened for inhibition of kinases in vitro, and compositions exhibiting inhibitory activity are then screened for activity in vivo. Compositions 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 are used in vitro It is preferable to do.

  Useful in vitro screens are described, for example, in Bioorg. Med. Chem. Lett. 2001, 11, 2775.

(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 preferable to present them as pharmaceutical formulations. The formulations of the present invention (which are used for both animals and humans) comprise at least one active ingredient (along with one or more acceptable carriers and optionally other therapeutic ingredients). This contains as defined above). These carriers must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient.

  These formulations include those suitable for the aforementioned administration routes. These formulations can conveniently be provided in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. Techniques and formulations are generally found at Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which 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 a non-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 pasta.

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

  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 (range between 0.1% and 20% with stepwise addition of 0.1% by weight (eg, 0.6% by weight, 0.7% by weight, etc.)), preferably It is contained in an amount of 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 emulgent, whereas it desirably contains at least one emulsifier and a fat or Contains oil or a mixture of 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.

  Suitable emulsions and emulsion stabilizers for use in the formulations of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monosteare. And sodium lauryl sulfate.

  The selection of an appropriate oil or fat for this formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with appropriate consistency to avoid leakage from tubes or other containers. Linear or branched monobasic or dibasic alkyl esters (eg di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, palmitic The acid ester 2-ethylhexyl, or a blend of branched esters known as 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.

  A pharmaceutical formulation of the invention contains one or more compounds of the invention, along with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. To do. 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, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, 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 (Eg corn starch or alginic acid); binders (eg cellulose, microcrystalline cellulose, starch, gelatin or acacia) and lubricants (eg magnesium stearate, stearic acid or talc). These tablets can be coated by known techniques (including microencapsulation) to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be used.

  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 oil (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 suspending agents (eg, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum); dispersants or wetting agents (eg, naturally occurring) Phosphatides (eg, lecithin), condensation products of alkylene oxide and fatty acids (eg, polyoxyethylene stearate), condensation products of ethylene oxide and long chain aliphatic alcohols (eg, heptadecaethyleneoxysetanol), ethylene oxide and And condensation products with fatty acid and partial esters derived from hexitol anhydrides (eg, polyoxyethylene sorbitol monooleate), which may also contain one or more aqueous suspensions. Preservatives (eg, ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), 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 present invention suitable for preparing aqueous suspensions by the addition of water provide this active ingredient along 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. Additional excipients such as sweeteners, flavoring 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 anhydrous hexitol (eg, sorbitan) Monooleate), and condensation products of its partial esters with ethylene oxide (eg, polyoxyethylene sorbitan monooleate) The emulsion may also contain sweeteners and flavoring agents. And elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose, and such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

  The pharmaceutical compositions of the invention may also be in the form of a sterile injectable formulation (eg, a sterile injectable aqueous suspension or a sterile injectable oily suspension). This suspension may be formulated according to the known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. This sterile injectable preparation is also a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent (eg, a solution in 1,3-butanediol). Or may be prepared as a lyophilized powder. Among the suitable vehicles and solvents that may be used are water, 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 form 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 (this is a suitable and convenient amount of carrier substance (this 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 / hour.

  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 lozenges (which contain the active ingredient in a seasoning base (usually sucrose and acacia or tragacanth)); pastilles (which are an inert base) (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, which contains, for example, cocoa butter or a salicylate.

  Formulations suitable for intrapulmonary or intranasal administration are, for example, 0.1 to 500 microns (ranging between 0.1 and 500 microns, several microns each (eg 0.5, 1 , 30, 35 microns, etc.), which can be inhaled rapidly 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 dry 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 conditions associated with kinase infection). Can be done.

  Formulations suitable for vaginal administration are provided as pessaries, tampons, creams, gels, pastes, foams or spray formulations, which in addition to this active ingredient are suitable carriers known in the art. contains.

  Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which include antioxidants, buffers, bacteriostats and solutes (which are intended for the purpose of this recipe) And isotonic with the blood of the ent; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.

  These formulations are 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, for 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 formulations are those containing a daily dose or unit daily sub-dose of the active ingredient or an appropriate fraction 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 It should be understood that flavoring agents can be included.

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

  A veterinary carrier is a substance useful for the purpose of administering this composition, which is a solid, liquid or gaseous substance, which is otherwise inert or acceptable in the veterinary field, It is compatible with this 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 or sustained release.

  The effective dose of the active ingredient depends at least on the nature of the condition to be treated, toxicity, whether the compound is used prophylactically (low dose), the delivery method, and the pharmaceutical formulation, and the usual dose Determined by the clinician using a step-by-step study. 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 active ingredient of the present invention is also used in combination with other active ingredients. Such combinations are selected based on the condition being treated, the interreactivity of the components 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 in one or more administrations.

  This combination therapy can provide "synergism" and "synergy", i.e., the effect achieved when the active ingredients are combined, rather than the sum of the effects resulting from the separate use of the compounds. high. 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) when due to 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 a product typically prepares a radiolabeled (eg, ¹⁴ C or ³ H) compound of the invention, which is detectable in animals (eg, rats, mice, guinea pigs, monkeys) or humans. (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 as they are labeled (others are isolated by using antibodies that can bind to 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 compounds of the present invention, even if they do not have their own kinase inhibitory activity, unless otherwise found specifically in vivo.

  Strategies and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. A compound is defined herein to be 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 that they cannot be hydrolyzed in vivo. The phosphonate prodrugs of the present invention are typically stable in the digestive system but are usually substantially hydrolyzed to their parent drug in the gastrointestinal tract, liver or other metabolic organs, or cells. Is done.

(Representative method for producing the compound of the present invention)
The present invention also relates to a number of methods for producing the compositions of the present 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 (Pergamon Press, New York, printed in 1993).

  A number of exemplary methods for 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.

(Scheme and Examples)
General aspects of these exemplary methods are described below and in the Examples. Each of the products of the following processes 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 to refer to contacting, mixing, reacting when used in connection with chemical synthesis operations. , Meaning contact, and other commonly used in the art indicating that one or more chemical elements are processed in a manner that converts them to one or more other chemical elements Means the term 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” It is synonymous with other expressions commonly used in the technical field of organic synthesis, which rationally indicates that compound 1 is “treated”, “reacted”, “reacted”, etc. with compound 2. It means that there is. For example, “treating” means the usual rational way of reacting organic chemicals. Unless otherwise stated, normal concentrations (0.01M-10M, typically 0.1M-1M), temperatures (-100 ° C-250 ° C, typically -78 ° C-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 that bind to or make separable the desired product, unreacted starting materials, reaction byproducts, and the like. 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 chelators (eg, crown ethers, liquid / liquid ion exchange) It may be a reagent (LIX) or the like.

  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. can get. ("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. Methods for determining optical purity include chiral esters of the racemic mixture (eg, menthyl ester (eg, (-) menthyl chloroformate) or Mosher ester, α-methoxy-α- (trifluoro) acetate in the presence of a base). Methyl) phenyl (Jacob III. (1982) J. Org. Chem. 47: 4165)) and analysis by NMR spectrum for the presence of two atropisomeric diastereomers. Stable diastereomers of atropic compounds can be separated and isolated by normal and reverse phase chromatography following the method for separating atropisomeric naphthyl-isoquinolines (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 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 nucleosides to 5'-hydroxy is a well-known method of preparing nucleoside phosphonic acid monoesters. This activated precursor is 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 substituted diols 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). Phosphorofluoridate 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 an aromatic triflate in the presence of a palladium catalyst (Petrakis et al., (1987) J. Am. Chem. Soc. 109: 2831; Lu et al., (1987) Synthesis, 726). In another method, 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) can be accomplished in a number of ways. 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, By treatment with aqueous sodium hydroxide solution 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, a palladium on 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 (benzyl)) is hydrogenated with a palladium catalyst or treated with hydrogen chloride in an ether-containing solvent (eg, dioxane). 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) Can be carried out by a number of reactions in which the substrate S32.2 is reacted with a 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 (e.g. pyridine)), or (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma) (in this case the reaction is carried out with a tertiary organic base (e.g. Carried out in a polar solvent (eg dimethylformamide) in the presence of diisopropylethylamine), or Aldrithiol-2 (Aldrich) (in this case the reaction is triarylphosphine (eg tonophenylphosphine)) In the presence of Medium (e.g., pyridine) in is performed) and the like. Alternatively, the conversion of phosphonate monoester S32.2 to diester S32.1 is performed as described above (Scheme 7) by using Mitsunobu reaction. 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 is converted to the phosphonate diester S32.1 by reacting this monoester with a halide R ¹ Br where R ¹ is alkenyl or arylalkyl, where the introduced R ¹ The group is alkenyl or arylalkyl. This alkylation reaction is carried out in a polar organic solvent (eg dimethylformamide or acetonitrile) in the presence of a base (eg cesium carbonate). Alternatively, the phosphonate monoester is converted to the phosphonate diester in a two step procedure. In the first step, the phosphonate monoester S32.2 is prepared from Organic Phosphorus Compounds, G.M. M.M. Kosolapoff, L.M. Maair, eds, Wiley, 1976, p. 17 can be converted to the chloro analog RP (O) (OR ¹ ) Cl by reaction with thionyl chloride or oxalyl chloride, etc., and the resulting product RP (O ) (OR ¹ ) Cl is then reacted with the hydroxy compound R ¹ OH in the presence of a base (eg triethylamine) to give the phosphonate diester S32.1.

Phosphonate R-Link-P (O) (OH) ₂ is a phosphonate diester R-Link-P (O) (OR ¹ ), except that only one molar proportion of component R ¹ OH or R ¹ Br is used. ₂ Can be 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 (eg, Aldrithiol-2 (Aldrich) and triphenylphosphine). The ring reaction can be converted to the phosphonate diester R-link-P (O) (OR ¹ ) ₂ S32.1 (Scheme 32, Reaction 6). This reaction is carried out in a basic solvent (eg pyridine). Alternatively, the phosphonic acid S32.3 can be obtained by coupling reaction in pyridine at about 70 ° C. using, for example, phenol and dicyclohexylcarbodiimide, where the phosphonic acid ester S32.1 (where R ¹ is aryl). ). Alternatively, phosphonic acid S32.3 is converted to 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.

  (Scheme 32)

（ホスホネートカルバメートの調製）
ホスホン酸エステルは、カルバメート連鎖を含有し得る。カルバメートの調製は、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)
Phosphonate esters can contain carbamate linkages. The preparation of carbamates 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 linkage. As shown in Scheme 33, in a general reaction to produce a carbamate, the alcohol S33.1 is converted to the 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 alternative reactions for preparing carbamates.

  Scheme 33, Example 1 illustrates the preparation of a carbamate using the chloroformyl 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 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 chloroformate compound S33.6 with imidazole to produce imidazolide S33.8. The imidazolide product is then reacted with amine S33.3 to give carbamate S33.7. The preparation of the imidazolide is performed 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 a 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 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 is carried out in an aprotic 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 a carbamate, wherein carbonate (R ″ O) ₂ CO S33.14 is reacted with alcohol S33.5 to yield the intermediate alkyloxycarbonyl S33.15. The latter reagent is then reacted with amine R′NH ₂ to give carbamate S33.7 The procedure by which reagent S33.15 is derived from hydroxybenzotriazole S33.19 is described in Synthesis, 1993, The procedure by which reagent S33.15 is derived from N-hydroxysuccinimide S33.20 is described in Tet.Lett., 1992, 2781; reagent S33.15 is 2-hydroxypyridine S33. The procedure derived from .23 is Tet.Lett., 1991, 4251. The procedure by which reagent S33.15 is derived from 4-nitrophenol S33.24 is described in Synthesis, 1993, 103. Between equimolar amounts of alcohol ROH and carbonate S33.14. The reaction is carried out at room temperature in an inert organic solvent.

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

  Scheme 33, Example 8 illustrates the preparation of carbamates 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 reaction is carried out at room temperature with an aprotic solvent (eg In acetonitrile) in the presence of a base (eg triethylamine) to give the carbamate S33.7.

  Scheme 33, Example 9, illustrates the preparation of carbamates 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) to give the carbamate S33.7.

Scheme 33, Example 10 illustrates the preparation of carbamates 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.

(Scheme 33. Preparation of carbamate)
(General reaction)

（例）

(Example)

（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 preparing amidates and esters from phosphonic acids. These reagents include Aldrithiol-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 (which is J. Org. Chem. (1984) 49: 1158), 1- (2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT) (this is Bioorg. Med. Chem. Lett. (1998) 8: 1013), Lomotris (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.M. 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 gem-dialkylaminophosphonate reagents.

Scheme 34 illustrates various methods for converting phosphonate diester S34.1 to phosphonbisamidate 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.

  (Scheme 34)

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エチルエステル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、次いで、Ｊ．Ｍｅｄ．Ｃｈｅｍ．（１９９７）４０（２３）：３８４２よれば、不安定であるかも知れない。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、ロイシンエチルエステル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 alanine ethyl ester S34.16 and dicyclohexylcarbodiimide in pyridine to give 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 then Med. Chem. (1997) 40 (23): 3842 may be unstable. This compound S34.18 was then Med. Chem. , 1995, 38, 2742, in a Mitsunobu reaction with leucine ethyl ester S34.19, triphenylphosphine and diethylazodicarboxylate to give the bisamidate product S34.20.

  Using the above procedure, but using a different amino ester S34.9 instead of leucine ethyl ester S34.19 or alanine ethyl ester 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 excess phenylalanine ethyl ester 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 phenylalanine ethyl ester, the corresponding product S34.5 is obtained.

  As yet another example, phosphonic acid S34.6 is converted to a mono or bis-activated derivative S34.7, where Lv is a leaving group (eg, chloro, imidazolyl, triisopropylbenzenesulfonyloxy, etc.). is there. 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 monoimidazoline 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 serine butyl ester 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 the different amino ester S34.9 instead of the serine butyl ester 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 alanine ethyl ester S34.33 in acetonitrile solution to give 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 N-methylalanine ethyl ester 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 alanine ethyl ester S34.33 or N-methylalanine ethyl ester S34.33a, the corresponding product S34.5 is obtained.

The intermediate monoamidate S34.3 is also first converted to the monoester S34.2 by activating the derivative S34.8 (where Lv is a leaving group (eg halo, imidazolyl, etc.) using the above procedure. Prepared from monoester 34.2 by first converting to 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. Reaction with thionyl chloride in dichloromethane as described in Letters, 1994, 35, 4097 gives 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 a 5% palladium on carbon catalyst to give the monoacid product S34.29. This product was subjected to Mitsunobu coupling procedure with equimolar amounts of alanine butyl ester S34.30, triphenylphosphine, diethylazodicarboxylate and triethylamine in tetrahydrofuran to give bisamidate product S34.31. It is done.

  Using the above procedure, but using different amino ester S34.9 instead of ethyl 3-amino-2-methylpropionate S34.27 or alanine butyl ester S34.30, 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. Maair Edit, Wiley, 1976. The bisamino compound S34.10 is then converted to the haloester S34.10 in the presence of a base (eg 4-dimethylaminopyridine (DMAP) or potassium carbonate) in a polar solvent (eg dimethylformamide) at an elevated temperature. Reaction with 12 (Hal = halogen, ie F, Cl, Br, I) yields 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 tyrosine propyl ester 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 tyrosine propyl ester to produce the bisamidate product S34.43.

  Using the above procedure, but using the different amino ester S34.9 instead of the tyrosine propyl ester 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 S35.1.

  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 alanine ethyl ester as described in Scheme 34 to yield amidate S35.1.

  Using the above procedure, but replacing the alanine ethyl ester S35.9 with a different amino ester S34.9, the corresponding product S35.10 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 amines and phosphonic acids (carbodiimide, Aldrithiol-2, PYBOP, Mitsunobu reaction, etc.) using the hydroxy compound R ³ OH (where R ³ The group is converted to the ester amidate product S35.3 by reaction with aryl, heterocycle, alkyl, cycloalkyl, haloalkyl, and the like.

  (Scheme 34, Example 1)

（スキーム３４、例２）

(Scheme 34, Example 2)

（スキーム３４、例３）

(Scheme 34, Example 3)

（スキーム３４、例４）

(Scheme 34, Example 4)

（スキーム３４、例５）

(Scheme 34, Example 5)

（スキーム３４、例６）

(Scheme 34, Example 6)

（スキーム３４、例７）

(Scheme 34, Example 7)

この方法の例は、スキーム３５、例１〜３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、アラニンエチルエステルとの反応により、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、５％炭素担持パラジウム触媒で触媒的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。

An example of this method is shown in Scheme 35, Examples 1-3. In the sequence shown in Example 2, phosphonate monobenzyl S35.11 is converted to monoamidate S35.12 by reaction with alanine ethyl ester using one of the methods described above. The benzyl group is then removed by catalytic hydrogenation with 5% palladium on carbon catalyst 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 alanine ethyl ester 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 N-methyltyrosine ethyl ester 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.

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

  (Scheme 35)

（スキーム３５、例１）

(Scheme 35, Example 1)

（スキーム３５、例２）

(Scheme 35, Example 2)

（スキーム３５、例３）

(Scheme 35, Example 3)

（スキーム３５、例４）

(Scheme 35, Example 4)

（スキーム３５、例５）

(Scheme 35, Example 5)

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

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

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

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

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

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

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

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

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

  (Scheme 36)

（スキーム３６、例１）

(Scheme 36, Example 1)

（スキーム３６、例２）

(Scheme 36, Example 2)

（スキーム３６、例３）

(Scheme 36, Example 3)

（スキーム３６、例４）

(Scheme 36, Example 4)

（スキーム３６、例５）

(Scheme 36, Example 5)

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 1.6. 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 36 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 36 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.

  (Scheme 37)

（スキーム３７、例１）

(Scheme 37, Example 1)

（スキーム３７ 例２）

(Scheme 37 Example 2)

（スキーム３７、例３）

(Scheme 37, Example 3)

（スキーム３７、例４）

(Scheme 37, Example 4)

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３８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と縮合すると、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。ホスファイトでアジリジンを開環すると、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 38. When 2-methyl-2-propanesulfinamide is condensed with acetone, sulfinyl imine S38.11 is obtained (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). . Ring opening of aziridine with phosphite yields S38.17 (Tetrahedron Lett. 1980, 21, 1623). Reprotecting S38.17 gives S38.14.

  (Scheme 38a)

（スキーム３８ｂ）

(Scheme 38b)

本発明は、以下の非限定的な実施例により、例示される。

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

Example 1
(Synthesis of representative compounds of Formulas 1 to 4)

本発明の代表的な化合物（例えば、上記）を、以下の方法にしたがって合成し得る。ＣＰ−６９０，５５０（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）を、ＷＯ ０２／０９６，９０９およびＷＯ ０３／０４８，１６２に記載されるとおりに調製し得る。２当量以上の塩基を使用して、α−シアノアミド位においてエノレートを形成し、次にジエチルホスホノメチルトリフラート（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７にしたがって，調製した）を添加することより、上に示す所望の化合物１．１を得る。溶媒（例えば、ＴＨＦ、ＤＭＦまたは他の無水溶媒）を、この反応のために使用し得る。ピロール窒素が所望のアルキル化に干渉する場合において、保護基（例えば、ＢＯＣ）を、アルキル化反応前に導入し得る。ＢＯＣ基の除去を、この反応生成物のＴＦＡへの曝露により達成し得る（Ｇｒｅｅｎｅ，Ｔ．，Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ Ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ，Ｗｉｌｅｙ−Ｉｎｔｅｒｓｃｉｅｎｃｅ，１９９９に記載される）。

Representative compounds of the invention (eg, above) can be synthesized according to the following methods. CP-690,550 (3- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo- Propionitrile) may be prepared as described in WO 02 / 096,909 and WO 03 / 048,162. Using more than 2 equivalents of base to form an enolate at the α-cyanoamide position, followed by addition of diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986, 27, 1477) The desired compound 1.1 shown in is obtained. Solvents such as THF, DMF or other anhydrous solvents can be used for this reaction. In cases where the pyrrole nitrogen interferes with the desired alkylation, a protecting group (eg, BOC) can be introduced prior to the alkylation reaction. Removal of the BOC group can be achieved by exposure of the reaction product to TFA (described in Greene, T., Protective Groups In Organic Synthesis, Wiley-Interscience, 1999).

  Another specific compound of the invention may be synthesized as follows:

（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、化合物２．１（ＷＯ ０２／０９６，９０９に記載されるとおりに調製した）を、最初にトシル基を用いて、ピロール窒素において保護する。次にＳａｋａｍｏｔｏ，Ｔ．ら（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．１９９４，３５，２９１９）により報告された手順を使用するホルミル化により、化合物２．３を提供する。次いで、この第１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）中で、塩基（例えば、水素化ナトリウム）で処理する。発泡が停止したとき、ジエチルホスホノメチルトリフラート（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８６，２７，１４７７にしたがって，調製した）を添加し、所望の生成物２．４を得る。ピペリジン窒素の脱ベンゼン化、次にシアノ−酢酸２，５−ジオキソ−ピロリジン−１−イルエステルとのカップリングにより、化合物２．５を得る。トシル保護基の除去により、所望の化合物２Ａを提供する。

(1-Benzyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine, compound 2.1 (in WO 02 / 096,909) Prepared as described) is first protected at the pyrrole nitrogen with the tosyl group. Next, Sakamoto, T. et al. Formylation using the procedure reported by Tetrahedron Lett. 1994, 35, 2919 provides compound 2.3. The primary alcohol is then treated with a base (eg, sodium hydride) in a solvent (eg, tetrahydrofuran or dimethylformamide). When effervescence ceases, diethylphosphonomethyl triflate (prepared according to Tetrahedron Lett., 1986, 27, 1477) is added to give the desired product 2.4. Debenzeneation of the piperidine nitrogen followed by coupling with cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester gives compound 2.5. Removal of the tosyl protecting group provides the desired compound 2A.

  Another specific compound of the invention may be synthesized as follows:

２−アミノ−６−クロロプリンを、米国特許出願第２００２／００６８７２１号に記載される手順と同様の手順に従い、ＤＭＦ中の３−（ｔ−ブチルジメチルシリルオキシ）フェネチルヨウ化物および水素化ナトリウムとともに加熱することより、Ｎ−９位をアルキル化する。２−アミノ基を、従来の方法（例えば、Ｊ．Ｍｅｄ．Ｃｈｅｍ．２００３，４６，５７６３に記載される）により、ヨード基に変換する。得られたヨウ化物を、パラジウム触媒（例えば、塩化ビス（トリフェニルホスフィン）パラジウム（ＩＩ））の存在下で、臭化シクロペンチル亜鉛と交差カップリングした（Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９９１，５６，１４４５）。所望の（４−｛２−シクロペンチル−９−［２−（３−ヒドロキシフェニル）エチル］−９Ｈ−プリン−６−イルアミノ）フェノキシメチル）ホスホン酸ジエチルエステルへの変換を、反応条件下（例えば、米国特許出願第２００２／００６８７２１号に記載される反応条件）で、６−クロロ置換体を、対応するホスホネート含有すアニリンで置き換え、次いで、フッ素化テトラブチルアンモニウムに曝露することにより、ｔ−ブチルジメチルシリル保護基を除去することにより、達成する。

2-Amino-6-chloropurine is combined with 3- (t-butyldimethylsilyloxy) phenethyl iodide and sodium hydride in DMF according to a procedure similar to that described in US Patent Application 2002/0068721. The N-9 position is alkylated by heating. The 2-amino group is converted to an iodo group by conventional methods (eg, as described in J. Med. Chem. 2003, 46, 5763). The resulting iodide was cross-coupled with cyclopentylzinc bromide (J. Org. Chem. 1991, 56, 1445) in the presence of a palladium catalyst (eg, bis (triphenylphosphine) palladium (II) chloride). ). Conversion to the desired (4- {2-cyclopentyl-9- [2- (3-hydroxyphenyl) ethyl] -9H-purin-6-ylamino) phenoxymethyl) phosphonic acid diethyl ester under reaction conditions (eg, Reaction conditions described in US Patent Application No. 2002/0068721) by replacing the 6-chloro substituent with the corresponding phosphonate-containing aniline and then exposing to fluorinated tetrabutylammonium. Achieved by removal of the silyl protecting group.

  Another specific compound of the invention may be synthesized as follows:

Ａ−４２０９８３を、溶媒（例えば、クロロホルム）中で、Ｈｕｎｉｇ塩基の存在下で、α−クロロエチルクロロホルメートと縮合し、次に酸性メタノール中で簡単に加熱することにより、脱メチル化する。得られた遊離ピペラジンを、溶媒（例えば、ジメチルホルムアミド）中で、塩基（例えば、炭酸カリウム）の存在下で、ジエチル２−ブロモエチルホスホネートでアルキル化し、所望の生成物を提供する。

A-420983 is demethylated by condensation with α-chloroethyl chloroformate in a solvent (eg, chloroform) in the presence of Hunig's base and then briefly heating in acidic methanol. The resulting free piperazine is alkylated with diethyl 2-bromoethylphosphonate in the presence of a base (eg, potassium carbonate) in a solvent (eg, dimethylformamide) to provide the desired product.

  Documents and patent citations in this specification are hereby expressly incorporated by reference herein where they are cited. The specifically cited sections or pages of the above cited studies are specifically incorporated by reference. The present invention has been described in detail so that those skilled in the art are well capable of implementing and using the subject matter of the following embodiments. It will be apparent that certain modifications of the methods and compositions of the following embodiments may be made within the scope and spirit of the invention.

In the embodiments herein, the subscript and superscript for a given variable are different. For example, R ₁ is different from R ¹ .

Claims (71)

One or more phosphonates and the substructure of formula I:

Or a compound comprising a pharmaceutically acceptable salt thereof,
Wherein L ¹ and L ² are —N— or —CR ^a —; and R ^a is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl.
Compound. Substructure of the following formula:

The compound of claim 1, comprising
here,
L ¹ and L ² are independently —N— or —CR ^a — provided that only ^one of L ¹ or L ² is a nitrogen atom;
R ^a is hydrogen, alkyl, aryl, or substituted aryl;
R ²⁰ is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkylaryl, cycloalkyl, substituted aryl, or —NR ^b R ^c ;
R ^b and R ^c are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or aralkyl;
R ²¹ is hydrogen, alkyl, cycloalkyl, substituted cycloalkyl, substituted alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; and R ²² and R ²³ are independently hydrogen, alkyl, substituted aryl, or Aralkyl,
Compound. Substructure of formula II:

The compound of claim 1, comprising: Substructure of formula IIIa, formula IVa, or formula Va:

The compound of claim 1, comprising: Formula 1, Formula 2, Formula 3, or Formula 4:

The compound of claim 1 having
here:
A ⁰ is A ¹ ;
A ¹ is:

Is;
A ³ is:

Is;
Y ¹ is independently O, S, N (R ^X ), N (OR ^X ), or N (N (R ^X ) (R ^X ));
Y ² is independently a bond, O, N (R ^X ), N (OR ^X ), N (N (R ^X ) (R ^X )), or —S (O) _{M 2} —; , Y ² is bonded to two phosphorus atoms, Y ² can also be C (R ² ) (R ² );
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 0-3 R ³ groups;
R ³ is R ^3a , R ^3b , R ^3c , or R ^3d , provided that when R ³ is attached to a heteroatom, R ³ is R ^3c or R ^3d ;
R ^3a is F, Cl, Br, I, —CN, N ₃ , or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^X , —N (R ^X ) (R ^X ), —SR ^X , —S (O) R ^X , —S (O) ₂ R ^X , —S (O) (OR ^X ), —S (O) ₂ (OR ^X ), —OC (Y ¹ ) R ^X , —OC (Y ¹ ) OR ^X , —OC (Y ¹ ) (N (R ^X ) (R ^X )), —SC ( Y ¹ ) R ^X , —SC (Y ¹ ) OR ^X , —SC (Y ¹ ) (N (R ^X ) (R ^X )), —N (R ^X ) C (Y ¹ ) R ^X , —N ( R ^X ) C (Y ¹ ) OR ^X , or —N (R ^X ) C (Y ¹ ) (N (R ^X ) (R ^X ));
R ^3d is —C (Y ¹ ) R ^X , —C (Y ¹ ) OR ^X , or —C (Y ¹ ) (N (R ^X ) (R ^X ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , each R ⁴ is substituted with 0-3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0-3 R ₂ groups;
W ⁶ being one independently a ^{W 3} is substituted with two or three ^{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;
L ¹ and L ² are —N— or —CR ^a —, but only ^one of L ¹ or L ² is a nitrogen atom;
R ^a is hydrogen, alkyl, aryl, or substituted aryl and R ²⁰ is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkylaryl, cycloalkyl, substituted aryl, or —NR ^b R ^c ;
R ^b and R ^c are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or aralkyl;
R ²¹ is hydrogen, alkyl, cycloalkyl, substituted cycloalkyl, substituted alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; and R ²² and R ²³ are independently hydrogen, alkyl, substituted aryl, or Aralkyl,
Compound. A ¹ has the following formula:

The compound according to claim 5, wherein A ¹ has the following formula:

The compound according to claim 5, wherein A ¹ has the following formula:

The compound according to claim 5, wherein A ¹ has the following formula:

The compound according to claim 5, wherein A ¹ has the following formula:

And W ^5a is a carbocyclic or heterocyclic ring, wherein W ^5a is independently substituted with 0 or 1 R ² group. 6. A compound according to claim 5, wherein M12a is 1. A ¹ has the following formula:

The compound according to claim 5, wherein A ¹ has the following formula:

The compound according to claim 5, wherein A ¹ has the following formula:

^6. A compound according to claim 5, wherein W ^5a is independently a carbocycle substituted with 0 or 1 R ² groups. A ¹ has the following formula:

And
Y ^2b is, O, or be a N ^{(R 2);} and M12d is 1,2,3,4,5,6,7 or 8, a compound according to claim 5. A ¹ has the following formula:

^6. A compound according to claim 5, wherein W ^5a is independently a carbocycle substituted with 0 or 1 R ² groups. A ¹ has the following formula:

^6. The compound of claim 5, wherein W ^5a is a carbocyclic or heterocyclic ring, wherein W ^5a is independently substituted with 0 or 1 R ² group. A ¹ has the following formula:

And
Y ^2b is, O, or be a N ^{(R 2);} and M12d is 1,2,3,4,5,6,7 or 8, a compound according to claim 5. A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein A ³ can be represented by the following formula:

Y ^1a is O or S; and Y ^2a is O, N (R ^X ), or S.
The compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein Y ^2b is O or N (R ^X ). A ³ can be represented by the following formula:

Because
R ¹ is independently H or alkyl consisting of 1 to 18 carbon atoms;
Y ^2b is O or N (R ^X ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
The compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

Because
Y ^2b is O or N (R ^X ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
The compound according to any one of claims 5 to 18. 25. The compound of claim 24, wherein M12d is 1. A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein W ⁵ is a carbocycle, a compound according to claim 27. A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein W ⁵ is phenyl, A compound according to claim 29. 32. The compound of claim 30, wherein M12b is 1. A ³ can be represented by the following formula:

Y ^1a is O or S; and Y ^2a is O, N (R ^X ), or S.
The compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein Y ^2b is O or N (R ^x ). A ³ can be represented by the following formula:

Because
R ¹ is independently H or alkyl consisting of 1 to 18 carbon atoms;
Y ^2b is O or N (R ^X ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
The compound according to any one of claims 5 to 18. R ¹ is H, A compound according to claim 34. 35. The compound of claim 34, wherein M12d is 1. A ³ can be represented by the following formula:

A is phenyl carbocycle, 0,1,2 or substituted with 3 ^{R 2} groups, the compounds according to any one of claims 5 to 18,. A ³ can be represented by the following formula:

Because
R ¹ is alkyl of from independently H or 1 to 18 carbon atoms, A compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein A ³ can be represented by the following formula:

Because
Y ^1a is O or S; and Y ^2a is O, N (R ² ), or S.
The compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

Because
Y ^1a is O or S;
Y ^2b is O or N (R ² ); and Y ^2c is O, N (R ^y ), or S.
The compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

Because
R ¹ is independently H or alkyl consisting of 1 to 18 carbon atoms;
Y ^1a is O or S;
Y ^2b is O or N (R ² );
Y ^2d is O or N (R ^y ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
The compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

Because
Y ^2b is O or N (R ² ); and
M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
The compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein Y ^2b is O or N (R ² ). A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein A ³ can be represented by the following formula:

Because
Y ^1a is O or S; and Y ^2a is O, N (R ² ), or S.
The compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

Because
Y ^1a is O or S;
Y ^2b is O or N (R ² ); and Y ^2c is O, N (R ^y ), or S.
The compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

Because
R ¹ is independently H or alkyl consisting of 1 to 18 carbon atoms;
Y ^1a is O or S;
Y ^2b is O or N (R ² );
Y ^2d is O or N (R ^y ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
The compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

Because
Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
The compound according to any one of claims 5 to 18. A ³ can be represented by the following formula:

The compound according to any one of claims 5 to 18, wherein Y ^2b is O or N (R ² ). A ³ can be represented by the following formula:

A is, wherein each R is independently _(C 1 ~C ₆₎ alkyl, A compound according to claim 5. A compound according to claim 2, comprising
R ^a is hydrogen or substituted aryl;
R ²⁰ is hydrogen, cycloalkyl, or —NR ^b R ^c ;
R ^b is hydrogen and R ^c is substituted alkyl or substituted aryl;
R ²¹ is hydrogen, alkyl, substituted cycloalkyl, or substituted aralkyl;
R ²² is hydrogen or alkyl; and R ²³ is hydrogen, substituted aryl, or substituted cycloalkyl, or aralkyl.
Compound. 56. The compound according to any one of claims 1 to 55, wherein the compound is a serine / threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase. A compound that inhibits VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase and / or EGF receptor tyrosine kinase. 56. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of any one of claims 1-55. 56. A unit dosage form comprising a compound according to any one of claims 1 to 55 and a pharmaceutically acceptable excipient. 56. A method for inhibiting a kinase in vitro or in vivo comprising contacting a sample in need of such treatment with a compound according to any one of claims 1-55. 60. The method of claim 59, wherein the contacting is in vivo. 56. A method of inhibiting a kinase in an animal comprising administering to the animal a compound of any one of claims 1-55. 62. The method of claim 61, wherein the compound is formulated with a pharmaceutically acceptable carrier. 64. The method of claim 62, wherein the formulation further comprises a second active ingredient. 64. The method according to any one of claims 59 to 63, wherein the kinase is serine / threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase. A VEGF receptor kinase, a PDGF receptor tyrosine kinase, a protein kinase C, an insulin receptor tyrosine kinase and / or an EGF receptor tyrosine kinase. 56. A method of treating cancer in an animal in need of treatment for cancer, comprising administering to said animal an effective amount of a compound according to any one of claims 1-55. 56. A compound according to any one of claims 1 to 55 for use in medical therapy. 56. Use of a compound according to any one of claims 1 to 55 for the preparation of a medicament for inhibiting a kinase in an animal. 68. Use according to claim 67, wherein said kinase is serine / threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor Use, which is a tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase and / or EGF receptor tyrosine kinase. 56. Use of a compound according to any one of claims 1 to 55 for the preparation of a medicament for treating cancer in an animal. A method for preparing compounds as described in the schemes and examples herein. 56. A method for preparing a pharmaceutical composition comprising mixing a compound according to any one of claims 1 to 55 with a pharmaceutically acceptable excipient. ,Method.