JP2012107074A - Small molecule immunopotentiator and assay for the detection - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide new immune potentiators, immunogenic compositions, new compounds and pharmaceutical compositions, and new methods for administering a vaccine, by administering small molecule immune potentiators in combination with antigens.SOLUTION: The invention provides immunostimulatory compositions comprising a small molecule immuno-potentiator (SMIP) compound and methods of administration thereof. Also methods for administering an SMIP compound in an effective amount to enhance the immune response of a subject to an antigen are provided. Further new compositions and methods for administering SMIP compounds alone or in combination with another agent for the treatment of cancer, infectious diseases and/or allergies/asthma are provided. In a further aspect, the invention relates generally to methods for screening of small molecule immuno-modulatory compositions.

Description

  In one embodiment, the present invention relates generally to compounds that can stimulate or modulate an immune response in a subject. More specifically, the present invention relates to a novel combination of antigen and small molecule used in vaccine therapy. These compounds in one embodiment can be used as adjuvants for prophylactic and therapeutic vaccines against infections and cancer. In another embodiment, these compounds can be used as immunotherapy against cancer, infections and / or allergies / asthma, either alone or in combination with existing therapies. In further embodiments, the present invention relates generally to methods for identifying small molecule immunomodulators, and more specifically, measuring immunological markers (eg, cytokines, chemokines, and / or growth factors). Relates to a high-throughput assay for the detection of immunopotentiators and immunosuppressive factors.

(Background of the Invention)
The immune response to specific antigens that are weakly antigenic can be enhanced by the use of vaccine adjuvants. Such an adjuvant enhances the immune response to a particular antigen and therefore it is the subject of interest and research in the medical community.

  Investigations have allowed the development of vaccines with antigenic epitopes that were previously impossible to produce. For example, currently available vaccines include synthetic peptides that mimic streptococcal, gonococcal, and malarial antigens. However, these purified antigens are generally weak antigens that require an adjuvant to elicit protective immunity. However, conventional vaccine adjuvants have many drawbacks that limit their general use and effectiveness. Again, this is excellent for vaccines but not for other uses.

  Substances that stimulate immune cells in vitro exhibit similar immunostimulatory effects in vivo. These compounds (eg, recombinant cytokines, pathogen products (eg, toxins, lipids, proteins / peptides, carbohydrates and nucleic acids) and other mammalian-derived immunostimulatory molecules (eg, heat shock proteins, complements, immune complexes) And proteoglycans) all elicit a non-negligible pro-inflammatory response both in vitro and in vivo.

  Historically, classical adjuvants were Freund's complete or incomplete adjuvant (ie, free of mycobacteria). Edmund Coley describes the potential of Coley's toxin for cancer immunotherapy. Other materials such as mineral oil and aluminum hydroxide have also been used as adjuvants, but they always suffer from disadvantages. For example, mineral oil is known to be tissue irritating and potentially carcinogenic. Alum (the only approved adjuvant in the United States) also induces granulation species at the site of inoculation and does not effectively induce cell-mediated immunity. Moreover, many currently available adjuvants have limited use due to the inclusion of components that are not metabolized in humans. In addition, most adjuvants require laborious procedures and their use, and in some cases are difficult to prepare because they require complex and expensive equipment for formulating vaccines and adjuvant systems. .

  Immunological adjuvants are described in Non-Patent Document 1 and Non-Patent Document 2. See also Patent Document 1; Patent Document 2; and Patent Document 3 for various vaccine adjuvants shown in the patent literature.

  The compounds are described in issued US Pat. Nos. 5,047,086 and 5,037,086 for the treatment of disorders responsive to agents that enhance cell-mediated immunity, general structure (a):

で記載される。列挙した特許に記載されるような分子の必須構成要素は、構造（ａ）に示されるようなアミド置換基である。その発明は、抗原との組み合わせを企図しなかった。

It is described in. An essential component of the molecules as described in the listed patents is an amide substituent as shown in structure (a). The invention did not contemplate combinations with antigens.

  Immunostimulatory oligonucleotides and polynucleotides are described in US Pat. U.S. Patent No. 6,057,031 describes adjuvants containing unmethylated CpG dinucleotides (CpG ODN) and non-nucleic acid adjuvants. U.S. Patent No. 6,057,031 describes a composition comprising an antigen, an antigenic CpG-ODN and a polycationic polymer.

  Furthermore, issued Patent Document 10, Patent Document 11, Patent Document 12, Patent Document 13, Patent Document 14, Patent Document 15, Patent Document 16, Patent Document 17, Patent Document 18, Patent Document 19, Patent Document 20, Patent Document 21, Patent Document 22 and Patent Document 23 are general structures (b) for use as “immune response modifiers”:

の化合物を開示する。

The compounds are disclosed.

  There are efforts to find new immunomodulators for use as adjuvants for vaccines and immunotherapy that overcome the shortcomings and deficiencies of conventional immunomodulators. In particular, adjuvant formulations that elicit strong cell-mediated and humoral immune responses against a wide range of antigens in humans and livestock, but lack the side effects of conventional adjuvants and other immune modulators, are highly desirable. . This need can be met by small molecule immune potentiators (SMIP). This is because small molecule platforms provide a variety of compounds for the selective manipulation of immune responses.

  Furthermore, it would be desirable to provide novel compounds with diverse ability to alter the level and / or profile of cytokine production in human immune cells. Compounds with structural differences often elicit the desired response via different mechanisms of action or modulate efficacy and reduce side effects when administered to a patient (e.g. Elicits the desired response with higher specificity for dendritic cells).

  The immunosuppressive effect of a cytostatic substrate makes the substrate useful in the therapy of autoimmune diseases such as multiple sclerosis, psoriasis and certain rheumatic diseases. Even here, their beneficial effects are unilaterally disadvantageous over severe side effects that require very low dosages and / or discontinuation of treatment.

  To date, immunosuppressive factors have also been very interesting due to the ability of immunosuppressive factors to reduce immune responses in surgery and transplantation where complete immune attack or rejection of the transplanted organ can be fatal .

  One object of the present invention is to have a significantly improved cytostatic or cytotoxic effect compared to conventional cytostatics (eg, vincristine, methotrexate, cisplatin, etc.) given alone. The resulting active substrate combination is to be provided. In that regard, chemotherapy may be provided that combines increased efficacy with a significant reduction in side effects and therapeutic dose. Thus, the therapeutic efficacy of known cytostatic drugs is increased. Also, certain cell lines that are insensitive to chemotherapy treatment can become sensitive by applying a combination of active substrates.

  Treatments that have reduced toxicity and can serve to enhance natural host defense against viral infections are highly beneficial. The present invention provides such therapeutic agents and further provides other related benefits.

Small molecule platforms provide a variety of compounds for the selective manipulation of immune responses necessary to increase the therapeutic index of drugs. Compounds with structural differences often elicit the desired response via different mechanisms of action or modulate efficacy and reduce side effects when administered to a patient (e.g. Elicits the desired response with a higher specificity for dendritic cells).
Accordingly, it would be beneficial to provide an assay for rapidly screening large quantities of small molecule compounds that may have immunomodulatory activity. The purpose of the present invention is to detect small molecules that can modulate immune responses. Is to provide a high-throughput screening for. It is also an object of the present invention to provide a method for making a broad library of compounds with a solid support resin that can be screened in the high throughput assay of the invention.
All of the above documents are incorporated by reference as if fully set forth herein.

US Pat. No. 4,806,352 US Pat. No. 5,026,543 US Pat. No. 5,026,546 US Pat. No. 4,547,511 US Pat. No. 4,738,971 International Publication No. 98/55495 Pamphlet International Publication No. 98/16247 Pamphlet US Patent Application No. 2002/0164341 US Patent Application No. 2002/0197269 US Pat. No. 4,689,338 US Pat. No. 5,389,640 US Pat. No. 5,268,376 U.S. Pat. No. 4,929,624 US Pat. No. 5,266,575 US Pat. No. 5,352,784 US Pat. No. 5,494,916 US Pat. No. 5,482,936 US Pat. No. 5,346,905 US Pat. No. 5,395,937 US Pat. No. 5,238,944 US Pat. No. 5,525,612 WO99 / 29693 pamphlet US patent application Ser. No. 09 / 361,544

Derek T O'Hagan and Nicholas M. Valiente, “Current Status of Immunological Adjuvants”, Ann. Rev. Immunol. 1986, Vol. 4, p. 369-388 Derek T O'Hagan and Nicholas M. Valiente, “Recent Advances in Vaccine Advantages and Delivery Systems”

(Short description of the table)
Table 1 lists the in vitro inhibitory activity of TNF-α for 1H-imidazoquinoline.

  Table 2 identifies potent SMIS compounds that were shown to be SMIP, and their analogs.

  Table 3 lists SMIS analogs that are SMIPs.

  Table 4 lists preferred SMIS compounds that can modulate an immune response in a patient and that are modified to elicit an immune response in the patient, and their corresponding references.

  Table 5 lists chemokines that can be immunological markers for identifying immune modulation.

  Table 6 lists interleukins that can be immunological markers for identifying immune modulation.

(Summary of the Invention)
The present invention provides novel immune enhancing factors, immunogenic compositions, novel compounds and pharmaceutical compositions, and novel methods of administering a vaccine by administering a small molecule immune enhancing factor in combination with an antigen. The present invention further provides compositions, novel compounds and pharmaceutical compositions for use in the treatment of cancer, infections, allergies, and asthma.

  The SMIP compounds used in the methods and compositions of the present invention are inexpensively produced and easily administered. These compounds have a sharper specificity potential compared to existing immune stimulants and thus provide an improved efficiency and safety profile.

  As an adjuvant, SMIP compounds, combined with numerous antigens and delivery systems, form the final vaccine product.

  As immunotherapy, SMIP compounds are used alone or other therapies (eg, antiviral, antiviral, antiviral, antiviral, antiviral, antiviral, antiviral, antiviral, antiviral, antiviral, antiviral, antiviral, Used in combination with bacteria, other immunomodulators, or therapeutic vaccine antigens) and drugs to reduce tumor growth.

  As an immunotherapy, SMIP compounds can also be used alone or in combination with other anti-cancer therapies (eg, chemotherapeutic agents, mAbs, or other immune enhancing agents) to treat cancer. . In addition, certain SMIPs that can induce type 1 cytokines (eg, IL-12, TNF, or IFN) have the ability to direct the immune response to less harmful sequelae, thus treating allergies or asthma Can be useful for. SMIP compounds include, for example, BCG, cholera, plague, typhoid, hepatitis B infection, influenza, inactivated polio, rabies, measles, mumps, rubella, oral polio, yellow fever, tetanus , Diphtheria, influenza b, meningococcal infections, and pneumococcal infections. SMIP compounds can be used in anti-cell proliferative effective amounts for the treatment of cancer. SMIP compounds can also be used in anti-Th2 / 2 type cytokine levels to disrupt the allergic / asthmatic immune response.

  In another embodiment, a method of treating cancer is provided, where a known anti-cancer factor is combined with a SMIP compound to reduce tumor growth in a subject. A number of suitable anti-cancer agents are contemplated for use in the methods of the present invention and are described more thoroughly in the detailed description.

  In accordance with the present invention, administering to the subject an effective dose of a combination comprising at least one SMIP and one MAb, wherein the combination is more effective than when the MAb is administered independently. Provided is a method of inhibiting tumor cell growth in a subject comprising the step of inhibiting cell growth. Further provided are methods of treating cancer with the combination comprising an additional SMIP compound or MAb and administering to a subject in need thereof.

  Additional embodiments, methods and compositions believed to be useful in the present invention are disclosed in US Patent Application Publication Nos. 10 / 814,480, 10 / 762,873, and 10 / 748,071. These patent applications are hereby incorporated by reference as if fully set forth herein.

In a further embodiment, the present invention provides a high-throughput assay for identifying small molecule immune modulators, the assay comprising:
a) contacting a plurality of test compounds with cells to form one or more test solutions;
b) incubating the test solution for at least 30 minutes;
c) measuring for elevated levels of one or more immunological markers in the test solution;
Wherein immunomodulation by one or more test compounds present in the plurality of test compounds increases the amount of the immunological marker in the test solution.

Another embodiment of the invention provides a high-throughput assay for identifying small molecule immune modulators, the assay comprising:
a) contacting a plurality of test compounds with cells to form one or more test solutions;
b) adding a known immune enhancing factor to the test solution and a control solution not containing the test compound;
c) incubating the test solution and the control solution for at least 1 hour;
d) measuring the level of one or more immunological markers in the test solution and in the control solution;
e) comparing the level of one or more immunological markers in the test solution with a corresponding level of one or more immunological markers in the control solution, between the test solution and the control solution; Detecting a difference in the level of one or more immunological markers;
Wherein a decrease in the level of one or more immunological markers in the test solution indicates immunosuppression by the one or more test compounds, and an increase in the level of one or more immunological markers in the test solution comprises: 1 shows immune enhancement by one or more test compounds.

Another embodiment of the invention provides a high-throughput assay for identifying small molecule immune modulators, the method comprising:
a) providing a mixture of test compounds divided into an archive portion and a screening portion from a combinatorial library, wherein (i) the mixture comprises a plurality of resin carrier beads to which the test compound is attached; ii) a step of attaching only one kind of separate test compound to each bead at a level deeper than 1 nmol;
b) contacting the screening moiety with a cell;
c) measuring for an elevated level of an immunological marker in the screening moiety, wherein the immunomodulation by one or more test compounds present in the screening moiety is an amount of the immunological marker Increasing the process;
d) individually distributing the beads from the archive portion in step (a) to a plurality of reaction vessels such that each vessel contains a single bead;
e) cleaving the test compound from the beads and separating the beads from the cleaved test compound, thereby providing a separate sample of each test compound;
f) screening each fragmented test compound to identify small molecule immune modulators;
g) performing mass spectroscopic analysis on the small molecule immunomodulator; and h) using the mass spectroscopic analysis to obtain a chemical identification of the small molecule immunomodulator from the preliminary portion.

  In another embodiment of the present invention, one method is provided that screens components of a combinatorial library for immunological activity and then performs non-synthetic analysis to identify and characterize specific components from the library. .

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ _１１ は、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換ヒドロキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アリールアミノ、置換および非置換ヘテロアリールアミノ、置換および非置換ヘテロシクリルアミノ、ならびに置換および非置換カルボシクリルアミノからなる群より選択され；
Ｒ _１２ は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、ならびに置換および非置換アルコキシアルキルからなる群より選択され；そして
Ｒ _１３ は、Ｈ、ヒドロキシル、アルコキシ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択されるか；あるいは
Ｒ _１２ およびＲ _１３ は結合して一緒になり、置換または非置換ヘテロシクリル基を形成し；そして
Ｒ _ｂ は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択される
方法。
（項目２）
項目１に記載の方法であって、Ｒ _１２ が、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキルからなる群より選択され；Ｒ _１３ が、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換非置換ヘテロアリールからなる群より選択され；そしてＲ _１１ が、式（Ｒ _１１ａ ）：

の構造としてさらに規定され、ここで
Ｒ _１４ およびＲ _１５ は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択されるか；あるいは
Ｒ _１４ およびＲ _１５ は、一緒になって置換または非置換ヘテロアリール基を形成する、方法。
（項目３）
項目２に記載の方法であって、Ｒ _１１ａ がＤＮＡ塩基であるように、Ｒ _１４ およびＲ _１５ が一緒になって置換ヘテロアリール基を形成する、方法。
（項目４）
項目３に記載の方法であって、前記ＤＮＡ塩基がアデニンである、方法。
（項目５）
項目２に記載の方法であって、Ｒ _１４ がアミノカルボニルである、方法。
（項目６）
項目２に記載の方法であって、Ｒ _１４ がヒドロキシである、方法。
（項目７）
項目１に記載の方法であって、Ｒ _１２ およびＲ _１３ が結合して一緒になり、図（ＩＶ _ａ ）：

に示されるようなヘテロシクリル基を形成し、ここで
Ｒ _１２ａ は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、ならびに置換および非置換アルコキシアルキルからなる群より選択され；そして
Ｒ _１３ａ は、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択される、
方法。
（項目８）
項目１〜７のいずれかに記載の方法であって、前記ＳＭＩＰが、ＴＮＦ−αレベルを上昇させ得る用量で投与される、方法。
（項目９）
項目１〜７のいずれかに記載の方法であって、前記ＳＭＩＰが、グルココルチコイドレセプター、ＤＮＡアルキル化、カルシニューリン、ＪＮＫ、ｐ３８キナーゼ、サイクリンキナーゼカスケード、ＰＤＥ ＩＶ、ＩＭＰＤＨ、ＤＨＯＤ、ｌｃｋ、およびチミジル酸シンターゼからなる群より選択される少なくとも１つの標的の活性を調節する、方法。
（項目１０）
項目１〜７のいずれかに記載の方法であって、前記免疫応答がサイトカインの産生に関与する、方法。
（項目１１）
項目１〜７のいずれかに記載の方法であって、前記免疫応答がＴＮＦ−αの産生増加に関与する、方法。
（項目１２）
項目１〜７のいずれかに記載の方法であって、前記患者がウイルス感染を患っている、方法。
（項目１３）
項目１２に記載の方法であって、前記ウイルス感染がＨＣＶである、方法。
（項目１４）
項目１〜７のいずれかに記載の方法であって、前記患者が進行した細胞増殖または癌を患っている、方法。
（項目１５）
項目１〜７のいずれかに記載の方法であって、前記患者がアレルギー疾患を患っている、方法。
（項目１６）
項目１〜７のいずれかに記載の方法であって、前記患者が喘息を患っている、方法。
（項目１７）
項目１２に記載の方法であって、前記ＳＭＩＰが別の因子と同時投与される、方法。
（項目１８）
項目１７に記載の方法であって、前記他の因子がワクチンである、方法。
（項目１９）
項目１３に記載の方法であって、前記ＳＭＩＰが別の因子と同時投与される、方法。
（項目２０）
項目１９に記載の方法であって、前記他の因子がワクチンである、方法。
（項目２１）
項目１４に記載の方法であって、前記ＳＭＩＰが別の因子と同時投与される、方法。
（項目２２）
項目１５に記載の方法であって、前記ＳＭＩＰが別の因子と同時投与される、方法。
（項目２３）
項目１６に記載の方法であって、前記ＳＭＩＰが別の因子と同時投与される、方法。
（項目２４）
項目１〜７のいずれかに記載の方法であって、前記ＳＭＩＰが別の因子と同時投与される、方法。
（項目２５）
項目１６に記載の方法であって、他の因子がワクチンである、方法。
（項目２６）
項目１〜７のいずれかに記載の方法であって、前記ＳＭＩＰが２０μＭ未満のレベルで存在し、ＴＮＦ−αの産生を誘発する、方法。
（項目２７）
小分子免疫調節因子を同定するためのハイスループットアッセイであって、該アッセイは、
ａ）複数の試験化合物を細胞と接触させて、１以上の試験溶液を形成する工程；
ｂ）該試験溶液を少なくとも３０分間インキュベートする工程；
ｃ）該試験溶液中の１以上の免疫学的マーカーの上昇したレベルについて測定する工程；
を包含し、ここで該複数の試験化合物中に存在する１以上の試験化合物による免疫調節が、該試験溶液中の該免疫学的マーカーの量を増加させる、ハイスループットアッセイ。
（項目２８）
項目２７に記載のハイスループットアッセイであって、前記小分子免疫調節因子がＳＭＩＰであり、前記免疫調節が免疫増強である、ハイスループットアッセイ。
（項目２９）
項目２８に記載のハイスループットアッセイであって、前記試験溶液中の前記免疫学的マーカーの量を、いずれの試験化合物も含まない非賦活化溶液と比較する工程をさらに包含する、ハイスループットアッセイ。
（項目３０）
項目２９に記載のハイスループットアッセイであって、前記非賦活化溶液が、前記試験溶液と平行して実行される、ハイスループットアッセイ。
（項目３１）
項目２８に記載のハイスループットアッセイであって、前記試験溶液中の前記免疫学的マーカーの量を、公知の免疫増強因子を含む賦活化溶液と比較する工程をさらに包含する、ハイスループットアッセイ。
（項目３２）
項目３１に記載のハイスループットアッセイであって、前記賦活化溶液が前記試験溶液と平行して実行される、ハイスループットアッセイ。
（項目３３）
項目３１に記載のハイスループットアッセイであって、前記免疫増強因子が、ＬＰＳ、ＣｐＧ、ｒｅｓｉｑｕｉｍｏｄ、ＰｏｌｙＩ：Ｃ（ｄｓＲＮＡ）、Ｐａｍ３−Ｃｙｓ、ＭＰＬ、および抗ＣＤ３からなる群より選択される、ハイスループットアッセイ。
（項目３４）
項目２８に記載のハイスループットアッセイであって、前記免疫学的マーカーがサイトカインである、ハイスループットアッセイ。
（項目３５）
項目２８に記載のハイスループットアッセイであって、前記免疫学的マーカーがケモカインである、ハイスループットアッセイ。
（項目３６）
項目２８に記載のハイスループットアッセイであって、前記免疫学的マーカーが成長因子である、ハイスループットアッセイ。
（項目３７）
項目２８に記載のハイスループットアッセイであって、前記免疫学的マーカーがサイトカインとケモカインとの両方である、ハイスループットアッセイ。
（項目３８）
項目２８に記載のハイスループットアッセイであって、前記免疫学的マーカーがサイトカインと成長因子との両方である、ハイスループットアッセイ。
（項目３９）
項目２８に記載のハイスループットアッセイであって、前記免疫学的マーカーがケモカインと成長因子との両方である、ハイスループットアッセイ。
（項目４０）
項目２８に記載のハイスループットアッセイであって、前記免疫学的マーカーがサイトカイン、ケモカインおよび成長因子である、ハイスループットアッセイ。
（項目４１）
項目２６に記載のハイスループットアッセイであって、前記免疫学的マーカーがＴＧＦ−βであり、前記小分子免疫調節因子がＳＭＩＳであり、そして前記免疫調節が免疫抑制である、ハイスループットアッセイ。 Further embodiments of the invention include those described in the detailed description.
For example, the present invention provides the following items.
(Item 1)
A method of eliciting an immune response in a patient comprising formula (IV):

Comprising administering a SMIP of wherein:
R ₁₁ is hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted Substituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted carbocyclyl, Substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted Selected from the group consisting of substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted arylamino, substituted and unsubstituted heteroarylamino, substituted and unsubstituted heterocyclylamino, and substituted and unsubstituted carbocyclylamino;
R ₁₂ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Selected from the group consisting of: substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted alkoxyalkyl;
R ₁₃ is selected from the group consisting of H, hydroxyl, alkoxy, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl; or
R ₁₂ and R ₁₃ are joined together to form a substituted or unsubstituted heterocyclyl group; and
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl
Method.
(Item 2)
The method of item 1, wherein R ₁₂ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Substituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl R ₁₃ is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted unsubstituted heteroaryl; and R ₁₁ is of the formula (R _11a ):

Is further defined as the structure of where
R ₁₄ and R ₁₅ are H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted Substituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, Substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and Substituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkyl, and substituted and unsubstituted carbocyclylalkyl are independently selected from the group consisting of acrylic alkenyl; or
The method wherein R ₁₄ and R ₁₅ are taken together to form a substituted or unsubstituted heteroaryl group.
(Item 3)
3. The method according to item 2, wherein R ₁₄ and R ₁₅ together form a substituted heteroaryl group such that R _11a is a DNA base .
(Item 4)
4. The method according to item 3, wherein the DNA base is adenine.
(Item 5)
3. The method according to item 2, wherein R ₁₄ is aminocarbonyl.
(Item 6)
The method according to item 2, wherein R ₁₄ is hydroxy.
(Item 7)
The method according to item 1, wherein R ₁₂ and R ₁₃ are joined together to form a diagram (IV _a ):

Forming a heterocyclyl group as shown in
R _12a is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Selected from the group consisting of: substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted alkoxyalkyl;
R _13a is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl,
Method.
(Item 8)
8. The method of any of items 1-7, wherein the SMIP is administered at a dose that can increase TNF-α levels.
(Item 9)
Item 8. The method according to any one of Items 1 to 7, wherein the SMIP is a glucocorticoid receptor, DNA alkylation, calcineurin, JNK, p38 kinase, cyclin kinase cascade, PDE IV, IMPDH, DHOD, lck, and thymidylic acid. A method of modulating the activity of at least one target selected from the group consisting of synthase.
(Item 10)
8. The method according to any one of items 1 to 7, wherein the immune response is involved in cytokine production.
(Item 11)
8. The method according to any one of items 1 to 7, wherein the immune response is associated with increased production of TNF-α.
(Item 12)
8. The method according to any one of items 1 to 7, wherein the patient is suffering from a viral infection.
(Item 13)
13. The method according to item 12, wherein the viral infection is HCV.
(Item 14)
8. The method according to any of items 1-7, wherein the patient is suffering from advanced cell proliferation or cancer.
(Item 15)
8. The method according to any one of items 1 to 7, wherein the patient suffers from an allergic disease.
(Item 16)
8. The method according to any one of items 1 to 7, wherein the patient is suffering from asthma.
(Item 17)
13. The method of item 12, wherein the SMIP is co-administered with another factor.
(Item 18)
18. The method according to item 17, wherein the other factor is a vaccine.
(Item 19)
14. The method of item 13, wherein the SMIP is co-administered with another factor.
(Item 20)
20. The method according to item 19, wherein the other factor is a vaccine.
(Item 21)
15. The method of item 14, wherein the SMIP is co-administered with another factor.
(Item 22)
16. The method of item 15, wherein the SMIP is co-administered with another factor.
(Item 23)
Item 17. The method according to item 16, wherein the SMIP is co-administered with another factor.
(Item 24)
8. The method according to any of items 1-7, wherein the SMIP is co-administered with another factor.
(Item 25)
Item 17. The method according to item 16, wherein the other factor is a vaccine.
(Item 26)
8. The method according to any of items 1-7, wherein the SMIP is present at a level of less than 20 μM and induces production of TNF-α.
(Item 27)
A high-throughput assay for identifying small molecule immunomodulators comprising:
a) contacting a plurality of test compounds with cells to form one or more test solutions;
b) incubating the test solution for at least 30 minutes;
c) measuring for elevated levels of one or more immunological markers in the test solution;
Wherein the immunomodulation by one or more test compounds present in the plurality of test compounds increases the amount of the immunological marker in the test solution.
(Item 28)
28. A high-throughput assay according to item 27, wherein the small molecule immunomodulator is SMIP and the immune modulation is immune enhancement.
(Item 29)
29. A high-throughput assay according to item 28, further comprising comparing the amount of the immunological marker in the test solution with a non-stimulated solution that does not contain any test compound.
(Item 30)
30. A high throughput assay according to item 29, wherein the non-stimulated solution is run in parallel with the test solution.
(Item 31)
29. The high throughput assay of item 28, further comprising comparing the amount of the immunological marker in the test solution with an activation solution comprising a known immune enhancing factor.
(Item 32)
32. A high throughput assay according to item 31, wherein the activation solution is performed in parallel with the test solution.
(Item 33)
32. The high-throughput assay according to item 31, wherein the immune enhancing factor is selected from the group consisting of LPS, CpG, requiquimod, PolyI: C (dsRNA), Pam3-Cys, MPL, and anti-CD3. Assay.
(Item 34)
29. A high throughput assay according to item 28, wherein the immunological marker is a cytokine.
(Item 35)
29. A high throughput assay according to item 28, wherein the immunological marker is a chemokine.
(Item 36)
29. A high throughput assay according to item 28, wherein the immunological marker is a growth factor.
(Item 37)
29. A high throughput assay according to item 28, wherein the immunological marker is both a cytokine and a chemokine.
(Item 38)
29. A high-throughput assay according to item 28, wherein the immunological marker is both a cytokine and a growth factor.
(Item 39)
29. A high-throughput assay according to item 28, wherein the immunological marker is both a chemokine and a growth factor.
(Item 40)
29. A high-throughput assay according to item 28, wherein the immunological markers are cytokines, chemokines and growth factors.
(Item 41)
27. A high-throughput assay according to item 26, wherein the immunological marker is TGF-β, the small molecule immunomodulator is SMIS, and the immunomodulation is immunosuppression.

(Detailed explanation)
Applicants are able to activate cytokine activity in cells, compounds that provide effective treatment for the disorders described herein and disorders apparent to those skilled in the art, and immunotherapy And / or vaccine adjuvants in combination with antigens have been discovered.

  For each of the following embodiments, the method of eliciting an immune response in a patient can be replaced with the use of SMIP in the manufacture of a medicament for eliciting an immune response in a patient. In other embodiments, SMIP is used in the manufacture of a medicament for treating infectious diseases, autoimmune diseases, allergies, or cancer. In other embodiments, SMIP is used in the manufacture of a medicament for use as an adjuvant. The SMIP of the present invention includes the SMIP described by Formula IL.

  One embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (I):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシル、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル（ｃａｒｂｏｃｙｃｌｙｌ）、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
Ｒ_ｅは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、ならびに置換および非置換アルコキシアルキルからなる群より選択され；そして
ｎは、１、２、または３である。

And wherein R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted And independently selected from the group consisting of and unsubstituted heteroaryl; and R _b is H, halogen, hydroxyl, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted Substituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, Replacement and non Substituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclyl Independently selected from the group consisting of alkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl Is;
R _e is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Selected from the group consisting of: substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted alkoxyalkyl; and n Is 1, 2 or 3.

In a more particular embodiment of formula I, R _{a at} the 1 position is H. In a more particular embodiment of formula I, R _{a at} the 2-position is a substituted or unsubstituted alkyl. In a more particular embodiment of formula I, R _b is H. In a more particular embodiment of formula I, R _{a at} the 3 position is H. In a more particular embodiment of formula I, R _e is substituted or unsubstituted alkyl.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (II):

のＳＭＩＰを投与する工程を包含し、ここで
点線は、付加結合の必要に応じてなされる配置を示しており、
Ｒ_６は、Ｈ、置換アルキルまたは非置換アルキルであり；Ｒ_７は＝Ｏであり、点線は存在しないか；あるいは
Ｒ_６は、存在せず；Ｒ_７が、Ｈ、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、ならびに置換および非置換カルボシクリルアルキルからなる群より選択され；点線は、付加結合の配置を示しており；
Ｘは、＝Ｎ−または＝Ｃ（Ｒ_８）−であって、ここでＲ_８が、Ｈ、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、ならびに置換および非置換カルボシクリルアルキルからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
ｎは、１、２、または３である。

In which the dotted line indicates the arrangement made as needed for the additional bond,
R ₆ is H, substituted alkyl or unsubstituted alkyl; R ₇ is ═O and there is no dotted line; or R ₆ is not present; R ₇ is H, hydroxy, amino, nitro, Cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonyl Amino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted Aralkyl, substituted and unsubstituted Roararukiru, substituted and unsubstituted heterocyclylalkyl, and is selected from the group consisting of substituted and unsubstituted carbocyclylalkyl; dotted line indicates the arrangement of additional bond;
X is ═N— or ═C (R ₈ ) —, wherein R ₈ is H, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, and substituted Oh It is selected from the group consisting of beauty unsubstituted carbocyclylalkyl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and n is 1, 2 Or 3.

In another embodiment, when R ₇ is ═O and R ₈ is heterocyclyl, this embodiment is not a substituted benzimidazole. In a more particular embodiment of Formula II, Examples 42, 43, and 44 are excluded.

In a more particular embodiment of formula II, R _b is H, halogen, or unsubstituted alkoxy. In a more particular embodiment of Formula II, R ₆ is H; R ₇ is ═O and there is no dotted line. In a more particular embodiment, R ₆ is H; R ₇ is ═O, there is no dotted line; X is CR ₈ and R ₈ is of the formula (R _8a ):

の構造としてさらに規定され、ここでＲ_９およびＲ_１０は、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択される。

Wherein R ₉ and R ₁₀ are independently from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl. Selected.

In a more particular embodiment of formula II, R ₆ is absent and R ₇ is H, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted Alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, Substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, and And it is selected from the group consisting of unsubstituted carbocyclylalkyl, and the dotted line is present. In more specific embodiments thereof, R ₇ is substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, and substituted and unsubstituted heterocyclyl. Selected from the group consisting of alkyl. In an even more specific embodiment of the formula, the aryl group of R ₇ is more specifically defined as a fused arylaryl or non-fused arylaryl, and the heteroaryl group of R ₇ is a fused heteroarylaryl, fused heteroaryl, More specifically defined as arylheteroaryl, non-fused heteroarylaryl, or non-fused heteroarylheteroaryl. In a more particular embodiment, X is N and R _{b at} the 5-position is a substituted arylamino group.

  Another embodiment of the present invention provides a method of eliciting an immune response in a patient, the method comprising formula (III):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
ｎは、独立して１、２、または３であり；そして
ｐは、１または２である。

And wherein R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclyl Independently selected from the group consisting of arylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl Is;
n is independently 1, 2, or 3; and p is 1 or 2.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (IV):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_１１は、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換ヒドロキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アリールアミノ、置換および非置換ヘテロアリールアミノ、置換および非置換ヘテロシクリルアミノ、そして置換および非置換カルボシクリルアミノからなる群より選択され；
Ｒ_１２は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、ならびに置換および非置換アルコキシアルキルからなる群より独立して選択され；そして
Ｒ_１３は、Ｈ、ヒドロキシ、アルコキシ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択されるか；あるいは
Ｒ_１２およびＲ_１３は結合して一緒になり、置換または非置換ヘテロシクリル基を形成し；そして
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択される。

And wherein R ₁₁ is hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyl Amino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted And unsubstituted hydroxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, The group consisting of substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted arylamino, substituted and unsubstituted heteroarylamino, substituted and unsubstituted heterocyclylamino, and substituted and unsubstituted carbocyclylamino Selected from;
R ₁₂ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Independently selected from the group consisting of substituted, unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted alkoxyalkyl ; and either R ₁₃ is, H, hydroxy, alkoxy, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and is selected from the group consisting of substituted and unsubstituted heteroaryl; or R ₁ And R ₁₃ come together and bonded, form a substituted or unsubstituted heterocyclyl group; and R _b is, H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted Substituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, Substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl Selected from the group consisting of

In more particular embodiments of formula IV, R ₁₂ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Substituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl R ₁₃ is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl; and R _11, formula ( _11a):

の構造としてさらに規定され、ここで
Ｒ_１４およびＲ_１５は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択されるか；またはＲ_１４およびＲ_１５は、一緒になって置換または非置換ヘテロアリール基を形成する。

Wherein R ₁₄ and R ₁₅ are H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted Independently from the group consisting of telocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl Or R ₁₄ and R ₁₅ together form a substituted or unsubstituted heteroaryl group.

In a more particular embodiment of formula R _11a , R ₁₄ and R ₁₅ are taken together to form a substituted heteroaryl group such that R _11a is a DNA base. In a more particular embodiment, the DNA base is adenine. In a more particular embodiment of formula R _11a , R ₁₄ is aminocarbonyl. In a more particular embodiment of formula R _11a , R ₁₄ is hydroxy.

In a more particular embodiment of formula IV, R ₁₂ and R ₁₃ are joined together to form formula (IV _a ):

に示すようなヘテロシクリル基を形成し、ここで
Ｒ_１２ａは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、ならびに置換および非置換アルコキシアルキルからなる群より選択され；そして
Ｒ_１３ａは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択される。

Wherein R _12a is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted Selected from the group consisting of substituted alkoxyalkyl; and R _13a is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (V):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_１６は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
ｎは、１、２、または３である。

And wherein R ₁₆ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted Carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted Le Bosi heterocyclylalkyl, substituted and unsubstituted aralkenyl is selected from the group consisting of substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkyl, and substituted and unsubstituted carbocyclylalkyl alkenyl;
R _c is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and n is 1, 2 Or 3.

  In a more specific embodiment of Formula V, Example 57 is excluded.

In a more particular embodiment of formula V, n is 1 and R _b is trifluoromethyl.

In a more particular embodiment of formula V, n is 1 and R _b is cyano.

In a more particular embodiment of formula V, R ₁₆ is of formula R _16a :

の構造としてさらに規定され、ここで
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
Ｒ_１７は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択される。

Wherein R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, Substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclyl Selected from the group consisting of alkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; R ₁₇ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted Substituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl , Substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl.

  In another embodiment of the present invention, a method for inducing an immune response in a patient is provided, which method comprises formula (VI):

のＳＭＩＰを投与する工程を包含し、ここで
Ｙ_１およびＹ_２は、独立してＮまたはＣＲ_ｂであり；
Ｒ_１８は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_Ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
ｎは、１、２、または３である。

Administering SMIP of wherein Y ₁ and Y ₂ are independently N or CR _b ;
R ₁₈ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbosi Selected from the group consisting of crylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _C is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and n is 1, 2 Or 3.

  In more specific embodiments of Formula VI, Examples 2-11 and Example 59 are excluded.

In a more particular embodiment of formula VI, at least one of Y ₁ and Y ₂ is N.

In a more particular embodiment of formula VI, Y ₁ and Y ₂ are both N.

In a more particular embodiment of formula VI, R ₁₈ is selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocyclyl, and substituted and unsubstituted heterocyclyl.

  In another embodiment of the present invention, a method of inducing an immune response in a patient is provided that includes administering a steroid SMIP to a patient in need thereof. In a more particular embodiment, the steroid SMIP has the formula (VII):

の構造としてより特定的に規定され、ここで
点線は、付加結合の必要に応じてなされる配置を示しているが、ただし２つの連続した結合は二重結合ではなく；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_１９は、単結合により結合しており、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルキルチオール、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
Ｒ_２０は、Ｈ、ヒドロキシ、シアノニトロ、カルボン酸、ハロゲン、アミノ、置換および非置換アルキル、置換および非置換アルキルチオール、置換および非置換アルキルアミノ、置換および非置換アルキルカルボニル、ならびに置換および非置換アルコキシからなる群より独立して選択されるか；あるいは
Ｒ_１９は＝Ｏであり、Ｒ_２０は存在せず；
Ｒ_２１は、単結合により結合しており、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択されるか；あるいは
Ｒ_２１は＝Ｏであり；
ＧはＯ−であり、Ｒ_８は、Ｈ、置換および非置換アルキル、置換および非置換アリール、ならびに置換および非置換ヘテロアリールからなる群より選択されるか；あるいは
ＧはＯ＝であり、Ｒ_８は存在せず；そして
Ｒ_２３は、Ｈ、または置換もしくは非置換アルキルであるか；あるいは
８位および９位は二重結合により結合し、Ｒ_２３は存在しない。

More specifically defined as the structure of ## STR4 ## where the dotted line indicates the arrangement made as needed for additional bonds, except that two consecutive bonds are not double bonds;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Selected;
R ₁₉ is linked by a single bond, H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkylthiol, substituted and unsubstituted alkenyl, substituted and unsubstituted Alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted And unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted And the group consisting of substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl And R ₂₀ is H, hydroxy, cyanonitro, carboxylic acid, halogen, amino, substituted and unsubstituted alkyl, substituted and unsubstituted alkylthiol, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylcarbonyl, and substituted And independently selected from the group consisting of unsubstituted alkoxy; or R ₁₉ is ═O and R ₂₀ is absent;
R ₂₁ is linked by a single bond, H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyl Amino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted And unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl Selected from the group consisting of: substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; Or R ₂₁ is ═O;
G is O- and R ₈ is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; or G is O = and R ₈ is not present; and R ₂₃ is H, or substituted or unsubstituted alkyl; or the 8- and 9-positions are linked by a double bond, and R ₂₃ is absent.

In another embodiment, R _{a at} the 3 position is not hydroxy. In a more particular embodiment of Formula VII, Example 62 is excluded.

  In a more particular embodiment, said steroid SMIP has the formula (VIII):

の構造として規定され、ここで
点線は、付加結合の必要に応じてなされる配置を示しているが、ただし２つの連続した結合は二重結合ではなく；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_１９は、単結合により結合しており、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルキルチオール、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
Ｒ_２０は、Ｈ、ヒドロキシ、シアノニトロ、カルボン酸、ハロゲン、アミノ、置換および非置換アルキル、置換および非置換アルキルチオール、置換および非置換アルキルアミノ、置換および非置換アルキルカルボニル、ならびに置換および非置換アルコキシからなる群より選択されるか；あるいは
Ｒ_１９は＝Ｏであり、Ｒ_２０は存在せず；
Ｒ_２１は、単結合により結合しており、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択されるか；あるいは
Ｒ_２１は＝Ｏであり；
ＧはＯ−であり、Ｒ_８は、Ｈ、置換および非置換アルキル、置換および非置換アリール、ならびに置換および非置換ヘテロアリールからなる群より選択されるか；あるいは
ＧはＯ＝であり、Ｒ_２２は存在せず；そして
Ｒ_２３は、Ｈ、または置換もしくは非置換アルキルであるか；あるいは
８位および９位は二重結合により結合し、Ｒ_２３は存在しない。

Where the dotted line shows the arrangement made as needed for additional bonds, except that two consecutive bonds are not double bonds;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Selected;
R ₁₉ is linked by a single bond, H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkylthiol, substituted and unsubstituted alkenyl, substituted and unsubstituted Alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted And unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted And the group consisting of substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl And R ₂₀ is H, hydroxy, cyanonitro, carboxylic acid, halogen, amino, substituted and unsubstituted alkyl, substituted and unsubstituted alkylthiol, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylcarbonyl, and substituted And R ₁₉ is ═O and R ₂₀ is absent;
R ₂₁ is linked by a single bond, H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyl Amino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted And unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl Selected from the group consisting of: substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; Or R ₂₁ is ═O;
G is O- and R ₈ is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; or G is O = and R ₂₂ is not present; and R ₂₃ is H or substituted or unsubstituted alkyl; or the 8- and 9-positions are linked by a double bond and R ₂₃ is absent.

In another embodiment, R _{a at} the 3 position is not hydroxy. In a more particular embodiment of Formula VIII, Example 62 is excluded.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (IX):

のＳＭＩＰを投与する工程を包含し、ここで
点線は、付加結合の必要に応じてなされる配置を示しているが、ただし２つの連続した結合は二重結合ではなく；
ＺはＣＲ_ｂまたはＮであり；
Ｒ_２４は、Ｈ、置換および非置換アルキル、アリール、置換および非置換ヘテロシクリル、置換および非置換ヘテロアリール、ならびに置換および非置換アルキル−アミノ−アルキルからなる群より選択され；
Ｒ_２５はＯ＝であるか、または単結合により結合しており、そしてＨ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキルからなる群より選択され；
Ｒ_２６は存在しないか、またはＨ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換スルホニル、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロシクリルアルキルからなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択されるが、ただし３位におけるＲ_ａはヒドロキシではなく；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択される。

In which the dotted line indicates the arrangement made as needed for additional bonds, except that two consecutive bonds are not double bonds;
Z is CR _b or N;
R ₂₄ is selected from the group consisting of H, substituted and unsubstituted alkyl, aryl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted heteroaryl, and substituted and unsubstituted alkyl-amino-alkyl;
R ₂₅ is O = or linked by a single bond and is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted Alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted And unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted Selected from the group consisting of substituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl;
R ₂₆ is absent or H, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy Selected from the group consisting of alkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclylalkyl;
R _a is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Where R _{a at} position 3 is not hydroxy;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and R _c is H, substituted and unsubstituted Selected from the group consisting of substituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.

  Another embodiment of the present invention provides a method of eliciting an immune response in a patient, the method comprising formula (XI):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択される。

And wherein R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted And selected from the group consisting of unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and R _c is H, Selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.

In a more particular embodiment of formula XI, R _{b at} position 1 is a nitrogen-containing heterocyclyl group selected from the group consisting of piperidine, morpholine, homomorpholine, piperidine, and pyrrolidine.

In a more particular embodiment of formula XI, R _{b at} position 2 is substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, and Selected from the group consisting of substituted and unsubstituted heterocyclylalkyl. In preferred embodiments thereof, the aryl group is more specifically defined as being fused arylaryl or non-fused arylaryl, and the heteroaryl group is fused heteroarylaryl, fused heteroarylheteroaryl, nonfused More specifically defined as being heteroarylaryl, or non-fused heteroarylheteroaryl.

  In another embodiment of the invention, a method of inducing an immune response is provided that includes administering macrocyclic SMIP to a patient in need thereof. In a more particular embodiment, the macrocycle SMIP is an analog of cyclosporine. In a more particular embodiment, the analog of cyclosporine has the formula (XII):

またはその立体異性体の構造を有し、ここで
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択される。

Or a stereoisomeric structure thereof, wherein R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and Independently selected from the group consisting of substituted and unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _c is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.

  In a more particular embodiment, said macrocycle SMIP has the formula (XIII):

またはその立体異性体の構造を有し、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ａは、置換Ｃ_１〜Ｃ_１６アルキル、非置換Ｃ_１〜Ｃ_１６アルキル、置換Ｃ_１〜Ｃ_１６アルケニル、非置換Ｃ_１〜Ｃ_１６アルケニル、置換Ｃ_１〜Ｃ_１６アルコキシ、または非置換Ｃ_１〜Ｃ_１６アルコキシからなる群より選択され；
Ｄは存在せず、それにより共有結合が形成されるか、または−ＣＨ（アルコキシ）−、−ＣＨ（アルコキシアルキル）−、−ＣＨ（アルキルアミノ）−、−ＣＨ（アミノアルキル）−、−ＣＨ（アルキルアミノアルキル)−、−Ｃ（＝Ｏ）−、−ＣＨ（アルキル）−
、および−ＣＨ_２−からなる群より選択され；
Ｒ_１は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_２は、Ｈ、ハロゲン、ヒドロキシ、＝Ｏ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
ｐは、１または２である。

Or a stereoisomeric structure thereof, where the dotted lines indicate the arrangements made as needed for additional bonds;
A is substituted C ₁ -C ₁₆ alkyl, unsubstituted C ₁ -C ₁₆ alkyl, substituted C ₁ -C ₁₆ alkenyl, unsubstituted C ₁ -C ₁₆ alkenyl, substituted C ₁ -C ₁₆ alkoxy, or unsubstituted C ₁ It is selected from the group consisting of -C ₁₆ alkoxy;
D is not present, thereby forming a covalent bond, or -CH (alkoxy)-, -CH (alkoxyalkyl)-, -CH (alkylamino)-, -CH (aminoalkyl)-, -CH (Alkylaminoalkyl)-, -C (= O)-, -CH (alkyl)-
And selected from the group consisting of —CH ₂ —;
R ₁ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R ₂ is H, halogen, hydroxy, ═O, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted Substituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, Substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted cal Selected from the group consisting of vocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl And R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and Unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted alkyl Vocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, Independently selected from the group consisting of substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and p is 1 or 2 .

In a more particular embodiment of formula XIII, R ₂ is substituted carbocyclylalkenyl.

In a more particular embodiment of formula XIII, A is a group A ₁ :

の構造としてさらに規定され、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_３は＝Ｏであるか、または単結合により結合しており、そしてＨ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリール基からなる群より選択される。

Where the dotted lines indicate the arrangements made as needed for additional coupling;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl And R ₃ is ═O or linked by a single bond and is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted Selected from the group consisting of substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl groups.

In a more particular embodiment of Formula _{A 1, R 1} is a substituted carbocyclylalkyl alkenyl, _{R 3} is = a O, D is -CH (alkoxy) - a.

In a more particular embodiment of formula XIII, A is a group A ₂ :

の構造としてさらに規定され、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_４は＝Ｏであるか、または単結合により結合しており、そしてＨ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリール基からなる群より選択される。

Where the dotted lines indicate the arrangements made as needed for additional coupling;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl And R ₄ is ═O or linked by a single bond and is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted Selected from the group consisting of substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl groups.

In a more particular embodiment of Formula _{A 2, R 1} is a substituted carbocyclylalkyl alkenyl, _{R 4} is = a O, D is -CH (alkoxy) - a.

As defined in any of Formula XIII, Formula A ₁ , or Formula A ₂ , R ₁ is represented by the formula (R _1a ):

の置換基としてさらに規定され、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ｒ_５は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
ｎは、１、２または３である。

Wherein the dotted line indicates the arrangement made as needed for the additional bond;
R ₅ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
n is 1, 2 or 3.

  In a more particular embodiment, said macrocycle SMIP has the formula (XIV):

またはその立体異性体の構造を有し、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
ｎは、１、２または３であり；そして
ｐは、１または２である。

Or a stereoisomeric structure thereof, where the dotted lines indicate the arrangements made as needed for additional bonds;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Selected;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _c is independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
n is 1, 2 or 3; and p is 1 or 2.

In a more particular embodiment of formula XIV, R _b is H.

In a more particular embodiment of formula XIV, R _c is methoxy.

  In a more particular embodiment, said macrocycle SMIP has the formula (XV):

またはその立体異性体の構造を有し、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ｅ_１は、−Ｎ＝、−（Ｒ_ａ）Ｃ＝、−（Ｒ_ｃ）Ｎ−、または−（Ｒ_ｃ）ＣＨ−であり；
Ｅ_２は、存在せず共有結合、−Ｏ−または−ＣＨＲ_ｃ−を形成しており；
Ｒ_２７は、Ｏ＝であるか、またはＨ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択されて単結合により結合しており；
Ｒ_２８は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；そして
Ｒ_２９は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択されるか；あるいは
Ｒ_２８およびＲ_２９は、酸素原子と結合して一緒になり、エポキシドを形成しており；
Ｒ_３０は、Ｈ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換スルホニル、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
ｎは、１、２または３である。

Or a stereoisomeric structure thereof, where the dotted lines indicate the arrangements made as needed for additional bonds;
E ₁ is —N═, — (R _a ) C═, — (R _c ) N—, or — (R _c ) CH—;
E ₂ is absent and forms a covalent bond, —O— or —CHR _c —;
R ₂₇ is O = or H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Selected from the group consisting of: linked by a single bond;
R ₂₈ is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl; And R ₂₉ is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl. Or R ₂₈ and R ₂₉ are joined together by an oxygen atom to form an epoxide;
R ₃₀ represents H, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and Unsubstituted sulfonyl, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted And unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted And unsubstituted carbocyclylalkenyl.
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Selected;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _c is independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl; and n is 1, 2 or 3 It is.

In a more particular embodiment of formula XV, E ₁ is —N═, E ₂ is —O—, and R ₂₇ is O═.

  In a more particular embodiment, said macrocycle SMIP has the formula (XVI):

またはその立体異性体の構造を有し、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ｔ_１は、−ＣＨ（Ｒ_ｃ）−、−Ｏ−、または−Ｎ（Ｒ_ｃ）−であり；
Ｒ_３０、Ｒ_３１およびＲ_３２は、独立してＯ＝であるか、またはＨ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_３３は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；そして
Ｒ_３４は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択されるか；あるいは
Ｒ_３３およびＲ_３４は、結合して一緒になり、置換炭素環、非置換炭素環、置換複素環、または非置換複素環を形成し；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択される。

Or a stereoisomeric structure thereof, where the dotted lines indicate the arrangements made as needed for additional bonds;
T ₁ is —CH (R _c ) —, —O—, or —N (R _c ) —;
R ₃₀ , R ₃₁ and R ₃₂ are independently O =, or H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted Selected from the group consisting of heterocyclyl and substituted and unsubstituted heteroaryl;
R ₃₃ is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl; And R ₃₄ is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl. Or R ₃₃ and R ₃₄ are joined together to form a substituted carbocycle, unsubstituted carbocycle, substituted heterocycle, or unsubstituted heterocycle;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl And R _c is independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.

In a more particular embodiment of formula XVI, R ₃₃ and R ₃₄ are joined together to form a compound of formula R _33a :

で示されるような構造を形成し、ここで
Ｔ_２は、−ＣＨ（Ｒ_ｃ）−、−Ｏ−、または−Ｎ（Ｒ_ｃ）−であり；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
ｎは、１、２または３である。

Wherein T ₂ is —CH (R _c ) —, —O—, or —N (R _c ) —;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and n is 1, 2 Or 3.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XVII):

のＳＭＩＰを投与する工程を包含し、ここで
点線は、付加結合の必要に応じてなされる配置を示しているが、ただし２つの連続した結合は二重結合ではなく；
Ｗ_１、Ｗ_２およびＷ_３は、独立して−ＣＨ（Ｒ_ａ）−、または−Ｎ（Ｒ_ｃ）−であり；
Ｗ_４は、−Ｏ−、−ＣＨ（Ｒ_ａ）−、または−Ｃ（Ｒ_ａ）＝であり、
Ｗ_５は、−Ｏ−、−ＣＨ（Ｒ_ａ）−、または＝Ｃ（Ｒ_ａ）−であるが、ただしＷ_４およびＷ_５が共に−Ｏ−となることはなく；
Ｗ_６は、−ＣＨ（Ｒ_ａ）−、＝Ｃ（Ｒ_ａ）−、またはＮＲ_ｃであり；
Ｗ_７は、−Ｏ−、または−ＣＨ（Ｒ_ａ）−であり；
Ｒ_３５、Ｒ_３６、Ｒ_３８およびＲ_３９は、独立してＯ＝であるか、またはＨ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_３７は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択される。

In which the dotted line indicates the arrangement made as needed for additional bonds, except that two consecutive bonds are not double bonds;
W ₁ , W ₂ and W ₃ are independently —CH (R _a ) —, or —N (R _c ) —;
W ₄ is —O—, —CH (R _a ) —, or —C (R _a ) ═,
W ₅ is —O—, —CH (R _a ) —, or ═C (R _a ) —, except that W ₄ and W ₅ are not both —O—;
W ₆ is —CH (R _a ) —, ═C (R _a ) —, or NR _c ;
W ₇ is —O— or —CH (R _a ) —;
R ₃₅ , R ₃₆ , R ₃₈ and R ₃₉ are independently O =, or H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted Selected from the group consisting of substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R ₃₇ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbosi Selected from the group consisting of crylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Selected;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and R _c is H, Selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.

In a more particular embodiment of formula XVII, W ₁ , W _2, and W ₃ are NH; W ₇ is —CH (R _a ) —; and R ₃₇ is aminocarbonylamino.

In a more particular embodiment of formula XVII, wherein W ₁ , W _2, and W ₃ are —CH (R _a ) —; W ₄ is —CH (R _a ) — or —C (R _a ) ═; W ₅ is —CH (R _a ) —, or ═C (R _a ) —; W ₆ is ═C (R _a ) —; W ₇ is —O—; and R ₃₇ Is H.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XVIII):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_４０は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；そして
Ｒ_４１は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択されるか；あるいは
Ｒ_４０およびＲ_４１は、結合して一緒になり、置換アリール、非置換アリール、置換ヘテロアリール、または非置換ヘテロアリール基を形成しており；
Ｒ_４２は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；そして
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択される。

And wherein R ₄₀ is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted And R ₄₁ is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and Selected from the group consisting of substituted and unsubstituted heteroaryl; or R ₄₀ and R ₄₁ are joined together to form a substituted aryl, unsubstituted aryl, substituted heteroaryl, or unsubstituted heteroaryl group. And;
R ₄₂ is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl; And R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl. Selected.

In a more particular embodiment of formula XVIII, R ₄₀ and R ₄₁ are joined together to form an optionally substituted benzyl group. In a more particular embodiment of formula XVIII where R ₄₀ and R ₄₁ are joined together to form an optionally substituted benzyl group, R ₄₂ is unsubstituted alkyl.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XIX):

のＳＭＩＰを投与する工程を包含し、
Ｄ_１は、−Ｎ＝、または−Ｃ（Ｒ_４６）＝であり；
Ｄ_２およびＤ_３は、共有結合、−Ｏ−、−Ｓ−、−ＮＨ−、および−ＮＲ_ｄ−からなる群より独立して選択され；
Ｒ_４３は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシルスルホニル、置換および非置換ヘテロアラルキルスルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_４４およびＲ_４５は、Ｈ、ハロゲン基、シアノ基、カルボン酸基、置換および非置換アルキル基、置換および非置換アルケニル基、置換および非置換アルキニル基、置換および非置換アルコキシカルボニル基、置換および非置換アミノカルボニル基、置換および非置換アルコキシアルキル基、置換および非置換カルボシクリル基、置換および非置換ヘテロシクリル基、置換および非置換アリール基、置換および非置換ヘテロアリール基、置換および非置換アラルキル基、置換および非置換ヘテロアラルキル基、置換および非置換ヘテロシクリルアルキル基、置換および非置換カルボシクリルアルキル基、置換および非置換アラルケニル基、置換および非置換ヘテロアラルケニル基、置換および非置換ヘテロシクリルアルケニル基、ならびに置換および非置換カルボシクリルアルケニル基からなる群より独立して選択され；
Ｒ_４６は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、−ＣＨ＝Ｎ−Ｎ−ＣＯ−Ｒ_ａ、−ＣＨ_２ＣＨＲ_ａＣＯＲ_ｂ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｄは、Ｈ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換スルホニル、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
ｎは、１、２または３であるが；
ただし、Ｒ_４３が、アミノ、アルキルアミノ、カルボニルアミノ、またはアルキルカルボニルアミノである場合は、Ｄ_２およびＤ_３は、共に共有結合である。

Administering a SMIP of
D ₁ is —N═ or —C (R ₄₆ ) ═;
D ₂ and D ₃ are independently selected from the group consisting of a covalent bond, —O—, —S—, —NH—, and —NR _d —;
R ₄₃ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxylsulfonyl, substituted and unsubstituted heteroaralkylsulfonyl, substituted and unsubstituted alkoxy, substituted And unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Substituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclyl Selected from the group consisting of alkenyl;
R ₄₄ and R ₄₅ are H, halogen group, cyano group, carboxylic acid group, substituted and unsubstituted alkyl group, substituted and unsubstituted alkenyl group, substituted and unsubstituted alkynyl group, substituted and unsubstituted alkoxycarbonyl group, substituted and Unsubstituted aminocarbonyl group, substituted and unsubstituted alkoxyalkyl group, substituted and unsubstituted carbocyclyl group, substituted and unsubstituted heterocyclyl group, substituted and unsubstituted aryl group, substituted and unsubstituted heteroaryl group, substituted and unsubstituted aralkyl group, Substituted and unsubstituted heteroaralkyl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted carbocyclylalkyl groups, substituted and unsubstituted aralkenyl groups, substituted and unsubstituted heteroaralkenyl groups, substituted and unsubstituted heterocyclylalkenyl groups , Line It is independently selected from the group consisting of substituted and unsubstituted carbocyclylalkyl alkenyl group;
R ₄₆ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, —CH═N—N _{-CO-R a, -CH 2 CHR} a COR b, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and Unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted From the group consisting of substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl Selected;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _c is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _d is H, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted sulfonyl, substituted and unsubstituted Substituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted And substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl And n is 1, 2 or 3;
However, when R ₄₃ is amino, alkylamino, carbonylamino, or alkylcarbonylamino, D ₂ and D ₃ are both covalent bonds.

In a more particular embodiment of formula XIX, D ₁ is CR ₄₆ , wherein R ₄₆ is —CH═N—N—CO—R _a , or —CH ₂ CHR _a COR _b . In a more particular embodiment of formula XIX, wherein D ₁ is CR ₄₆ and R ₄₆ is —CH═N—N—CO—R _a or —CH ₂ CHR _a COR _b , R ₄₃ is H.

In a more particular embodiment of formula XIX, R ₄₃ is a substituted or unsubstituted heteroaralkylsulfonyl.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XX):

のＳＭＩＰを投与する工程を包含し、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ｑ_１は、−Ｎ（Ｒ_ｄ）−、または−ＣＨ（Ｒ_ｂ）−であり；
Ｑ_２は、−Ｎ（Ｒ_ｃ）−、＝Ｎ−、または＝Ｃ（Ｒ_ｂ）−であり；
Ｒ_４７は存在しないか、＝ＮＲ_ｃ、または−ＣＨ（Ｒ_ｂ）−であり；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_ｄは、Ｈ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換スルホニル、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
ｎは、１、２または３である。

In which the dotted line indicates the arrangement made as needed for additional attachment;
Q ₁ is —N (R _d ) —, or —CH (R _b ) —;
Q ₂ is —N (R _c ) —, ═N—, or ═C (R _b ) —;
R ₄₇ is absent, = NR _c , or —CH (R _b ) —;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _c is independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _d is H, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted sulfonyl, substituted and unsubstituted Substituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted And substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl And n is 1, 2 or 3.

In another embodiment, when n is 2, R _{b at the} 2 and 3 positions is not methoxy. In a more particular embodiment of Formula XX, Examples 22 and 23 are excluded.

In a more particular embodiment of formula XX, Q ₁ is —N (R _d ) —, Q ₂ is —C (R _b ) ═, and R ₄₇ is ═NR _c .

In a more particular embodiment of formula XX, Q ₁ is —CH (R _b ) —, Q ₂ is —N (R _c ) —, and R ₄₇ is —CH (R _b ) —. It is. In more specific embodiments of formula XX, wherein Q ₁ is —CH (R _b ) —, Q ₂ is —N (R _c ) —, and R ₄₇ is —CH (R _b ) —, R _{c in 2} is substituted or unsubstituted heteroaryl.

In a more particular embodiment of formula XX, R ₄₇ is absent, Q ₁ is —N (R _d ) —, and Q ₂ is ═N—.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXI):

のＳＭＩＰを投与する工程を包含し、ここで
点線は、付加結合の必要に応じてなされる配置を示しているが、ただし２つの連続した結合は二重結合ではなく；
Ｒ_４８は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_４９は、＝ＣＨ_２、＝Ｏであるか、または単結合により結合しており、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_５０およびＲ_５１は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択される。
式ＸＸＩのより特定の実施形態において、Ｒ_４８は：

In which the dotted line shows the arrangement made as needed for additional bonds, except that two consecutive bonds are not double bonds;
R ₄₈ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbosi Selected from the group consisting of crylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R ₄₉ is ═CH ₂ , ═O, or linked by a single bond, H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, Substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted Substituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted From the group consisting of substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl Selected;
R ₅₀ and R ₅₁ are from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Independently selected; and R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino Substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted And unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbosi Independently selected from the group consisting of crylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl.
In a more particular embodiment of formula XXI, R ₄₈ is:

である。

It is.

  In a more particular embodiment of formula XXI, positions 1 and 3 are in the R configuration.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXII):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_５８は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；そして
Ｒ_５９は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換アミノカルボニルアルキル、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択される。

And wherein R ₅₈ is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted And R ₅₉ is selected from the group consisting of H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, Substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted aminocarbonylalkyl, substituted and unsubstituted sulfonyl, substituted And unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, The group consisting of substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl More independently selected.

In a more particular embodiment of formula XXII, R ₅₈ is unsubstituted alkyl such as propyl.

In a more particular embodiment of formula XXII, R ₅₈ is:

などの置換されるアミノカルボニルアルキルである。

And substituted aminocarbonylalkyl.

  Further embodiments of the invention include SMIP of structure XXI or XXII, and in those more specific embodiments, administration of the SMIP inhibits cannabinoid receptors in the patient.

  Another embodiment of the present invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXIII):

のＳＭＩＰまたはその立体異性体を投与する工程を包含し、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ｒ_５２は、二重結合により結合し、＝Ｏ、置換および非置換アルケニル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、置換および非置換カルボシクリルアルケニル、置換および非置換イミンからなる群より選択されるか、または単結合により結合し、Ｈ、ハロゲン基、ヒドロキシ基、アミノ基、ニトロ基、シアノ基、カルボン酸基、置換および非置換アルキル基、置換および非置換アルケニル基、置換および非置換アルキニル基、置換および非置換アルキルアミノ基、置換および非置換カルボニルオキシ基、置換および非置換アルコキシカルボニル基、置換および非置換アミノカルボニル基、置換および非置換カルボニルアミノ基、置換および非置換スルホニル基、置換および非置換アルコキシ基、置換および非置換アルコキシアルキル基、置換および非置換カルボシクリル基、置換および非置換ヘテロシクリル基、置換および非置換アリール基、置換および非置換ヘテロアリール基、置換および非置換アラルキル基、置換および非置換ヘテロアラルキル基、置換および非置換ヘテロシクリルアルキル基、置換および非置換カルボシクリルアルキル基、置換および非置換アラルケニル基、置換および非置換ヘテロアラルケニル基、置換および非置換ヘテロシクリルアルケニル基、ならびに置換および非置換カルボシクリルアルケニル基からなる群より選択され；
Ｒ_５３は、Ｈ、ハロゲン基、ヒドロキシ基、アミノ基、ニトロ基、シアノ基、カルボン酸基、置換および非置換アルキル基、置換および非置換アルケニル基、置換および非置換アルキニル基、置換および非置換アルキルアミノ基、置換および非置換カルボニルオキシ基、置換および非置換アルコキシカルボニル基、置換および非置換アミノカルボニル基、置換および非置換カルボニルアミノ基、置換および非置換スルホニル基、置換および非置換アルコキシ基、置換および非置換アルコキシアルキル基、置換および非置換カルボシクリル基、置換および非置換ヘテロシクリル基、置換および非置換アリール基、置換および非置換ヘテロアリール基、置換および非置換アラルキル基、置換および非置換ヘテロアラルキル基、置換および非置換ヘテロシクリルアルキル基、置換および非置換カルボシクリルアルキル基、置換および非置換アラルケニル基、置換および非置換ヘテロアラルケニル基、置換および非置換ヘテロシクリルアルケニル基、ならびに置換および非置換カルボシクリルアルケニル基からなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択される。

Administering a SMIP or a stereoisomer thereof, wherein the dotted line indicates the configuration made as required for the additional bond;
R ₅₂ is linked by a double bond and is ═O, substituted and unsubstituted alkenyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, substituted and unsubstituted carbocyclylalkenyl. , Selected from the group consisting of substituted and unsubstituted imines, or bonded by a single bond, H, halogen group, hydroxy group, amino group, nitro group, cyano group, carboxylic acid group, substituted and unsubstituted alkyl group, Substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted carbonyloxy groups, substituted and unsubstituted alkoxycarbonyl groups, substituted and unsubstituted aminocarbonyl groups, substituted and unsubstituted A carbonylamino group, a substituted and unsubstituted sulfonyl group, Substituted and unsubstituted alkoxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted carbocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups, substituted and unsubstituted aralkyl groups Substituted and unsubstituted heteroaralkyl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted carbocyclylalkyl groups, substituted and unsubstituted aralkenyl groups, substituted and unsubstituted heteroaralkenyl groups, substituted and unsubstituted heterocyclylalkenyls A group selected from the group consisting of substituted and unsubstituted carbocyclylalkenyl groups;
R ₅₃ is H, halogen group, hydroxy group, amino group, nitro group, cyano group, carboxylic acid group, substituted and unsubstituted alkyl group, substituted and unsubstituted alkenyl group, substituted and unsubstituted alkynyl group, substituted and unsubstituted Alkylamino groups, substituted and unsubstituted carbonyloxy groups, substituted and unsubstituted alkoxycarbonyl groups, substituted and unsubstituted aminocarbonyl groups, substituted and unsubstituted carbonylamino groups, substituted and unsubstituted sulfonyl groups, substituted and unsubstituted alkoxy groups, Substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted carbocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups, substituted and unsubstituted aralkyl groups, substituted and unsubstituted heteroaralkyls Groups, substituted and unsubstituted Telocyclylalkyl groups, substituted and unsubstituted carbocyclylalkyl groups, substituted and unsubstituted aralkenyl groups, substituted and unsubstituted heteroaralkenyl groups, substituted and unsubstituted heterocyclylalkenyl groups, and substituted and unsubstituted carbocyclylalkenyl groups Selected from the group consisting of:
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl And R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and Unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted alkyl Vocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, Independently selected from the group consisting of substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl.

In a more particular embodiment of formula XXIII, R ₅₂ is represented by Figure R _52a :

で示すような置換カルボシクリルアルケニルであり、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ｒ_５４は、＝ＣＨ_２、＝Ｏであるか、または単結合により結合し、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択される。

Substituted carbocyclylalkenyls, as shown by the dotted line, where the dotted line indicates the configuration made as needed for the additional bond;
R ₅₄ is ═CH ₂ , ═O or bonded by a single bond, H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and Unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy Substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and non-substituted Selected from the group consisting of substituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl And R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl To be selected.

In a more particular embodiment of formula R _52a , R ₅₄ is ═CH ₂ and R _{a at the} 6 and 7 positions is hydroxy.

In a more particular embodiment of formula XXIII, R ₅₃ is selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkoxyalkyl.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXIV):

のＳＭＩＰを投与する工程を包含し、ここで
点線は、付加結合の必要に応じてなされる配置を示しているが、ただしＲ_５６が二重結合により結合している場合、Ｒ_５７は存在せず；
Ｖ_１は、ＣＲ_ｂまたはＮＲ_ｄであり；
Ｒ_５５は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_５６は、＝Ｏであり、Ｒ_５７は存在しないか；あるいは
Ｒ_５６は、単結合により３位に結合しており、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
Ｒ_５７は、単結合により３位に結合しており、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、ならびに置換および非置換カルボニルからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
Ｒ_ｄは、Ｈ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換スルホニル、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択される。

Comprising administering a SMIP, wherein dotted line is shown an arrangement to be made as needed for additional bond, provided that if R ₅₆ is bonded by a double bond, R ₅₇ is absent Z;
V ₁ is CR _b or NR _d ;
R ₅₅ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbosi Selected from the group consisting of crylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R ₅₆ is ═O and R ₅₇ is not present; or R ₅₆ is linked to the 3-position by a single bond and is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and non- Substituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, Substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, Replacement and non Substituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclyl Selected from the group consisting of alkenyl; and R ₅₇ is attached to the 3-position by a single bond and is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl And selected from the group consisting of substituted and unsubstituted carbonyls;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and R _d is H, Carboxylic acids, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxyalkyl, substituted and Unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclyl Alkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkyl, and is selected from the group consisting of substituted and unsubstituted carbocyclylalkyl alkenyl.

In a more particular embodiment of formula XXIV, V ₁ is N-alkyl-amino, or N-alkyl-heterocyclyl. In more specific embodiments of formula XXIV, where V ₁ is N-alkyl-amino, or N-alkyl-heterocyclyl, R ₅₆ and R ₅₇ are independently substituted or unsubstituted alkyl, and are in position 3 through a single bond Is bound to. In a more particular embodiment thereof, R ₅₆ is ═O, R ₅₇ is absent, V ₁ is CR _b , and preferably R _b is alkenyl.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXV):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_６０は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_６１は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、ならびに置換および非置換アルコキシアルキルからなる群より選択され；そして
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択される。

R ₆₀ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted hetero Heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, is selected from the group consisting of substituted and unsubstituted heterocyclylalkyl, and substituted and unsubstituted carbocyclylalkyl alkenyl;
R ₆₁ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Selected from the group consisting of: substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted alkoxyalkyl; and R _b is, H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyl Xy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and Unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted Selected from the group consisting of aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl.

In a more particular embodiment of formula XXV, R _b is heteroarylsulfonyl.

In a more particular embodiment of formula XXV, R ₆₀ is an aryl group or an aralkyl group, wherein the aryl group associated with the single aryl group or alkyl group is more particular as a non-fused arylaryl group Is stipulated. Any embodiment Formula XXV; XXV wherein R _b is heteroarylsulfonyl; or R ₆₀ is an optionally substituted aryl or aralkyl group, wherein the aryl group or alkyl group alone In preferred embodiments of XXV, wherein the aryl group to which it is attached is more specifically defined as a non-fused arylaryl group, R ₆₁ is amino, substituted alkylamino, or unsubstituted alkylamino.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXVI):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
Ｒ_ｄは、Ｈ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換スルホニル、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択される。

And wherein R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted And selected from the group consisting of unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and R _d is H, carboxylic acid, Substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl Substituted, unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl Substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkyl, and is selected from the group consisting of substituted and unsubstituted carbocyclylalkyl alkenyl.

In a more particular embodiment of formula XXVI, R _b is a substituted benzyl group.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXVII):

のＳＭＩＰを投与する工程を包含し、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ｒ_６２は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換アリールカルボニルオキシ、置換および非置換ヘテロアリールカルボニルオキシ、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択される。

In which the dotted line indicates the arrangement made as needed for additional attachment;
R ₆₂ represents H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted arylcarbonyloxy, substituted And unsubstituted heteroarylcarbonyloxy, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted And unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbo Selected from the group consisting of cyclylalkenyl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and R _c is H, Independently selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.

In a more particular embodiment of formula XXVII, R ₆₂ is substituted or unsubstituted heteroarylcarbonyloxy.

  In a more particular embodiment of Formula XXVII, the dotted line indicates the arrangement that is made as needed for the additional bond.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXVIII):

のＳＭＩＰを投与する工程を包含し、ここで
Ｕ_１は、−ＣＨ（Ｒ_ａ）−または−Ｏ−であり；
Ｒ_６３は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；そして
Ｒ_６４は、Ｈ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換スルホニル、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択されるか；あるいは
Ｒ_６３およびＲ_６４は一緒になって、必要に応じて置換されるヘテロシクリル基を形成し；
Ｒ_６５は、Ｈ、ハロゲン、アミノ、ヒドロキシ、スルホニル、−Ｏ−ＰＯ_３、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択される。

Administering, wherein U ₁ is —CH (R _a ) — or —O—;
R ₆₃ is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl; And R ₆₄ is H, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted sulfonyl, substituted and Unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and non-substituted Selected from the group consisting of substituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl Or R ₆₃ and R ₆₄ together form an optionally substituted heterocyclyl group;
R ₆₅ is H, halogen, amino, hydroxy, sulfonyl, —O—PO ₃ , substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted hetero Selected from the group consisting of aryl;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Selected;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and R _c is H, substituted and unsubstituted Selected from the group consisting of substituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.

In a more particular embodiment of formula XXVIII, R ₆₃ and R ₆₄ are taken together and optionally substituted formula R _63a :

のヘテロシクリル基を形成し、ここで
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択される。

Wherein R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted Independently selected from the group consisting of heteroaryl; and R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, Substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Replacement al Coxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted Selected from the group consisting of substituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl.

In a more particular embodiment of formula XXVIII, wherein R ₆₃ and R ₆₄ are taken together to form an optionally substituted heterocyclyl group of formula R _63a , U ₁ is —CH ₂ —, R _b of R _63a is alkylamino.

In a more particular embodiment of formula XXVIII, R _{b at} the 4 position is para-methoxybenzyl.

In a more particular embodiment of formula XXVIII, R ₆₅ is —O—PO ₃ .

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXIX):

のＳＭＩＰを投与する工程を包含し、ここで
点線は、付加結合の必要に応じてなされる配置を示しており；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
Ｒ_ｅは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、ならびに置換および非置換アルコキシアルキルからなる群より選択され；そして
ｎは、１、２または３である。
式ＸＸＩＸのより特定の実施形態において、１位、３位および４位におけるＲ_ｂは、ヒドロキシである。
式ＸＸＩＸのより特定の実施形態において、点線は付加結合の必要に応じてなされる配置を示しており、５位におけるＲ_ｂは、アミノである。
本発明の別の実施形態は、患者において免疫応答を誘発する方法を提供し、この方法は、式（ＸＸＸ）：

In which the dotted line indicates the arrangement made as needed for additional attachment;
R _a is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _e is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Selected from the group consisting of: substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted alkoxyalkyl; and n Is 1, 2 or 3.
In a more particular embodiment of formula XXIX, R _{b at the} 1, 3 and 4 positions is hydroxy.
In a more particular embodiment of formula XXIX, the dotted line indicates the optional configuration required for the additional bond, and R _{b at} the 5-position is amino.
Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXX):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_６６およびＲ_６７は、独立してＨ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アミノスルホニル、置換および非置換アルキルアミノスルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換アリールオキシ、置換および非置換ヘテロアリールオキシ、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルであり；そして
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択される。
式ＸＸＸのより特定の実施形態において、Ｒ_６７は、置換アミノスルホニル、非置換アミノスルホニル、置換アルキルアミノスルホニル、または非置換アミノスルホニルである。式ＸＸＸのより特定の実施形態において、Ｒ_６６は、置換アリールオキシ、非置換アリールオキシ、置換ヘテロアリールオキシ、または非置換ヘテロアリールオキシである。
式ＸＸＸのより特定の実施形態において、３位におけるＲ_ｂは、置換または非置換カルボニルアミノである。
本発明の別の実施形態は、患者において免疫応答を誘発する方法を提供し、この方法は、式（ＸＸＸＩ）：

And wherein R ₆₆ and R ₆₇ are independently H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted And unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted Aminosulfonyl, substituted and unsubstituted alkylaminosulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted aryl Ruoxy, substituted and unsubstituted heteroaryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted Aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, Substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted Minocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted Substituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and Independently selected from the group consisting of unsubstituted heterocyclylalkenyl and substituted and unsubstituted carbocyclylalkenyl.
In more specific embodiments of formula XXX, R ₆₇ is substituted aminosulfonyl, unsubstituted aminosulfonyl, substituted alkylaminosulfonyl, or unsubstituted aminosulfonyl. In more specific embodiments of formula XXX, R ₆₆ is substituted aryloxy, unsubstituted aryloxy, substituted heteroaryloxy, or unsubstituted heteroaryloxy.
In a more particular embodiment of formula XXX, R _{b at} the 3 position is a substituted or unsubstituted carbonylamino.
Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXXI):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_６８およびＲ_６９は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；そして
ｎは、１、２または３である。
式ＸＸＸＩのより特定の実施形態において、Ｒ_６８は、置換または非置換アリール基である。
式ＸＸＸＩのより特定の実施形態において、Ｒ_６９は、必要に応じて置換される４Ｈ−ピラン−４−オンである。
本発明の別の実施形態は、患者において免疫応答を誘発する方法を提供し、この方法は、式（ＸＸＸＩＩ）：

R ₆₈ and R ₆₉ are H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl. And independently selected from the group consisting of substituted and unsubstituted heteroaryl; R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and Selected from the group consisting of unsubstituted heterocyclyl and substituted and unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _c is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl; and n is 1, 2 or 3.
In a more particular embodiment of formula XXXI, R ₆₈ is a substituted or unsubstituted aryl group.
In a more particular embodiment of formula XXXI, R ₆₉ is an optionally substituted 4H-pyran-4-one.
Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXXII):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_７０は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルキルアミノ、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；そして
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択される。
式ＸＸＸＩＩのより特定の実施形態において、Ｒ_７０は、Ｒ_７０ａ：

And wherein R ₇₀ is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkylamino, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted And R _a is selected from the group consisting of substituted and unsubstituted heteroaryl, and substituted and unsubstituted heteroaryl; and R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, Independently selected from the group consisting of substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.
In a more particular embodiment of formula XXXII, R ₇₀ is R _70a :

としてさらに規定され、ここで
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択される。

Where R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl And R _c is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.

In a more particular embodiment, R _70a is:

として規定される。
本発明の別の実施形態は、患者において免疫応答を誘発する方法を提供し、この方法は、式（ＸＸＸＩＩＩ）：

Is defined as
Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXXIII):

のＳＭＩＰを投与する工程を包含し、ここでＲ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択される。
式ＸＸＸＩＩＩのより特定の実施形態において、１位および２位におけるＲ_ｂは、置換または非置換アラルキルおよびヘテロアラルキルからなる群より独立して選択される。
式ＸＸＸＩＩＩのより特定の実施形態において、Ｒ_ａは、トリメトキシフェニルである。本発明の別の実施形態は、患者を処置する方法を提供し、この方法は、必要としている患者にテルペンＳＭＩＰを投与する工程を包含し、ここで投与に際し、該患者において免疫応答が誘発される。
より特定の実施形態において、該テルペンＳＭＩＰは、式（ＸＸＸＩＶ）：

And wherein R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted And selected from the group consisting of unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and R _c is H, Independently selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.
In a more particular embodiment of formula XXXIII, R _{b at the} 1 and 2 positions is independently selected from the group consisting of substituted or unsubstituted aralkyl and heteroaralkyl.
In a more particular embodiment of formula XXXIII, R _a is trimethoxyphenyl. Another embodiment of the invention provides a method of treating a patient, comprising administering a terpene SMIP to a patient in need, wherein upon administration, an immune response is elicited in the patient. The
In a more particular embodiment, the terpene SMIP has the formula (XXXIV):

の構造であり、ここで
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_７１は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択される。

Where R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Independently selected from the group consisting of: and R ₇₁ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and Unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxy Archi , Substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted Independently selected from the group consisting of substituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl.

In a more particular embodiment of formula XXXIV, R ₇₁ is a substituted or unsubstituted aryl group, more specifically defined as a substituted or unsubstituted non-fused arylaryl group.

In a more particular embodiment of formula XXXIV, wherein R ₇₁ is a substituted or unsubstituted non-fused arylaryl group, said substituted or unsubstituted arylaryl group is R _71a :

として規定され、ここで
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
ｎは、独立して１、２または３である。
より特定の実施形態において、前記テルペンＳＭＩＰは式(ＸＸＸＶ)：

Where R _a is from H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Selected independently from the group consisting of;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and n is independently 1, 2 or 3.
In a more particular embodiment, said terpene SMIP has the formula (XXXV):

の構造であり、ここで
Ｒ_７４は、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_７５およびＲ_７６は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択されるか；あるいは
Ｒ_７５およびＲ_７６は、結合して一緒になり、エポキシドを形成し；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択される。

Wherein R ₇₄ is selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R ₇₅ and R ₇₆ are from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl _R75 and _R76 are joined together to form an epoxide; and _Rc is H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted Selected from the group consisting of substituted heterocyclyl and substituted and unsubstituted heteroaryl.

In a more particular embodiment of formula XXXV, R ₇₄ is of formula R _74a :

の構造としてさらに規定され、ここで
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_ｅは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、ならびに置換および非置換アルコキシアルキルからなる群より独立して選択される。

Wherein R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted Independently selected from the group consisting of heteroaryl; and R _e is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, Substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted Non Independently selected from the group consisting of substituted alkoxyalkyl.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXXVI):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_７２は、Ｈ、ハロゲン、アミノ、ヒドロキシ、スルホニル、−Ｏ−ＰＯ_３、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択される。

Of comprising administering a SMIP, wherein R ₇₂ is, H, halogen, amino, hydroxy, sulfonyl, -O-PO _3, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, Selected from the group consisting of substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl; and R _c is H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted Independently selected from the group consisting of heteroaryl.

In a more particular embodiment of formula XXXVI, R _c is H.

In a more particular embodiment of formula XXXVI, R ₇₂ is —O—PO ₃ .
Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XXXVII):

のＳＭＩＰまたはその薬学的に受容可能な塩を投与する工程を包含し、ここで
Ｔ_１およびＴ_２は、独立してＯ、Ｓ、ＣＨＲ_ｃ、またはＮＲ_ｃであり；
Ｒ_７２およびＲ_７３は、Ｈ、ハロゲン、アミノ、ヒドロキシ、スルホニル、−ＰＯ_３、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
ｎは、１、２または３である。

Administering SMIP or a pharmaceutically acceptable salt thereof, wherein T ₁ and T ₂ are independently O, S, CHR _c , or NR _c ;
R ₇₂ and R ₇₃ are H, halogen, amino, hydroxy, sulfonyl, —PO ₃ , substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted Independently selected from the group consisting of heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and R _c is H, Selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
n is 1, 2 or 3.

In more specific embodiments of formula XXXVII, Examples 2, 6, 9, 11, 20, and 21 are excluded.

In addition, R _b of formula XXXVII can be H and the pharmaceutically acceptable salt can be sodium.

In a more particular embodiment of formula XXXVII, T ₁ and T ₂ are both S. In addition, R _b can be H and the pharmaceutically acceptable salt is sodium.

In a more particular embodiment of formula XXXVII, R ₇₂ and R ₇₃ are —PO ₃ . Further, R _b can be H and the pharmaceutically acceptable salt can be sodium.

  Another embodiment of the present invention includes administering a ruthenium complex SMIP to a patient in need thereof, and provides a method of treating a patient in which an immune response is elicited in the patient. In a more particular embodiment, the ruthenium complex SMIP consists of at least two nitrogen-containing heteroaryl groups (eg, imidazole). In an even more specific embodiment, the ruthenium complex SMIP consists of 6 nitrogen-containing heteroaryl groups (eg, imidazole).

  In a more particular embodiment, said ruthenium complex SMIP has the formula (XXXVIII):

の構造であり、ここで
Ｎ_{Ｈアリール}は、置換または非置換窒素含有ヘテロアリール基である。

Where N _{H aryl} is a substituted or unsubstituted nitrogen-containing heteroaryl group.

  In a more particular embodiment of formula XXXVIII, the nitrogen-containing heteroaryl group is acridine, carbazole, β-carboline, cinnoline, imidazole, indazole, indole, indolizine, isoindole, isoquinoline, isothiazole, oxazole, isoxazole, naphthyridine. , Perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolidine, quinoxaline, and thiazole. The

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising the formula (XXXIX):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_７７は、Ｈ、ハロ、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルキルアミノ、置換および非置換ヘテロアラルキルアミノ、置換および非置換ヘテロシクリルアルキルアミノ、置換および非置換カルボシクリルアルキルアミノ、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_ｄは、Ｈ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換スルホニル、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択される。

And wherein R ₇₇ is H, halo, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclyl Alkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkylamino, substituted and unsubstituted heteroaralkylamino, substituted and unsubstituted heterocyclylalkylamino, substituted and unsubstituted carbocyclylalkylamino, substituted and unsubstituted aralkenyl, Selected from the group consisting of substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl And R _d is H, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted sulfonyl Substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted Selected from the group consisting of unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl Is done.

In a more particular embodiment of formula XXXIX, R ₇₇ is selected from the group consisting of substituted and unsubstituted aralkylamino, and substituted and unsubstituted heteroaralkylamino.

    Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XL):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_７８は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換ヘテロアラルコキシ、置換および非置換アラルコキシ、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
ｎは、１、２または３である。

And wherein R ₇₈ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted hetero Kurylalkyl, substituted and unsubstituted heteroaralkoxy, substituted and unsubstituted aralkoxy, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and Selected from the group consisting of substituted and unsubstituted carbocyclylalkenyls;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl And R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and Unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted alkyl Vocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, Independently selected from the group consisting of substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and n is 1, 2 or 3 It is.

In a more particular embodiment of formula XL, R ₇₈ is substituted or unsubstituted aralkoxy.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XLI):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_８０は、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｄは、Ｈ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換スルホニル、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
ｎは、１、２または３である。

And wherein R ₈₀ is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted And selected from the group consisting of unsubstituted heteroaryl;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Selected;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _c is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _d is H, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted sulfonyl, substituted and unsubstituted Substituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted And substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl And n is 1, 2 or 3.

In a more particular embodiment of formula XLI, R ₈₀ is undecanyl.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XLII):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
ｎは、１、２または３である。

And wherein R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclyl Independently selected from the group consisting of arylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl And n is 1, 2 or 3.

In a more particular embodiment of formula XLII, R _{b at} the 1-position is a substituted alkyl group, further defined as carbonylalkyl, or -alkyl-COOH.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XLIII):

のＳＭＩＰを投与する工程を包含し、ここで
Ｘ_１は、−ＣＯ−、−Ｏ−、−Ｓ−、−ＮＨ−、スルホニル、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換カルボニルアルキル、カルボニル、置換および非置換アルコキシカルボニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、アミノカルボニル、カルボニルアミノ、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、スルホンアミド、イミン、ならびにチオ尿素からなる群より選択され；
Ｒ_８１は、Ｈ、置換および非置換アリール、置換および非置換ヘテロシクリル、置換および非置換カルボシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｅは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、ならびに置換および非置換アルコキシアルキルからなる群より独立して選択され；そして
ｐは、１または２である。

And wherein X ₁ is —CO—, —O—, —S—, —NH—, sulfonyl, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted Alkynyl, substituted and unsubstituted carbonylalkyl, carbonyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, aminocarbonyl, carbonylamino, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl Selected from the group consisting of, sulfonamido, imine, and thiourea;
R ₈₁ is selected from the group consisting of H, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted carbocyclyl, and substituted and unsubstituted heteroaryl;
R _a is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _c is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _e is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Independently selected from the group consisting of substituted, unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted alkoxyalkyl And p is 1 or 2.

In a more particular embodiment of formula XLIII, X ₁ is substituted or unsubstituted alkenyl. In a more particular embodiment of formula XLIII, wherein X ₁ is substituted or unsubstituted alkenyl, R ₈₁ is substituted or unsubstituted aryl. In its preferred embodiment, R ₈₁ is aryl substituted with a sulfonyl group or an alkylsulfonyl group.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising the formula (XLIV):

のＳＭＩＰを投与する工程を包含し、ここで
Ｘ_２は、−ＣＯ−、−Ｏ−、−Ｓ−、−ＮＨ−、スルホニル、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換カルボニルアルキル、カルボニル、置換および非置換アルコキシカルボニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、スルホンアミド、イミン、ならびにチオ尿素からなる群より選択され；
Ｒ_８２は、Ｈ、置換および非置換アリール、置換および非置換ヘテロシクリル、置換および非置換カルボシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；そして
ｐは、１または２である。

And wherein X ₂ is —CO—, —O—, —S—, —NH—, sulfonyl, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted Alkynyl, substituted and unsubstituted carbonylalkyl, carbonyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted Selected from the group consisting of alkoxy, substituted and unsubstituted alkoxyalkyl, sulfonamido, imine, and thiourea;
R ₈₂ is selected from the group consisting of H, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted carbocyclyl, and substituted and unsubstituted heteroaryl;
R _a is independently from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl Selected R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted Carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocycle , Substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, Selected from the group consisting of substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and p is 1 or 2.

In a more particular embodiment of formula XLIV, X ₂ is a substituted alkenyl further defined as optionally substituted -alkenyl-carbonyl-oxy-. In more specific embodiments thereof, R ₈₂ is substituted or unsubstituted heterocyclyl (eg, morpholine).

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising the formula (XLV):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_８３は、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換カルボシクリルアミノ、置換および非置換ヘテロシクリルアミノ、置換および非置換アリールアミノ、置換および非置換ヘテロアリールアミノ、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；そして
ｎは、１、２または３である。

And wherein R ₈₃ is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted carbocyclylamino, substituted and unsubstituted Rocyclylamino, substituted and unsubstituted arylamino, substituted and unsubstituted heteroarylamino, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and Selected from the group consisting of unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _c is independently selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl; and n is 1, 2 or 3 It is.

In another embodiment of the invention, when both R _c and R _b groups are all H, R ₈₃ is not an alkyl group substituted with a piperidinyl group. In another embodiment of Formula XLV, Example 15 is excluded.

In a more particular embodiment of formula XLV, R _{b at} the 3 position can be a substituted or unsubstituted carbocyclyl.

In a more particular embodiment of formula XLV, R ₈₃ is substituted or unsubstituted carbocyclylamino. Further, R _{b at} the 3 position can be a substituted or unsubstituted carbocyclyl.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (XLVI):

のＳＭＩＰを投与する工程を包含し、ここで
Ｘ_３は、置換または非置換アルキル基であり；
Ｘ_４は、共有結合であるか、または−ＣＯ−、−Ｏ−ＣＯ−Ｎ（Ｒ_ａ）−、−Ｏ−、−Ｓ−、−ＮＨ−、スルホニル、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換カルボニルアルキル、カルボニル、置換および非置換アルコキシカルボニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、スルホンアミド、イミン、ならびにチオ尿素からなる群より選択され；
Ｒ_８４は、Ｈ、置換および非置換カルボシクリル基、置換および非置換ヘテロシクリル基、置換および非置換アリール基、ならびに置換および非置換ヘテロアリール基からなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
ｎは、１、２または３である。

Administering a SMIP of wherein X ₃ is a substituted or unsubstituted alkyl group;
X ₄ is a covalent bond or —CO—, —O—CO—N (R _a ) —, —O—, —S—, —NH—, sulfonyl, substituted and unsubstituted alkyl, substituted and non-substituted. Substituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted carbonylalkyl, carbonyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted Selected from the group consisting of carbonylamino, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, sulfonamido, imine, and thiourea;
R ₈₄ is selected from the group consisting of H, substituted and unsubstituted carbocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heteroaryl groups;
R _a is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and n is 1, 2 Or 3.

In a more particular embodiment of formula XLVI, X ₃ is ethyl and X ₄ is —O—CO—NH—.

In a more particular embodiment of formula XLVI, R _b is H. Further, X ₃ can be ethyl and X ₄ can be —O—CO—NH—.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising the formula (XLVII):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
ｎは、１、２または３である。

And wherein R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted And selected from the group consisting of unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and n is 1, 2 Or 3.

In a more particular embodiment of formula XLVII, R _{b at} the 2-position is a substituted or unsubstituted alkylcarbonylamino.

In a more particular embodiment of formula XLVII, R _a is H.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising the formula (XLVIII):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_８４、Ｒ_８５およびＲ_８６は、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、ならびに置換および非置換ヘテロアリールの基からなる群より独立して選択され；そして
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択される。

Wherein R ₈₄ , R ₈₅ and R ₈₆ are from substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl groups. And R _c is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl.

In a more particular embodiment of formula XLVIII, R ₈₄ , R ₈₅ and R ₈₆ are independently substituted or unsubstituted aryl.

In a more particular embodiment of formula XLVIII, R ₈₄ , R ₈₅ and R ₈₆ are independently substituted or unsubstituted phenyl.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising the formula (XLIX):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より独立して選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；
Ｒ_ｃは、Ｈ、置換および非置換アルキル、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｄは、Ｈ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換スルホニル、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択され；
Ｒ_ｅは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、ならびに置換および非置換アルコキシアルキルからなる群より選択され；
ｎは、１、２または３であり；そして
ｐは、１または２である。

And wherein R _a is H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted And independently selected from the group consisting of unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl;
R _c is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _d is H, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted sulfonyl, substituted and unsubstituted Substituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted And substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl Selected from the group consisting of;
R _e is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Selected from the group consisting of: substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted alkoxyalkyl;
n is 1, 2 or 3; and p is 1 or 2.

In a more particular embodiment of formula XLIX, R _d is a substituted or unsubstituted carbocyclylalkyl.

In a more particular embodiment of formula XLIX, R _{a at} the 1 position is a substituted or unsubstituted alkyl.

In a more particular embodiment of formula XLIX, R _{a at} the 2-position is a substituted or unsubstituted alkoxy.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (L):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_８７は、Ｈ、置換および非置換アルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアラルキル、置換および非置換カルボシクリルアルキル、置換および非置換アリールアミノ、置換および非置換ヘテロアリールアミノ、置換および非置換ヘテロシクリルアミノ、ならび置換および非置換カルボシクリルアミノからなる群より選択され；
Ｒ_ａは、Ｈ、ハロゲン、アミノ、ヒドロキシ、置換および非置換アルキル、置換および非置換アルコキシ、置換および非置換アリール、置換および非置換ヘテロシクリル、ならびに置換および非置換ヘテロアリールからなる群より選択され；
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
ｎは、１、２または３である。

And wherein R ₈₇ is H, substituted and unsubstituted alkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted And unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylaralkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted arylamino, substituted and unsubstituted heteroarylamino, substituted and unsubstituted heterocyclylamino, Selected from the group consisting of optionally substituted and unsubstituted carbocyclylamino;
R _a is selected from the group consisting of H, halogen, amino, hydroxy, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted Substituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocycle Independently selected from the group consisting of arylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl; and n is 1, 2 Or 3.

In a more particular embodiment of formula L, R _b is H.

In a more particular embodiment of formula L, R ₈₇ is a substituted aryl group or a substituted heteroaryl group. Further, R _b can be H. In more particular embodiments of formula L wherein R ₈₇ is a substituted aryl group or a substituted heteroaryl group, the aryl group or heteroaryl group of R ₈₇ can be substituted with a malonate. Further, R _b can be H.

  Another embodiment of the invention provides a method of eliciting an immune response in a patient, the method comprising formula (LI):

のＳＭＩＰを投与する工程を包含し、ここで
Ｒ_ｂは、Ｈ、ハロゲン、ヒドロキシ、アミノ、ニトロ、シアノ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルキルアミノ、置換および非置換カルボニルオキシ、置換および非置換アルコキシカルボニル、置換および非置換アミノカルボニル、置換および非置換カルボニルアミノ、置換および非置換スルホニル、置換および非置換アルコキシ、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より独立して選択され；そして
Ｒ_ｄは、Ｈ、カルボン酸、置換および非置換アルキル、置換および非置換アルケニル、置換および非置換アルキニル、置換および非置換アルコキシカルボニル、置換および非置換カルボニル、置換および非置換スルホニル、置換および非置換アルコキシアルキル、置換および非置換カルボシクリル、置換および非置換ヘテロシクリル、置換および非置換アリール、置換および非置換ヘテロアリール、置換および非置換アラルキル、置換および非置換ヘテロアラルキル、置換および非置換ヘテロシクリルアルキル、置換および非置換カルボシクリルアルキル、置換および非置換アラルケニル、置換および非置換ヘテロアラルケニル、置換および非置換ヘテロシクリルアルケニル、ならびに置換および非置換カルボシクリルアルケニルからなる群より選択される。

And wherein R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclyl Independently selected from the group consisting of arylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl And R _d is H, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted carbonyl, substituted and unsubstituted sulfonyl, substituted And unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl , Substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl Selected from the group.

In a more particular embodiment of formula LI, R _d is a substituted or unsubstituted carbonyl.

In a more particular embodiment of formula LI, R _d is methylcarbonyl.

  In one embodiment of the present invention, the compounds of Table 3 (Examples 2-67) are excluded from any embodiment disclosed herein. In another embodiment of the present invention, any compound disclosed in US Patent Application Publication No. 10/814480 is excluded from any embodiment disclosed herein. A preferred specific embodiment to which the above disclaimer applies is an embodiment of Formula I-LI.

Another embodiment of the present invention provides a method for identifying SMIP, which method includes:
a. Identifying the core skeleton of the SMIS;
b. Substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, amino, alkylamino, dialkylamino, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, carbonyl, carbonyloxy, sulfonyl, carbonylamino, aminocarbonyl, guanidyl Modifying or adding at least one variable substituent of the core backbone of the SMIS having a substituent selected from the group consisting of: guanidinyl, and alkoxycarbonyl to form an SMIS analog;
c. Contacting the SMIS analog with cells to form a reaction solution;
d. Monitoring the reaction solution for an immune response to the SMIS analog; and e. Identifying the immune response to the SMIS analog by detecting increased levels of cytokine or TNF-α, wherein the SMIS analog capable of inducing cytokine production or TNF-α production is SMIP.

  In a more particular embodiment, the cell is a human peripheral blood mononuclear cell. In another embodiment, the cell is a human monocyte-derived cell (particularly THP-1). In another embodiment, the cell is a mouse monocyte-derived cell (eg, Raw 264.7). In another more specific embodiment, the reaction solution is incubated at about 37 ° C.

  In another more specific embodiment, the reaction solution is at least about 2 hours, or at least about 5 hours, or at least about 10 hours, or at least about 15 hours, or at least about 18 hours, or about Incubate for 18 hours.

  In another more specific embodiment, the cells are human peripheral blood mononuclear cells; and the reaction solution is at least about 2 hours, or at least about 5 hours, or at least about 10 hours, or at least If incubated for about 15 hours, or at least about 18 hours, or about 18 hours, the reaction solution is incubated at about 37 ° C.

  In another more specific embodiment, the above step of detecting increased levels of cytokines or TNF-α is performed by using a primary plate-binding antibody for capture and then a secondary biotinylated anti-TNF antibody. Is called. In a more specific embodiment, the secondary biotinylated anti-TNF antibody is detected using streptavidin-europium. In a more particular embodiment thereof, an increased level of cytokine or TNF-α in the reaction solution is identified by an increased europium number. In an even more specific embodiment, the increased europium number is identified by time resolved fluorescence.

Further embodiments of the invention include SMIPs of Structures IL, or more particularly SMIPs of that embodiment, which SMIPs are co-administered with another factor (eg, vaccine) Provided is the use of SMIPs of formulas IL and another factor for simultaneous, separate or sequential administration. In a more particular embodiment, the other factor is an antigen. In another more specific embodiment, the use is for eliciting an immune response in a patient. In another embodiment, the use is for treating an infection, autoimmune disease, allergy, or cancer. In another embodiment, the use is as an adjuvant.

  Other embodiments provide a pharmaceutical preparation or system, the pharmaceutical preparation or system comprising: (a) a first pharmaceutical agent comprising a SMIP of formula IL; and (b) Two pharmaceutical agents, wherein the first pharmaceutical agent and the second pharmaceutical agent are either a mixture or a separate composition. In a more particular embodiment, the second factor is an antigen. More specifically, the factor is a factor for simultaneous separate administration or sequential administration. In another more specific embodiment, the use is for eliciting an immune response in a patient. In another embodiment, the use is for treating an infection, autoimmune disease, allergy, or cancer. In another embodiment, the use is as an adjuvant.

  A kit, comprising: (a) a first pharmaceutical agent comprising a SMIP of Formulas IL; and (b) a second pharmaceutical agent. In a more particular embodiment, the second factor is an antigen. More specifically, the factor is a factor for simultaneous separate administration or sequential administration. In another more specific embodiment, the use is for eliciting an immune response in a patient. In another embodiment, the use is for treating an infection, autoimmune disease, allergy, or cancer. In another embodiment, the use is as an adjuvant.

  Another embodiment provides the use of SMIPs of formulas IL and another factor in the manufacture of a combination medicament. In a more particular embodiment, the other factor is an antigen. In another more specific embodiment, the use is for eliciting an immune response in a patient. In another embodiment, the use is for treating an infection, autoimmune disease, allergy, or cancer. In another embodiment, the use is as an adjuvant.

  Another embodiment provides the use of a SMIP of formulas IL in the manufacture of a medicament, wherein the medicament is co-administered with another factor. In a more particular embodiment, the second factor is an antigen. In another more specific embodiment, the use is for eliciting an immune response in a patient. In another embodiment, the use is for treating an infection, autoimmune disease, allergy, or cancer. In another embodiment, the use is as an adjuvant.

  Another embodiment provides for the use of an antigen in the manufacture of a medicament, wherein the medicament is co-administered with a SMIP of formulas IL.

  The two factors are preferably administered within 4 hours of each other.

  Another embodiment provides the use of a SMIP of formulas IL in the manufacture of a medicament, which medicament is for administration to a patient pretreated with another factor. In a more particular embodiment, the second factor is an antigen. In another more specific embodiment, the use is for eliciting an immune response in a patient. In another embodiment, the use is for treating an infection, autoimmune disease, allergy, or cancer. In another embodiment, the use is as an adjuvant.

  Another embodiment provides the use of an antigen in the manufacture of a medicament, wherein the medicament is for administration to a patient pretreated with a SMIP of Formulas IL. This pretreatment can be recent (eg, within 24 hours prior to administration of the drug), intermediate (eg, before 24 hours but within 4 weeks), or more distant These may be very far apart (eg at least 6 months ago) (eg at least 4 weeks ago) and these times refer to the closest pretreatment dose. The patient may be refractory to treatment with the pharmaceutical agent administered in the pretreatment. In another more specific embodiment, the use is for eliciting an immune response in a patient. In another embodiment, the use is for treating an infection, autoimmune disease, allergy, or cancer. In another embodiment, the use is as an adjuvant.

  Another embodiment provides the use of a SMIP of formulas IL in the manufacture of a medicament, which medicament is for administration to a patient with a tumor or infection that is resistant to treatment with another factor. It is.

  Further embodiments of the present invention include SMIPs of Structures IL, or more particularly SMIPs of that embodiment, which are administered at a dose that can increase TNF-α levels.

  Further embodiments of the invention include SMIPs of structures IL, or more particularly SMIPs thereof, which SMIPs are glucocorticoid receptors, DNA alkylation, calcineurin, JNK, p38 kinase, cyclin kinase cascade. Modulates the activity of at least one target selected from the group consisting of: PDE IV, IMPDH, DHOD, lck, and thymidylate synthase.

  Further embodiments of the invention include SMIPs of structures IL, or more particularly SMIPs thereof, wherein the immune response includes the production of cytokines.

Further embodiments of the present invention include SMIPs of structures IL, or more particularly SMIPs thereof, wherein the immune response includes increased production of TNF-α. Including a SMIP of structure I-L, or more particularly a SMIP of that embodiment, the patient suffers from a viral infection (eg, HCV). In preferred embodiments, the SMIP is co-administered with another factor (eg, a vaccine).

  Further embodiments of the invention include SMIPs of Structures IL, or more particularly SMIPs of that embodiment, wherein the patient suffers from advanced cell proliferation or cancer. In preferred embodiments, the SMIP is co-administered with another factor (eg, a vaccine).

  Further embodiments of the present invention include SMIPs of structures IL, or more particularly SMIPs of that embodiment, wherein the patient suffers from an allergic disease. In preferred embodiments, the SMIP is co-administered with another factor (eg, a vaccine).

  Further embodiments of the present invention include SMIPs of structures IL, or more particularly SMIPs of that embodiment, wherein the patient suffers from asthma. In preferred embodiments, the SMIP is co-administered with another factor (eg, a vaccine).

  Further embodiments of the invention include SMIPs of structures IL, or more particularly SMIPs of that embodiment, that SMIP is present at a level of less than 20 μM and induces the production of TNF-α.

  Candidate small molecule enhancers can be identified in vitro. Compounds are screened for the ability to activate immune cells in vitro. One indicator of such activation is induction of cytokine production (eg, TNF-α production). Small molecules that induce apoptosis can be identified as having this activity. These small molecule immunoenhancing factors have potential utility as adjuvants and immunotherapy.

Another embodiment of the present invention provides a method for identifying SMIP, which method includes:
a) contacting the compound and cells to form a cell culture;
b) incubating the cell culture for at least 1 hour;
c) monitoring for increased TNF-α levels in the cell culture;
d) Identifying the SMIP by increased TNF-α levels in the cell culture.

  In a more particular embodiment, the cell is a human peripheral blood mononuclear cell. In another more specific embodiment, the cell culture is incubated at about 37 ° C.

  In another more specific embodiment, the cell culture is at least about 2 hours, or at least about 5 hours, or at least about 10 hours, or at least about 15 hours, or at least about 18 hours, or Incubate for about 18 hours.

  In another more specific embodiment, the cells are human peripheral blood mononuclear cells; and the cell culture is at least about 2 hours, or at least about 5 hours, or at least about 10 hours, or When incubated for at least about 15 hours, or at least about 18 hours, or about 18 hours, the cell culture is incubated at about 37 ° C.

  In another more specific embodiment, the cells are human peripheral blood mononuclear cells; and the cell culture is at least about 2 hours, or at least about 5 hours, or at least about 10 hours, or When incubated for at least about 15 hours, or at least about 18 hours, or about 18 hours, the cell culture is incubated at about 37 ° C.

  In another more specific embodiment, the step of monitoring increased levels of increased TNF-α in the cell culture uses a primary plate-binding antibody for capture and then a secondary biotinylated anti-TNF antibody. Is done by using In a more specific embodiment, the secondary biotinylated anti-TNF antibody is detected using streptavidin-europium. In a more particular embodiment thereof, increased levels of increased TNF-α in the cell culture are identified by increased europium values. In an even more specific embodiment, the increased europium number is identified by fluorescence that disappears over time.

Another embodiment of the present invention provides a method of identifying the effectiveness of SMIP, which method includes:
a) contacting the compound with the cell and, alternatively, contacting the LPS with the cell to form a compound cell culture and an LPS cell culture;
b) incubating the compound cell culture and the LPS cell culture for at least 1 hour;
c) monitoring for increased TNF-α levels in the compound cell culture and the LPS cell culture;
d) comparing the increased TNF-α level in the compound cell culture with the increased TNF-α level in the LPS cell culture;
e) identifying the effectiveness of the SMIP by increasing the TNF-α level in the compound cell culture relative to the increased TNF-α level in the LPS cell culture.

  In a more particular embodiment, the cell is a human peripheral blood mononuclear cell. In another more specific embodiment, the compound cell culture and the LPS cell culture are incubated at about 37 ° C.

  In another more specific embodiment, the compound cell culture and the LPS cell culture are at least about 2 hours, or at least about 5 hours, or at least about 10 hours, or at least about 15 hours, or Incubate for at least about 18 hours or about 18 hours.

  In another more specific embodiment, the cells are human peripheral blood mononuclear cells; and the compound cell culture and the LPS cell culture are at least about 2 hours, or at least about 5 hours, or When incubated for at least about 10 hours, or at least about 15 hours, or at least about 18 hours, or about 18 hours, the cell culture is incubated at about 37 ° C.

  In another more specific embodiment, the step of monitoring increased levels of increased TNF-α in the compound cell culture and the LPS cell culture uses a primary plate-binding antibody for capture, and then This is done by using a secondary biotinylated anti-TNF antibody. In a more specific embodiment, the secondary biotinylated anti-TNF antibody is detected using streptavidin-europium. In a more particular embodiment thereof, increased levels of increased TNF-α in the compound cell culture and the LPS cell culture are identified by increased europium values. In an even more specific embodiment, the increased europium number is identified by fluorescence that disappears over time.

One embodiment of the present invention provides a high-throughput assay for identifying small molecule immune modulators, the assay comprising:
a) contacting a plurality of test compounds with cells to form one or more test solutions;
b) incubating the test solution for at least 30 minutes;
c) measuring for elevated levels of one or more immunological markers in the test solution;
And immunomodulation with one or more test compounds present in the plurality of test compounds results in an increase in the amount of the immunological marker in the test solution.

  In a more specific embodiment, the small molecule immunomodulator is SMIP and the immunomodulation is immune enhancement. More specific embodiments provide a high-throughput assay further comprising comparing the amount of immunological marker between the test solution and a non-stimulated solution lacking any test compound. More specifically, this non-activating solution is run in parallel with the test solution.

  In a more specific embodiment, the high throughput assay further comprises comparing the amount of immunological marker between the test solution and an activation solution containing a known immune enhancing factor. Still further, the activation solution is run in parallel with the test solution. In another more specific embodiment, the immunopotentiator is selected from the group consisting of LPS, CpG, resiquimod, Poly I: C (dsRNA), Pam3-Cys, MPL, and anti-CD3.

  In another more specific embodiment, the immunological marker is a cytokine. In another more specific embodiment, the immunological marker is a chemokine. In another more specific embodiment, the immunological marker is a growth factor. In another more specific embodiment, the immunological marker is both a cytokine and a chemokine. In another more specific embodiment, the immunological marker is both a cytokine and a growth factor. In another more specific embodiment, the immunological marker is both a chemokine and a growth factor. In another more specific embodiment, the immunological markers are cytokines, chemokines and growth factors.

  In another more specific embodiment, the immunological marker is TGF-β, the small molecule immunomodulator is SMIS, and the immunomodulation is immunosuppression.

  In another embodiment of the high throughput assay, an initial step of providing the plurality of test compounds bound to one or more carrier resins is provided. In a more specific embodiment, the plurality of test compounds are cleaved from the carrier resin prior to contacting them with cells. In another more specific embodiment, the carrier resin is a bead and the bead is dispensed such that a single bead is dispensed into separate wells of a multi-well plate. In another more specific embodiment, each bead comprises between 20 and 100 test compounds. In another more specific embodiment, the high throughput screening further comprises comparing the amount of immunological marker between the test solution and an activation solution comprising a known immune enhancing factor. In another more specific embodiment, the activation solution is run in parallel with the test solution. In another more specific embodiment, the immunopotentiator is selected from the group consisting of LPS, CpG, resiquimod, Poly I: C (dsRNA), Pam3-Cys, MPL, and anti-CD3. In another more specific embodiment, the high throughput assay further comprises comparing the amount of immunological marker between the test solution and a non-stimulated solution lacking any test compound. In another more specific embodiment, the non-activating solution is run in parallel with the test solution. In another more specific embodiment, the immunological marker is a cytokine. In another more specific embodiment, the immunological marker is a chemokine. In another more specific embodiment, the immunological marker is a growth factor. In another more specific embodiment, the immunological marker is both a cytokine and a chemokine. In another more specific embodiment, the immunological marker is both a cytokine and a growth factor. In another more specific embodiment, the immunological marker is both a chemokine and a growth factor. In another more specific embodiment, the immunological markers are cytokines, chemokines and growth factors.

  In another more specific embodiment, the test solution is at least 1 hour, or at least 2 hours, or at least 3 hours, or at least 4 hours, or at least 5 hours, or at least 6 hours, or at least 10 hours, or at least Incubate for 15 hours, or at least 18 hours.

  In another more specific embodiment, the test compound has a molecular weight of less than 700 g / mol.

  In another more specific embodiment, the immunological marker is detected by a fluorescent dye conjugated to a capture antibody.

  In another more specific embodiment, said cytokine is selected from the group consisting of IL 1-26, TNF-α, TNF-β, IFN-α, IFN-β and IFN-γ.

  In another more specific embodiment, said cytokine is selected from the group consisting of IL-Ib, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and IL-13. Is done.

In another more specific embodiment, the chemokine is selected from the group consisting of CXCL 1-16, XCL 1-2, CX ₃ CL 1, and CCL 1-28.

  In another more specific embodiment, the growth factor is selected from the group consisting of GM-CSF, G-CSF and M-CSF.

  In another more specific embodiment, the plurality of test compounds is dispensed into a multi-well plate such that one test compound is dispensed per well.

  In another more specific embodiment, the plurality of test compounds is dispensed into a multi-well plate such that one test compound is dispensed per well. Alternatively, the plurality of test compounds are added to one or more containers such that more than one test compound is present in each container.

  In another more specific embodiment, the identification of the small molecule immunomodulator is performed by increasing the number of test compounds contained in a well exhibiting immunomodulatory activity until the small molecule immune modulator is isolated. This is done by successfully screening a small subset.

  In another more specific embodiment, the plurality of test compounds refers to at least 20 different test compound types.

  In another more specific embodiment, the cell is a human PBM cell or a mu-spleen cell.

Another embodiment of the present invention provides a high-throughput assay for identifying small molecule immune modulators, the assay comprising:
a) contacting a plurality of test compounds with cells to form one or more test solutions;
b) adding a known immune enhancing factor to the test solution and a control solution not containing the test compound;
c) incubating the test solution and the control solution for at least 1 hour;
d) measuring the level of one or more immunological markers in the test solution and in the control solution;
e) comparing the level of the one or more immunological markers in the test solution with a corresponding level of the one or more immunological markers in the control solution, between the test solution and the control solution; Detecting a difference in the level of one or more immunological markers;
Wherein a decrease in the level of one or more immunological markers in the test solution indicates immunosuppression by the one or more test compounds, and an increase in the level of one or more immunological markers in the test solution comprises: 1 shows immune enhancement by one or more test compounds.

  In another more specific embodiment, the immunopotentiator is added at a suboptimal level so that the immunological marker is only partially stimulated.

  Another embodiment provides a high-throughput screen further comprising comparing the amount of immunological marker between the test solution and any test compound or non-stimulated solution lacking an immunopotentiator. Furthermore, the non-activating solution is executed in parallel with the test solution. In another more specific embodiment, the immunopotentiator is selected from the group consisting of LPS, CpG, resiquimod, Poly I: C (dsRNA), Pam3-Cys, MPL, and anti-CD3.

  In another embodiment, the immunological marker is a cytokine. In another more specific embodiment, the immunological marker is a chemokine. In another more specific embodiment, the immunological marker is a growth factor. In another more specific embodiment, the immunological marker is both a cytokine and a chemokine. In another more specific embodiment, the immunological marker is both a cytokine and a growth factor. In another more specific embodiment, the immunological marker is both a chemokine and a growth factor. In another more specific embodiment, the immunological markers are cytokines, chemokines and growth factors.

  In another more specific embodiment, the test solution is in another more specific embodiment, the test solution is at least 1 hour, or at least 2 hours, or at least 3 hours, or at least 4 hours, or at least 5 Incubate for hours, or at least 6 hours, or at least 10 hours, or at least 15 hours, or at least 18 hours.

  In another more specific embodiment, the test compound has a molecular weight of less than 700 g / mol.

  In another more specific embodiment, the immunological marker is detected by a fluorescent dye conjugated to a capture antibody.

  In another more specific embodiment, said cytokine is selected from the group consisting of IL 1-26, TNF-α, TNF-β, IFN-α, IFN-β and IFN-γ.

  In another more specific embodiment, said cytokine is selected from the group consisting of IL-Ib, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and IL-13. Is done.

In another more specific embodiment, said chemokine is CXCL 1-16, XCL
Selected from the group consisting of 1-2, CX ₃ CL 1, and CCL 1-28.

  In another more specific embodiment, the growth factor is selected from the group consisting of GM-CSF, G-CSF and M-CSF.

  In another more specific embodiment, the plurality of test compounds is dispensed into a multi-well plate such that one test compound is dispensed per well.

  In another more specific embodiment, the plurality of test compounds is dispensed into a multi-well plate such that one test compound is dispensed per well. Alternatively, the plurality of test compounds are added to one or more containers such that more than one test compound is present in each container.

  In another more specific embodiment, the identification of the small molecule immunomodulator is performed by increasing the number of test compounds contained in a well exhibiting immunomodulatory activity until the small molecule immune modulator is isolated. This is done by successfully screening a small subset.

  In another more specific embodiment, the plurality of test compounds refers to at least 20 different test compound types.

  In another more specific embodiment, the cell is a human PBM cell or a mu-spleen cell.

  In another embodiment of the high throughput assay, an initial step of providing the plurality of test compounds bound to one or more carrier resins is provided. In a more specific embodiment, the plurality of test compounds are cleaved from the carrier resin prior to contacting them with cells. In another more specific embodiment, the carrier resin is a bead and the bead is dispensed such that a single bead is dispensed into separate wells of a multi-well plate. In another more specific embodiment, each bead comprises between 20 and 100 test compounds. In another more specific embodiment, the high throughput screening further comprises comparing the amount of immunological marker between the test solution and an activation solution comprising a known immune enhancing factor. In another more specific embodiment, the activation solution is run in parallel with the test solution. In another more specific embodiment, the immunopotentiator is selected from the group consisting of LPS, CpG, resiquimod, Poly I: C (dsRNA), Pam3-Cys, MPL, and anti-CD3. In another more specific embodiment, the high throughput assay further comprises comparing the amount of immunological marker between the test solution and a non-stimulated solution lacking any test compound. In another more specific embodiment, the non-activating solution is run in parallel with the test solution. In another more specific embodiment, the immunological marker is a cytokine. In another more specific embodiment, the immunological marker is a chemokine. In another more specific embodiment, the immunological marker is a growth factor. In another more specific embodiment, the immunological marker is both a cytokine and a chemokine. In another more specific embodiment, the immunological marker is both a cytokine and a growth factor. In another more specific embodiment, the immunological marker is both a chemokine and a growth factor. In another more specific embodiment, the immunological markers are cytokines, chemokines and growth factors.

Another embodiment of the present invention provides a high-throughput assay for identifying small molecule immune modulators, the method comprising:
a) providing a mixture of test compounds divided into an archive portion and a screening portion from a combinatorial library, wherein (i) the mixture comprises a plurality of resin carrier beads to which the test compound is attached, and ( ii) a step of attaching only one type of test compound to each of the beads at a level deeper than 1 nmol;
b) contacting the screening moiety with a cell;
c) measuring for elevated levels of an immunological marker in the screening portion, wherein the immunomodulation by one or more test compounds present in the screening portion is dependent on the amount of the immunological marker Increasing the process;
d) individually distributing the beads from the archive portion in step (a) to a plurality of reaction vessels such that each vessel contains a single bead;
e) severing the test compound from the beads and separating the beads from the severed test compound, thereby providing a separate sample of each test compound;
f) screening each fragmented test compound to identify small molecule immune modulators;
g) performing mass spectroscopic analysis on the small molecule immunomodulator; and h) using the mass spectroscopic analysis to obtain a chemical identification of the small molecule immunomodulator from the preliminary portion.

  In another more specific embodiment, the screening moiety is incubated for at least 2 hours.

  In a more specific embodiment, the small molecule immunomodulator is SMIP and the immunomodulation is immune enhancement. In another embodiment, the high-throughput assay provides a high-throughput assay further comprising comparing the amount of immunological marker between the test solution and a non-stimulated solution lacking any test compound. In another more specific embodiment, the non-activating solution is run in parallel with the test solution.

  Another embodiment provides a high-throughput assay further comprising comparing the amount of immunological marker between the screening moiety and an activation solution comprising a known immune enhancing factor. In another more specific embodiment, the activation solution is run in parallel with the test solution. In another more specific embodiment, the immunopotentiator is selected from the group consisting of LPS, CpG, resiquimod, Poly I: C (dsRNA), Pam3-Cys, MPL, and anti-CD3.

  In a more particular embodiment, the immunological marker is a cytokine. In another more specific embodiment, the immunological marker is a chemokine. In another more specific embodiment, the immunological marker is a growth factor. In another more specific embodiment, the immunological marker is both a cytokine and a chemokine. In another more specific embodiment, the immunological marker is both a cytokine and a growth factor. In another more specific embodiment, the immunological marker is both a chemokine and a growth factor. In another more specific embodiment, the immunological markers are cytokines, chemokines and growth factors.

  In another more specific embodiment, the immunological marker is TGF-β, the small molecule immunomodulator is SMIS, and the immunomodulation is immunosuppression.

  In another more specific embodiment, the cell is a human PBM cell or a mu-spleen cell.

  In another more specific embodiment, the test solution is at least 1 hour, or at least 2 hours, or at least 3 hours, or at least 4 hours, or at least 5 hours, or at least 6 hours, or at least 10 hours, or at least Incubate for 15 hours, or at least 18 hours.

  In another more specific embodiment, the test compound has a molecular weight of less than 700 g / mol.

  In another more specific embodiment, the immunological marker is detected by a fluorescent dye conjugated to a capture antibody.

  In another more specific embodiment, said cytokine is selected from the group consisting of IL 1-26, TNF-α, TNF-β, IFN-α, IFN-β and IFN-γ.

  In another more specific embodiment, said cytokine is selected from the group consisting of IL-Ib, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and IL-13. Is done.

In another more specific embodiment, said chemokine is CXCL 1-16, XCL
Selected from the group consisting of 1-2, CX ₃ CL 1, and CCL 1-28.

  In another more specific embodiment, the growth factor is selected from the group consisting of GM-CSF, G-CSF and M-CSF.

  In another more specific embodiment, the plurality of test compounds is dispensed into a multi-well plate such that one test compound is dispensed per well.

  In another more specific embodiment, the plurality of test compounds is dispensed into a multi-well plate such that one test compound is dispensed per well. Alternatively, the plurality of test compounds are added to one or more containers such that more than one test compound is present in each container.

  In another more specific embodiment, the identification of the small molecule immunomodulator is performed by increasing the number of test compounds contained in a well exhibiting immunomodulatory activity until the small molecule immune modulator is isolated. This is done by successfully screening a small subset.

  In another more specific embodiment, the plurality of test compounds refers to at least 20 different test compound types.

  It should be understood that the organic compounds described herein may exhibit reduced tautomerism. It should be understood that the present invention encompasses any tautomeric form of the depicted structure. The compound contains an asymmetrically substituted carbon atom. Such asymmetrically substituted carbon atoms result in a mixture of stereoisomers at a particular asymmetrically substituted carbon atom or a compound containing a single stereoisomer. As a result, racemic mixtures of the above compounds, mixtures of diastereomers, and single diastereomers are included in the invention. The terms “S” and “R” configurations are described in IUPAC 1974 Recommendations, Section E, Fundamental Stereochemistry, PureAppl. Chem. (1976) 45, 13-30. The terms α and β are used for the ring portion of the cyclic compound. The α side of the reference plane is the side where the preferred substituents are in lower numbered positions. Substituents on the opposite side of the reference plane are assigned the β descriptor. It should be shown that this usage is different from that for cyclic stereoparents where “α” means “bottom plane” and indicates absolute configuration. The terms α-configuration and β-configuration are as defined in the Chemical Abstracts Index Guide-Appendix IV (1987), paragraph 203.

  The SMIP compound may or may not be used with an antigen, for example, in therapeutic applications for the treatment of cancer or infection. SMIP compounds can also be used in combination with other therapeutic agents (eg, antiviral agents and monoclonal antibodies) in different therapeutic applications.

  One preferred embodiment of a method for inducing an immunostimulatory effect in a patient is a vaccine in an amount effective to stimulate an immune response (eg, a cellular immune response) and an immune response (eg, cellular) to the vaccine. It relates to administering an immunogenic composition comprising a SMIP compound as a vaccine adjuvant in an amount effective to enhance the immune response).

  It is contemplated that a vast number of diseases can be treated with SMIP compounds and compositions of the present invention. Preferred methods of the invention include bacterial diseases, fungal diseases, viral diseases, malignant tumors, hyperlipidemia, and ischemic heart diseases (eg, digestive diseases, cardiovascular diseases, urological / genital diseases, immunity) SMIP compounds are included as single agents or in combination with other agents to treat diseases including diseases, cranial nerve diseases, eye diseases, skin diseases, and nasal, ear and throat diseases).

  Examples of such diseases that are sensitive to combinations of SMIP compounds and SMIP are: bacterial diseases (eg, bacterial corneal ulcers, bacterial conjunctivitis, bacterial food poisoning, septic shock, endotoxin shock, bacterial Endocarditis, bacterial pneumonia, bacterial aneurysms, and bacterial cerebral aneurysms); viral diseases (eg, fungal meningitis, fungal corneal ulcers, fungal skin diseases, candidiasis, and Ringworm); viral diseases (eg, viral gastroenteritis, viral hepatitis, viral, viral inflammatory, viral myocarditis, viral meningitis, viral enterocolitis, viral encephalitis) , Viral pneumonia, and AIDS); massive malignancies (eg, renal cell carcinoma, mycosis fungoides, and chronic granulomatosis); blood Malignant tumors (eg colon cancer, rectal cancer, colon cancer, stomach cancer, thyroid cancer, tongue cancer, bladder cancer, ciliary cancer, hepatocellular carcinoma, prostate cancer, uterine cancer, pharyngeal cancer, lung cancer, breast cancer, malignant melanoma , Capoji sarcoma, brain tumor, neuroblastoma, ovarian tumor, testicular tumor, pancreatic tumor, kidney cancer, adrenal tumor, hemangioendothelioma, adult T cell leukemia (ATL), chronic myelogenous leukemia (CML), and malignant lymphoma) Autoimmune diseases, allergic diseases and viral diseases (eg active chronic hepatitis, atrophic nephritis, autoimmune hemolytic anemia, Graves' disease, Behcet's disease, Crohn's disease, CRST syndrome, cold hemagglutinin hemolytic anemia, Idiopathic ulcerative colitis, Goodpasture syndrome, hyperthyroidism, chronic thyroiditis, alveolar inflammation, glomerulonephritis, idiopathic thrombocytopenic purpura, juvenile diabetes, insulin dependence Diabetes mellitus, leukopenia, multiple sclerosis, myasthenia gravis, paroxysmal cold hemoglobinuria, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, rheumatic fever, Rheumatoid arthritis, Sjogren's syndrome, sympathetic ophthalmitis, systemic progressive sclerosis, Wegener's granulomatosis, asthma, atopic dermatitis, bronchial asthma, graft-versus-host disease, allergic rhinitis, hay fever, and bee Allergies to toxins); liver disease (eg alcoholic hepatitis, toxic hepatitis, viral cirrhosis, alcoholic cirrhosis, toxic cirrhosis, biliary cirrhosis, fatty liver, liver tumors, and hepatic vascular disorders); Disease (eg, cholangitis, cholecystitis, primary sclerosing cholangitis, gallbladder tumor) Pancreatic diseases (eg, acute failure, pancreatic tumors, and pancreatic cysts); cardiovascular diseases (eg, ischemia, ischemic heart disease, cerebral ischemia, basilar artery migraine, Abnormal blood vessels in the base of the brain, stroke, aneurysm of the base of the brain, arteriosclerosis, vascular endothelial damage, non-insulin dependent diabetes, mesenteric vascular occlusion, and superior mesenteric artery syndrome); neurological disease ( For example, Parkinson's disease, spinal atrophy, amyotrophic lateral sclerosis, Alzheimer's disease, dementia, cerebrovascular dementia, AIDS dementia, and meningitis); gastrointestinal diseases (eg, peptic ulcer, peptic esophagus) Ulcers (peptic esophagus ulcer), intestinal polyps, intestinal adhesions, intestinal stiffness, and gastric ulcers; development of psychosis, central nervous system inhibitors, habitual alcohol, and breathing Sleep disorders, which are caused by the failure of the system.

  Agents that are used in combination with SMIP compounds that are intended to be useful in treating the aforementioned diseases include agents that are well known in the art (eg, anesthetics, hypnotic sedatives, anti-anxiety agents, anti-anxiety agents, anti-anxiety agents, Glaze, antipyretic, stimulant, stimulant amine, antiparkinsonian, neuropsychiatric agent, central nervous system agent, skeletal muscle relaxant, autonomic nervous system agent, antispasmodic agent, cytotoxic agent, monoclonal antibody, eye Drugs, nasal and ear drugs, anti-vertigo drugs, cardiotonic drugs, antiarrhythmic drugs, diuretics, decompression agents, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemia drugs, respiratory stimulants, antitussive And expectorants, bronchodilators, allergic drugs, antidiarrheal drugs, drugs for intestinal disorders, peptic ulcer drugs, gastric digestives, antacids, gallbladder drugs, pituitary hormone drugs, salivary gland hormone drugs, thyroid hormones Agent, antithyroid drug, anabolic steroid , Corticosteroids, androgens, estrogen, progesterone, mixed hormones, urinary and reproductive organs, anal, surgical sterilization / disinfectant, wound protection, purulent disease topical, Analgesics, antipruritics, astringents, anti-inflammatory agents, external medicines for parasitic skin diseases, emollients, cauterizing agents, dental / oral medicines, vitamins, inorganic preparations, auxiliary liquids, hemostatic agents, anticoagulants, Drugs for liver disease, antidote, addictive addiction, gout treatment, enzyme preparation, diabetes, antitumor, antihistamine, antibody (eg, ketolide, aminoglycoside, sulfonamide, and / or β-lactam ), Chemotherapeutic agents, biological preparations, anthelmintics, antiprotozoal agents, pharmaceutical drugs, X-ray contrast agents, and diagnostic agents.

  Further methods of the invention are provided and the compositions described herein are used for the treatment of cancer and the reduction of tumor growth. In one aspect, the SMIP compounds of the invention are used in combination with known MAbs for the treatment of cancer. In presently preferred aspects of this embodiment of the invention, the antibody and SMIP compound are administered. This antibody alone has an inhibitory effect on tumor cell proliferation, and SMIP compounds may be particularly preferred to induce the production of cytokines.

  In accordance with another embodiment of the present invention, there is provided a therapeutic composition for inhibiting tumor cell growth in a subject, the composition comprising at least one SMIP compound and a MAb and a pharmaceutically acceptable carrier. The combination is effective to inhibit the growth of tumor cells in certain mammals, rather than when the agents are administered individually.

  In another embodiment, a method of treating cancer is provided and a known anticancer agent is used in combination with a SMIP compound to reduce tumor growth in a subject. Many suitable anticancer agents are contemplated for use in the methods of the present invention. Indeed, the present invention contemplates, but is not limited to, administration of a number of anticancer agents such as: agents that induce apoptosis; polynucleotides (eg, ribozymes); polypeptides (eg, enzymes); drugs; 25 mimetics; 25 alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies conjugated to anticancer drugs, toxins, and / or radionuclides; Modifiers (eg, interferon [eg, IFN-a] and interleukin [eg, IL-2]); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (Eg, all-trans retinoic acid, etc.); gene 30 therapy reagents; antisense therapy reagents and nucleotides Etc. and angiogenesis inhibitors; Reochido; tumor vaccines. Many other examples of chemotherapeutic compounds and anti-cancer therapies suitable for co-administration with the disclosed SMIP compounds are known to those skilled in the art.

  In a preferred embodiment, the anticancer agent comprises an agent that induces or stimulates apoptosis. Factors that induce apoptosis include, but are not limited to: radiation (eg, W); kinase inhibitors (eg, epidermal growth factor receptor [EGFR] kinase; inhibitors (vascular growth factor receptor [VGFR]) Kinase inhibitors, fibroblast growth factor 5 receptor [FGFR] kinase inhibitors, platelet-derived growth factor receptor [PGFR] I kinase inhibitors, and Bcr-Abl kinase inhibitors (eg, STI-571, Gleevec, and Glivec)); antisense Molecules; antibodies [eg, Herceptin and Rituxan]; antiestrogens [eg, raloxifene and tamoxifen]; antiandrogens [eg, flutamide, bicalutamide, finasteri , Aminoglutetamide, ketoconazole, and corticosteroids]; cyclooxygenase 2 (COX-2) inhibitors [eg, Celecoxib, meloxicam, NS-398, and nonsteroidal anti-inflammatory drugs I (NSAIDs)]; and cancer chemistry Therapeutic agents [eg, Irinotecan (Camptosar), CPT-Il, Fludarabine (Fludara), Dacarbazine (DTIC), Dexamethasone, Mitoxantrone, Mylotarg, VP-; 16, Cisplatin, 5-FU, Doxrubicin, Taxotere or Taxol] Cell signaling molecules; ceramides and cytokines; and staurospurines.

  In another embodiment, a method for treating allergy is provided, wherein the method administers a SMIP compound either alone or in combination with other agents known to be effective against allergies. Including this step, this combination is more effective in the treatment of allergic conditions than if the known agent was not accompanied by the addition of SMIP compounds. In a more preferred embodiment, the known agent is an antihistamine and / or leukotriene inhibitor. In another preferred embodiment, the allergic condition is asthma. In another preferred embodiment, the allergic condition is selected from the group consisting of allergic rhinitis, skin diseases, and urticaria. In an even more preferred embodiment, the combination is administered to the subject enterally, parenterally, nasally, subcutaneously, or intraarterially.

  In another embodiment, the present invention provides a method of screening a SMIP compound and a test compound, the method comprising: SMIP compound; test compound; providing a first group of cells; Contacting the first group of cells with the SMIP compound and the test compound; and observing the effect of contacting the first group of cells with the SMIP compound and the test compound. In some of these embodiments, the present invention further compares the effects observed in the first cell against a second group of cells that are contacted only with the SMIP compound or only with the test compound. Provide additional steps. The effects that can be observed include changes in cell proliferation, changes in TNFα levels, changes in the amount of virus infected by the cells, changes in the level of bacterial infection in the cells, changes in the histamine levels in the cells, changes in the apoptotic stats. , And changes in the expression of Bcl-2 family proteins, but are not limited thereto.

  In another embodiment, methods of making the compounds and compositions described herein are provided and are intended to be included within the scope of the present invention.

  Qualitative and quantitative measurements of the immune response of a compound or composition can be performed by methods known in the art (eg, antigen-specific antibody production, lymphocyte (eg, CD4 + T cells, CD8 + T cells or NK cells) specific methods). Population activation and / or measurement of cytokines (eg, measurement of production of IFN, IL-2, IL-4 or IL-12) can be performed. Examples of the method for measuring a specific antibody reaction include enzyme-linked immunosorbent assay (ELISA) as known in the art. Measurement of the number of specific types of lymphocytes (eg, CD4 + T cells) can be accomplished using, for example, fluorescence cell analysis separation (FACS). Cytotoxic assays are described, for example, by Raz et al. (1994), Proc. Natl. Acad. Sci. USA 91: 9519-9523. Serum levels of cytokines can be measured, for example, by ELISA. Such assays are described, for example, in Selected Methods in Cellular Immunology (1980), edited by Michel and Shiigi, W.M. H. Freeman and Co.

  In one embodiment, the compound or composition (eg, SMIP compound) is a 20 μM (or 10 μM, or 200 μM, or 300 μM) level of SMIP compound in an in vitro cell-based assay of human peripheral blood mononuclear cells, It is considered effective in eliciting an immune response in causing the production of TNF-α, the level of human peripheral blood mononuclear cells is about 500,000 per mL, and these cells are The compound is exposed to about 18-24 hours (eg, about 24 hours).

  For example, the above method of stimulating a local immune response in a selected cell or tissue of a patient induces a stimulation of the local immune response, and the selected cell or tissue is infected or cancerous. In one embodiment, the selected cell or tissue is infected with a fungus or bacterium. In another embodiment, the selected cell or tissue is inflamed by allergy, eg, in an asthmatic state. In another embodiment, the selected cell or tissue is infected with a virus or bacterium. In an even more specific embodiment, the infectious agent is HCV, HIV, HBV, HSV, H. Pylori, HSV1 or HSV2, or human papillomavirus.

  The methods and compounds disclosed herein generally manipulate immune responses away from type 2 cytokine secretion and effector mechanisms (eg, IgE production and / or mast cell / basophil activation) Can be used for the treatment of asthma.

  The immunogenic compositions of the present invention may include additional pharmaceutically acceptable ingredients, excipients, carriers, and the like that are well known to those skilled in the art.

The vaccine composition can include additional adjuvants. Preferred adjuvants that enhance the effectiveness of the composition include, but are not limited to: (1) aluminum salts (alum) (eg, aluminum hydroxide, aluminum phosphate, aluminum sulfate, etc.); ) Oil-in-water emulsion formulations (with or without other specific immunostimulants such as muramyl peptides or bacterial cell wall components) (eg (a) 5% squalene, 0.5% Tween 80, MF59 ^™ (WO 90/14837), formulated with a microfluidizer into sub-micron particles, and 0.5% Span85 (with various amounts of MTP-PE as required), (B) microfluidized to a sub-micron emulsion or larger particle size SAF containing 5% squalene, 0.5% Tween 80, 5% pluronic block polymer L121 and thr-MDP, either vortexed to make an emulsion, and (c) 2% squalene, 0.2% Ribi ^TM adjuvant comprising Tween 80 and one or more bacterial cell wall components selected from the group consisting of monophospholipid A (MPL), trehalose dimycolate (TDM) and cell wall skeleton (CWS), preferably MPL + CWS (DetoxTM) System (RAS) (Ribi Immunochem, Hamilton, MT)); (3) Saponin adjuvant (eg, QS21 or Stimulon ^™ (Cambridge Bioscience, Worcester, M.) A) can be used) or particles made therefrom (eg ISCOM (immunostimulatory complex)) This ISCOMS can lack additional detergent (eg WO 00/07621)); (4) complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA); (5) cytokines (eg, interleukins (IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL- 12 (WO 99/44636), etc.), interferon (eg, gamma interferon), macrophage colony stimulating factor (M-CSF), tumor necrosis factor (TNF), etc.)); (6) S. pneumoniae as necessary Monophosphoryl lipid A (MPL) or 3 substantially in the absence of alum. O-diacylate MPL (3dMPL) (eg WO 00/56358); and RC529 (7) eg QS21 and / or a combination of oil-in-water emulsions and 3dMPL (eg EP-A-0835318); (8) CpG (9) a polyoxyethylene ether or a polyoxyethylene ester (for example, WO 99 /) containing a motif (ie containing at least one CG dinucleotide together with 5 methylcytosine used in place of cytosine as needed) 52549); (10) in combination with a polyoxyethylene sorbitan ester surfactant (WO 0121207) combined with octoxynol or at least one further non-ionic surfactant (eg octoxynol), Polyoxyethylene alkyl ether surfactants or polyoxyethylene alkyl ester surfactants (WO 01/21152); (11) Saponins and immunostimulatory oligonucleotides (eg CpG oligonucleotides) (WO 00/62800); (12) Immunostimulatory and metal salt particles (eg WO 00/23105); (13) Saponins and oil-in-water emulsions (eg WO 99/11241); (14) Saponins (eg QS21) + 3dMPL = IL-12 ( (Optionally + sterol) (eg WO 99/57659) (14) Other substances that act as immunostimulants that enhance the effectiveness of the composition. In one particular embodiment, alum (especially aluminum phosphate and / or aluminum hydroxide) and MF59 are preferred for use with saccharide antigens.

  The present invention also relates to a method of administering a vaccine composition. The vaccine is administered in an amount effective to stimulate an immune response. The amount that constitutes an effective amount includes, inter alia, the particular vaccine used, the particular adjuvant compound being administered and their amount, the immune response to be enhanced (humoral mediated or cell mediated), (eg, suppressed It depends on the state of the immune system, which is easily infectious and stimulated, and on the desired therapeutic outcome. Therefore, it is generally impractical to indicate the amount that constitutes an effective amount of this vaccine. However, one of ordinary skill in the art can readily determine the appropriate amount by considering such factors.

  The immunogenic compositions of the present invention can be produced by conventional methods well known to those skilled in the art (eg, oral, subcutaneous, nasal, topical) in animals (eg, mammals, humans and non-humans (eg, small animals, poultry). And the like)).

  Suitable vaccines include, but are not limited to, any substance that provides either a humoral mediated immune response or a cell mediated immune response, or both. Suitable vaccines include live and bacterial antigens and inactivated viral antigens, tumor-derived antigens, protist antigens, organism-derived antigens, fungal antigens, and bacterial antigens, toxoids, toxins, polysaccharides, proteins , Glycoproteins, peptides and the like. Traditional vaccines (eg BCG (live bacteria) vaccine, cholera vaccine, plague vaccine, and typhoid (killed bacteria) vaccine, hepatitis B vaccine, influenza vaccine, inactivated polio vaccine, and rabies (inactivated) Virus) vaccine, measles vaccine, mumps vaccine, rubella vaccine, oral polio vaccine, SARS vaccine, and yellow fever (live virus), pertussis and diphtheria (toxoid), hemophilus influenza b, meningococcus, and pneumococci (bacteria) The vaccines used in connection with the sex polysaccharides) can also be used. Any antigen known in the art or disclosed herein can also be used.

  Furthermore, it is contemplated that certain currently experimental vaccines, particularly those that do not cause a strong immune response (eg, recombinant proteins, glycoproteins, and peptides) will also find use in connection with SMIP compounds. Exemplary experimental subunit antigens include viral diseases (eg, adenovirus, AIDS, chickenpox, cytomegalovirus, dengue fever, feline leukemia, poultry plague, hepatitis A, hepatitis B, hepatitis C). , HSV-1, HSV-2, swine cholera, influenza A, influenza B, Japanese encephalitis, measles, parainfluenza, rabies, RS virus, SARS virus, rotavirus, wart, and yellow fever) Can be mentioned.

  Specific antigens for use in the present invention include, but are not limited to, those listed below. Numbers in parentheses indicate typical sources of that antigen. The list of sources follows the list of antigens, and each source is incorporated by reference in its entirety.

Specific antigens include: N. serogroup B. protein antigens (1-7) from M. meningitides; outer membrane vesicle (OMV) preparations (8, 9, 10, 11) from meningitidis; serogroups A, C, W135 and / or Y. Saccharomyces cerevisiae (eg, oligosaccharides (12) from serogroup C (13)); Saccharogenic antigens from Streptococcus pneumoniae (14, 15, 16); antigens from gonorrhoeae (1, 2, 3); antigens from Chlamydia pneumoniae (17, 18, 19, 20, 21, 22, 23); antigens from Chlamydia trachonzatis (24); Activated virus) antigens (25, 26); hepatitis B virus antigens (eg, surface and / or core antigens (eg, 26, 27)); hepatitis C virus antigens (28) An antigen from Bordetella pertussis (e.g. pertussis holotoxin (PT) and filamentous hemagglutinin (FHA) from B. pertussis optionally combined with pertactin and / or agglutinogen 2 and agglutinogen 3 (29); 30)); diphtheria antigen ( For example, diphtheria toxoid (31: Chapter 3) (eg, CRM197 variant (32))); tetanus antigen (eg, tetanus toxoid (31: Chapter 4)); Helicobacter pylori derived protein antigen (eg, CagA ( 33), VacA (33), NAP (34), HopX (5), HopY (35) and / or urease); saccharide antigens from Haemophilus influenzae B (13); antigens from Porphyromonas gingivalis (36); polio antigens (37,38) (eg IPV or OPV); rabies antigen (eg lyophilized inactivated virus (40, RabAvert ^™ )); measles antigen, mumps antigen and / or rubella antigen (31: 9th Chapter 1 Chapter, and chapter 11); influenza antigen (31: chapter 19) (eg hemagglutinin and / or neuraminidase surface protein; antigen from Moraxella catarrhalis (41); antigen from Streptococcus agalactiae (group B streptococci) (42, 43); an antigen from Streptococcus pyogenes (Group A Streptococcus) (43, 44, 45); and an antigen from Staphylococcus aureus (46).

  The composition may contain one or more of the antigens described above.

If a saccharide or carbohydrate antigen is used, this antigen is preferably conjugated with a carrier protein to enhance antigenicity (47-56). Preferred carrier proteins are bacterial toxins or bacterial toxoids (eg diphtheria toxoid or tetanus toxoid). CRM ₁₉₇ diphtheria toxoid is particularly preferred. Other suitable carrier proteins include N. meningitides outer membrane protein (57), synthetic peptide (58, 59), heat shock protein (60), pertussis protein (61, 62), H. pneumoniae. Influenzae-derived protein D (63), C.I. difficile-derived toxin A or toxin B (64). If the mixture contains capsular saccharides from both serogroup A and serogroup C, the MenA saccharide: MenC saccharide ratio (w / w) is greater than 1 (eg 2: 1, 3: 1 4: 4, 5: 1, 10: 1 or more). N. Saccharides from different serogroups of meningitides can be conjugated to the same or different carrier proteins.

  Any suitable conjugation reaction can be used, optionally with any suitable linker. Toxin protein antigens can be detoxified as necessary (eg, detoxification of pertussis toxin by chemical and / or genetic means (30)). When a diphtheria antigen is included in the composition, it is also preferred to include a tetanus antigen and a pertussis antigen. Similarly, where a tetanus antigen is included it is also preferred to include a diphtheria antigen and a pertussis antigen. Similarly, where a pertussis antigen is included, it is also preferred to include diphtheria and tetanus antigens.

  A pharmaceutical composition comprising a compound described herein can contain additives (eg, excipients). Suitable pharmaceutically acceptable excipients include processing agents and drug delivery modifiers and enhancers (eg, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, Starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, low melting wax, ion exchange resin, and any combination of two or more thereof. Other suitable pharmaceutically acceptable excipients are described in “Remington's Pharmaceutical Sciences”, Mack Pub. Co. , New Jersey (1991).

  A pharmaceutical composition comprising a compound of the invention is in any form suitable for the intended method of administration, including, for example, a solution, suspension, or emulsion. Liquid carriers are typically used to prepare solutions, suspensions, or emulsions. Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvents, pharmaceutically acceptable oils or pharmaceutically acceptable fats, and the like, and A mixture of two or more thereof is mentioned. The liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity modifiers, Stabilizers, etc.). Suitable organic solvents include, for example, monohydric alcohols (eg, ethanol) and polyhydric alcohols (eg, glycol). Suitable oils include, for example, soybean oil, coconut oil, olive oil, sunflower oil, cottonseed oil and the like. For parenteral administration, the carrier can also be an oily ester (eg, ethyl oleate, isopropyl myristate, etc.). The compositions of the present invention can also be in the form of microparticles, microcapsules, etc., and any combination of two or more thereof.

  The compounds and combinations of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The composition of the present invention in the repolyme form may contain stabilizers, preservatives, excipients and the like in addition to the compound of the present invention. Preferred lipids are both natural and synthetic phospholipids and phosphatidylcholines (lecithins). Methods for forming liposomes are known in the art. See, for example, Prescott, Methods in Cell Biology, Vol. W. , P. See 33 et seq. (1976).

  Other additives include immunostimulants known in the art. Immunostimulatory oligonucleotides and polynucleotides are described in PCT WO 98/55495 and PCT WO 98/16247. US Patent Application 2002/0164341 describes an adjuvant comprising an unmethylated CpG dinucleotide (CpG ODN) and a non-nucleic acid adjuvant. US Patent Application No. 2002/0197269 describes a composition containing an antigen, an antigenic CpG-ODN and a polycationic polymer. Other immunostimulatory additions described in the art, for example, as described in US Pat. Nos. 5,026,546; 4,806,352; and 5,026,543 Agents can be used. In addition, SMIP compounds as described in USSN 60 / 458,888 are contemplated as effective co-administration agents or combinations with the compositions of the present invention. These SMIPs can also function as vaccine adjuvants.

  For example, Lee, “Diffusion-Controlled Matrix Systems”, pp. 155-198 and Ron and Langer, “Erodible Systems”, pp. 199-224, “Treatise on Controlled Drug Delivery”, A.M. Kydonieus, edited by Marcel Dekker, Inc. A slow broadcast delivery system such as a diffusion control matrix system or an erodible system as described in New York 1992 can be used. The matrix can be, for example, a biodegradable material that can spontaneously degrade (eg, by hydrolysis or enzymatic cleavage (eg, with a protease)) in situ and in vivo. The delivery system can be, for example, a naturally occurring or synthetic polymer or copolymer (eg, in the form of a hydrogel). Exemplary polymers having cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides, poly (phosphoesters), polyamides, polyurethanes, poly (imide carbonates), and poly (phosphazenes). .

  The compounds of the present invention can be administered enterally, orally, parenterally, in the tongue, in a conventional dosage unit formulation containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired. It can be administered below, by inhalation spray, rectally, or topically. For example, suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoresis, intravenous, intramuscular, intraperitoneal, intranasal, subcutaneous, rectal and the like. Topical administration can also include the use of transdermal administration (eg, transdermal patches or iontophoretic devices). As used herein, the term “parenteral” includes subcutaneous injections, intravenous, intramuscular, intrasternal injection techniques or infusion techniques.

  Injectable preparations (eg, sterile injectable aqueous suspensions or sterile injectable oily suspensions) can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or sterile injectable suspension in a non-toxic parenterally acceptable diluent or solvent (eg, 1,3-propanediol). Like a solution in). Commonly acceptable vehicles and solvents that can be utilized are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids (eg oleic acid) find use in injectable preparations.

  Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols. This excipient is solid at ambient temperature, but is liquid at rectal temperature and therefore melts in the rectum and releases the drug.

  Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain additional materials in addition to an inert diluent, such as a lubricant (eg, magnesium stearate), as a normal practice. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. In addition, tablets and pills can be prepared by enteric coating.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and inert diluents commonly used in the art (eg, water), and An elixir may be mentioned. Such compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.

  An effective amount of a compound of the invention generally includes any amount sufficient to detectably treat a disorder described herein.

  Successful treatment of a subject in accordance with the present invention is a reduction or alleviation of symptoms in a subject suffering from a medical or biological disorder, for example, stopping further progression of the disorder or preventing the disorder. Can cause triggering.

  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. However, the specific dose level for any particular patient depends on the activity of the specific compound utilized, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion It is understood that it depends on various factors, including the combination of drugs, and the severity of the particular disease being treated. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the ordinary clinician's skill and judgment.

  The compounds can be used in the form of salts derived from inorganic or organic acids. These salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, hydrogen sulfate, butyrate , Camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, Fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, Oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate Salts, tartrate, thiocyanate, p- toluenesulfonate and undecanoate, and the like. In addition, basic nitrogen-containing groups include lower alkyl halides (eg, methyl chloride, ethyl chloride, propyl chloride, butyl chloride, methyl bromide, ethyl bromide, propyl bromide, butyl bromide, methyl iodide, iodide). Ethyl, propyl iodide, and butyl iodide); dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate), long chain halides (eg, decyl chloride, lauryl chloride, myristyl chloride, stearyl chloride, odor) Decyl iodide, lauryl bromide, myristyl bromide, stearyl bromide, decyl iodide, lauryl iodide, myristyl iodide, stearyl iodide, and the like), aralkyl halides (such as benzyl bromide and phenethyl bromide), etc. Can be quaternized with factors. Water or oil soluble or dispersible products are thereby obtained. Examples of acids that can be utilized to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and oxalic acid, maleic acid, succinic acid, and citric acid. Organic acids. Basic addition salts can be prepared in situ during final isolation and purification of the compound of formula (I), or separately, the carboxylic acid moiety can be converted to a suitable base (eg, pharmaceutically acceptable). Possible metal cation hydroxides, carbonates or bicarbonates) or ammonia or can be prepared by reacting with organic primary, secondary or tertiary amines. Pharmaceutically acceptable salts include cations based on alkali and alkaline earth metals (eg, sodium, lithium, potassium, calcium, magnesium, aluminum salts, etc.), as well as non-toxic ammonium cations, Examples include, but are not limited to, quaternary ammonium cations and amine cations (including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like). Other representative organic amines useful for the formation of base addition salts include diethylamine, methylenediamine, ethanolamine, diethanolamine, piperazine and the like.

  Other additives include immunostimulants known in the art. Immunostimulatory oligonucleotides and polynucleotides are described in PCT WO 98/55495 and PCT WO 98/16247. US Patent Application 2002/0164341 describes an adjuvant comprising an unmethylated CpG dinucleotide (CpG ODN) and a non-nucleic acid adjuvant. US Patent Application No. 2002/0197269 describes a composition containing an antigen, an antigenic CpG-ODN and a polycationic polymer. Other immunostimulatory additions described in the art, for example, as described in US Pat. Nos. 5,026,546; 4,806,352; and 5,026,543 Agents can be used.

The present invention is intended to encompass all possible combinations of the embodiments described herein.
(Definition)
As used above and elsewhere herein, the following terms and abbreviations have the meanings defined below.

ATP: adenosine triphosphate BCG bacilli bovine tuberculosis Calmette Guerin bacilli BSA: bovine serum albumin FHA filamentous hemagglutinin GCMS gas chromatography / mass spectrometer Pylori Helicobacter pylori HAV Hepatitis A virus HBV Hepatitis B virus HCV Hepatitis C virus HIV Human immunodeficiency virus HPLC High performance liquid chromatography HSV Herpes simplex virus IC ₅₀ value: Level of inhibitor that reduces measured activity by 50% IFN Interferon IL Interleukin IMS Immunomagnetic Separation IPV Inactivated Poliovirus LCMS Liquid Chromatography / Mass Spectrometer LPS Lipopolysaccharide Men A Type A Meningococcus Men C Type C Meningococcus Men B Type B Meningococcus Men W Type W meningococcus Men Y Type Y meningococcus MeOH Methanol NANB Non-A non-B hepatitis NMR Nuclear magnetic resonance OMV Outer membrane vesicles PBMC Peripheral blood mononuclear cells PT Pertussis holotoxin oxin)
Rt Room temperature (25 ° C)
SMIP small molecule immune enhancement factor SMIS small molecule immunosuppressive factor TLC thin layer chromatography TNF-α tumor necrosis factor-α
The methods of the present invention are useful for treating “allergic diseases” and are accomplished in a manner similar to other immunotherapeutic methods described herein.

  “Allergen” refers to a substance (antigen) that can elicit an allergic or asthmatic response in a susceptible subject. The list of allergens is huge and can include pollen, insect venom, animal dander, dust, fungal spores, and drugs (eg, penicillin).

  “Asthma” refers to a disorder of the respiratory system characterized by inflammation, airway narrowing and increased airway responsiveness to inhaled factors. Asthma is frequently but not exclusively associated with atopic or allergic symptoms.

  The term “leukotriene inhibitor” refers to any factor or compound that inhibits, suppresses or prevents, or otherwise interacts with, the action or activity of leukotrienes, including but not limited to, for example, 5-lipoxygenase (“5 -LO ") inhibitors, 5-lipoxygenase activating protein (" FLAP ") antagonists, and leukotriene D4 (" LTD4 ") antagonists).

  “Immune stimulation” or “immunity enhancement” refers to activation of the immune system, including fluid activation or cell activation (eg, activation of cells such as killer (T or NK) cells or dendritic cells of the immune system). For example, increasing cytokine production from dendritic cells and improving overall host defense (immune response).

  An “immunogenic composition” refers to a composition that can modulate the production of cytokines in a subject, thereby resulting in immune enhancement in that subject.

  An “immunostimulatory effective amount” is an effective amount for activating the immune system (for example, increasing cytokine production from dendritic cells and improving overall host defense (immune response)).

  “Enhance immune response to an antigen” by a compound means that the immune response is improved compared to the absence of the compound. Compositions that elicit an improved immune response generally include one antigen and one that elicit a greater immune response than a composition that includes one antigen but does not include one or more small molecule immune enhancing compounds. A composition comprising a small molecule immunity enhancing compound. In this embodiment, the compound acts as an adjuvant and is used, for example, in vaccine compositions and methods.

  The term “small molecule immunomodulator” or “small molecule immunomodulator composition” refers to a small molecule compound of less than about MW 800 g / mol that can stimulate or suppress an immune response in a patient.

  “Modulate” refers to inducing or inhibiting.

  “Immunosuppression” or “immunosuppression” refers to deactivation of the immune system (eg, preventing or reducing cytokine production from dendritic cells and globally attenuating host defense (immune response)). To express.

  Reference to “sub-optimal levels” is due to a reduction in the amount of factor in the system, and the addition of another factor that can stimulate an increase or response of the factor may result in immunological markers (eg, cytokines, chemokines, and (Or / or growth factor) that is less effective than the highest effect of that factor on that system.

  Reference to “a suboptimal level such that the immunological marker is only partially stimulated” refers to an increase in the factor or the addition of another factor that can stimulate the response, such as an immunological marker (eg, a cytokine , Chemokines, and / or growth factors) indicates the level of factors that cause the immunological response to be less than maximum.

  Reference to “compound” is intended to indicate a small molecule having a molecular weight of less than 800 g / mol, preferably less than 700 g / mol, unless otherwise specified.

  A “test compound” is a compound that has the same meaning as the compound and is being tested for activity (eg, immunomodulation, immunosuppression, or immune enhancement).

  The term “plurality of compounds” refers to more than one type of compound. More preferably, it represents at least 10 compounds, and even more preferably represents 20-100 compounds.

  “High-throughput assay” is intended to indicate an assay that can simultaneously identify certain properties of a wide variety of compounds, particularly immunosuppression and / or immune enhancement.

  A “capturing antibody” is an antibody that can bind a specific immunological marker (eg, a specific chemokine, cytokine, or growth factor). The capture antibody is preferably labeled with a fluorescent dye so that it can be recognized and quantified. See US Pat. No. 6,268,222 B1 “Luminex Technologies”.

  Reference to “well”, as will be apparent to those skilled in the art, indicates a container for containing a reaction mixture for the assay, and more specifically, a test solution as further described herein. It is intended to indicate a container for containing a control solution, an activation solution, or a non-activation solution.

  “Non-stimulating solution” refers to a reaction mixture to which no factors capable of modulating the immune response have been added.

  “Stimulation solution” refers to a reaction mixture to which a known immune stimulant or immune enhancing factor has been added.

  “Immune enhancement factors” include, among others, LPS, CpG, resquimod (or R848), adjuvants or SMIPs disclosed in any reference cited herein, Poly I: C (dsRNA), Pam3 -Cys, MPL, and stimulatory antibodies, especially anti-CD3.

  Reference to “immunological marker” refers to a substance produced as a result of immunomodulation. Unless otherwise specified, immunological markers can be present as a result of immune enhancement or immunosuppression. Preferred immunological markers include cytokines, chemokines, and growth factors.

  Preferred “cytokines” include IL 1-30 (as described in Table 6), and TNF-α, TNF-β, IFN-α (family), IFN-β, and IFN-γ.

  References to “IL 1 to IL 30”

からなる群より選択されるインターロイキンサイトカインを示す。より好ましいインターロイキンとしては、ＩＬ−１ｂ、ＩＬ−２、ＩＬ−４、ＩＬ−５、ＩＬ−６、ＩＬ−１０、ＩＬ−１２およびＩＬ−１３が挙げられる。ＩＬ １〜３０のそれぞれの受託ＩＤ番号が表６に列挙される。

An interleukin cytokine selected from the group consisting of: More preferred interleukins include IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 and IL-13. The trust ID numbers for each of IL 1-30 are listed in Table 6.

References to “chemokines” include: CXCL1 including CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL13, CXCL14, CXCL1 and CXCL1 CX ₃ C chemokines including CX ₃ CL1; and CCL1, CCL2, CCL3, CCL3L1, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL10, CCL11, CCL12, CCL13, CCL14, CCL16, CCL17, CCL17, CCL17, CCL17 , CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27 CC chemokines including and CCL28 are shown and further explanation is given in Table 5.

  “Growth factors” that can be immunological markers include, among others, GM-CSF, G-CSF, M-CSF, VEGF, EGF, HGF and FGF.

  The term “providing” includes synthesizing and / or purchasing when referring to a compound that is bound to a carrier resin.

  The terms “solid phase”, “resin carrier bead” and “bead” refer to any solid support or substrate on which a chemical synthesis reaction step can be performed, including screening and / or a series of reaction steps. The term thus includes particulate substrates (eg, polystyrene resins traditionally used in standard Fmoc chemical synthesis).

  The term “library” or “combination library” includes, inter alia, a collection of sub-libraries each containing 2 to 500 components or compounds, more preferably about 10 to 100 components or compounds. Such sub-library components or compounds are a variety of synthetic molecules that have been prepared using standard combinatorial chemistry (see, eg, Furka et al., Int. J. Peptide Protein Res. 37: 487-493 ( 1991); and Lam et al., Nature, 354: 82-84 (1991)).

  The term “effective amount” is an amount necessary or sufficient to achieve a desired biological effect. For example, an effective amount of a compound for treating an infectious disorder may be that amount necessary to elicit an antigen-specific immune response upon exposure to an infectious agent. This effective amount may vary depending on, for example, the condition being treated, the weight of the subject, and the severity of the disease. One of ordinary skill in the art can readily determine this effective amount empirically without undue experimentation.

  As used herein, “effective amount for treatment” refers to an amount sufficient to alleviate, ameliorate, stabilize, reverse, slow down, or delay the progression of a condition such as a medical condition.

  A “subject” or “patient” is a human or vertebrate (dog, cat, pocket pet, marmoset, horse, cow, pig, sheep, goat, elephant, giraffe, chicken, lion, monkey, owl, Including rats, squirrels, slender loris, and mice).

  “Poket pet” refers to a group of vertebrates that can fit into a large coat pocket, such as, for example, hamsters, chinchillas, ferrets, rats, guinea pigs, gerbils, rabbits, and owl moths.

  As used herein, the term “pharmaceutically acceptable ester” refers to an ester, including esters that hydrolyze in vivo and readily degrade in the human body leaving the parent compound or salt thereof. Suitable ester groups include, for example, ester groups derived from pharmaceutically acceptable aliphatic carboxylic acids, in particular alkanonic acids, alkenoic acids, cycloalkanonic acids, and alkanedioic acids, each of which alkyl The moiety or alkenyl moiety conveniently has up to 6 carbon atoms. Representative examples of specific esters include, but are not limited to, formic acid esters, acetic acid esters, propionic acid esters, butyric acid esters, acrylic acid esters, and ethyl succinic acid esters.

  The compounds of the present invention may be used in the form of salts, as in “pharmaceutically acceptable salts” derived from inorganic or organic acids. These salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, hydrogen sulfate, butyrate, camphor Acid salt, camphorsulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumaric acid Salt, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate Oxalate, pamoate, pectate, sulfate, 3-phenylpropionate, picrate, pival Salts, propionate, succinate, tartrate, thiocyanate, p- toluenesulfonate, and undecanoate salts. In addition, basic nitrogen-containing groups include lower alkyl halides (eg, methyl chloride, ethyl chloride, propyl chloride, butyl chloride, methyl bromide, ethyl bromide, propyl bromide, butyl bromide, methyl iodide, iodide). Ethyl, propyl iodide, and butyl iodide); dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate), long chain halides (eg, decyl chloride, lauryl chloride, myristyl chloride, stearyl chloride, odor) Decyl iodide, lauryl bromide, myristyl bromide, stearyl bromide, decyl iodide, lauryl iodide, myristyl iodide, stearyl iodide, and the like), aralkyl halides (such as benzyl bromide and phenethyl bromide), etc. Can be quaternized with factors. Water or oil soluble or dispersible products are thereby obtained.

  The term “pharmaceutically acceptable prodrug” as used herein, within the scope of sound medical judgment, humans and lower animals with an excessive toxic response, stimulation response, allergic response, etc. Suitable for use in contact with other tissues, proportional to a reasonable risk-beneficial ratio and effective for the intended use, as well as, where possible, the zwitterionic forms of the compounds of the invention Represents a prodrug. The term “prodrug” refers to a compound that is rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough study Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, A.M. C. S. Symposium Series, Volume 14, and Edward B. Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. By way of example, prodrugs such as those described in US Pat. No. 6,284,772 can be used.

  The term “incubate” refers to maintaining the system under certain conditions to facilitate a particular reaction.

  The term “preparing” with respect to a solution or combination of components includes mixing, adding, or combining the components in any order, and obtaining a solution or compound of the component in its final form.

  The term “SMIP” refers to small molecule immune enhancing compounds, including small molecule compounds of less than about MW 800 g / mol that can stimulate or modulate a pro-inflammatory response in a patient. In one embodiment, SMIP compounds can stimulate human peripheral blood mononuclear cells to produce cytokines, chemokines, and / or growth factors.

  The term “SMIS” refers to small molecule immunosuppressive compounds and includes small molecule compounds of less than about MW 800 g / mol that can suppress or modulate an immune response in a patient. In one embodiment, SMIS compounds may inhibit the ability of human peripheral blood mononuclear cells to produce cytokines, chemokines, and / or growth factors. In another embodiment, the SMIS compound can stimulate TGF-β and thereby suppress the immune response. In some embodiments, the compounds of interest of the present invention are their analogs, or “SMIS analogs”, which are generally known in the art as suppressing the immune system. It is intended to represent a derivative of a compound. Preferred embodiments include the compounds and their analogs described in the following U.S. Patents, U.S. Patent Application Publications, and PCT Publications, which are fully presented herein. , Incorporated by reference:

加えて、ＳＭＩＳアナログは、コルチゾール、シクロフォスファミド、６−メルカプトプリン、メトトレキサートおよびそのポリグルタミン酸誘導体、アザチオプリン代謝産物、ミゾリビン、シクロスポリンＡ、ＦＫ−５０６（タクロリムス）、ラパマイシン、レフルノマイド（ｌｅｆｌｕｎｏｍｉｄｅ）およびそれらの代謝産物、ブリクイナー（ｂｒｅｑｕｉｎａｒ）、タクロリムス、ミコフェノール酸モフェチル、ならびにミコフェノール酸からなる群より選択される小分子が挙げられる。さらに、免疫増強能力を有するアナログが存在する好ましい「ＳＭＩＳ」化合物としては、表４中に列挙される実施例が挙げられる。

In addition, SMIS analogs include cortisol, cyclophosphamide, 6-mercaptopurine, methotrexate and its polyglutamic acid derivatives, azathioprine metabolites, mizoribine, cyclosporin A, FK-506 (tacrolimus), rapamycin, leflunomide and them A small molecule selected from the group consisting of the metabolite of, quinquina, tacrolimus, mycophenolate mofetil, and mycophenolic acid. Furthermore, preferred “SMIS” compounds in which analogs with immunopotentiating capabilities are present include the examples listed in Table 4.

  Analogs of SMIS compounds are limited to those that include substitution modifications and additions to the core scaffold. The core backbone of SMIS can be functionally identified by those skilled in the art as the smallest unit responsible for activity. Structurally, the core backbone of SMIS can be identified as a conserved region between several similar compounds (from the same source), mainly between the compounds listed in close proximity. For example, it will be apparent to those skilled in the art that the core backbone for Examples 86-91 (source: Aventis) is a substituted benzamide. Similarly, the core skeleton of Examples 111-115 is identified by a macrocyclic cyclosporine-like structural motif. In the absence of a variety of compounds to guide elucidation and a single species is present (eg, Example 167), the core skeleton is an aromatic or non-aromatic heterocyclic group, aromatic or non-aromatic Central region comprising a non-aromatic polycyclic group, or an aromatic or non-aromatic heteroalkyl group (eg, isobenzofuran-1 (3H) -one for Example 167) or an ionic complex (eg, ruthenium) It is limited to. Preferred skeletons include steroids, terpenes, macrocycles, ruthenium complexes, cannabinoids, aminoazavinyl compounds, benzazole compounds, acylpiperazine compounds, indoledione compounds, tetrahydroisoquinoline (THIQ) compounds, anthraquinone compounds, indandione compounds, phthalimide compounds. , Benzocyclodione compound, aminobenzimidazole quinolinone (ABIQ) compound, hydraphthalimide compound, pyrazolopyrimidine compound, quinazilinone compound, quinoxaline compound, triazine compound, tetrahydropyrrolidinoquinoxaline compound, pyrrole compound, benzophenone compound, sterol Compounds, and isoxazole compounds. Suitable substituents for modification and / or addition to the core skeleton include, for example, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted Substituted amino group, substituted or unsubstituted alkylamino group, substituted or unsubstituted dialkylamino group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heteroaralkyl group, Substituted or unsubstituted heterocyclyl group, substituted or unsubstituted heterocyclylalkyl group, substituted or unsubstituted carbonyl group, substituted or unsubstituted carbonyloxy group, substituted or unsubstituted sulfonyl group, substituted or unsubstituted carbonylamino group, substituted or unsubstituted Aminocarbonyl group, substituted or unsubstituted guanidinyl groups, or include substituted or unsubstituted alkoxycarbonyl group.

  The term “steroid SMIP” has 17 carbon atoms arranged in four rings as the main component, sterols and bile acids, adrenal hormones and sex hormones, certain herbal medicines (eg, digitalis compounds), and certain Represents a synthetic fat-soluble organic SMIP containing a precursor of vitamins and derivatives thereof. Preferred steroid skeletons for derivatization include pregnane, estrane, cholestane, gonane, and androstane, among others.

  The term “macrocyclic SMIP” is any non-aromatic SMIP or only partially aromatic in which at least 12 adjacent atoms selected from carbon, N, O or S are joined together in a cyclic moiety. It represents a certain SMIP. Preferred macrocycles include cyclosporine, sirolimus, tacrolimus, and derivatives thereof.

  The term “terpene SMIP” refers to SMIP comprising at least one terpene moiety.

The term “ruthenium complex SMIP” refers to SMIP having a large number of organic compounds forming an ion-bonded complex centered on a central ruthenium atom. A preferred organic compound that forms a complex with a ruthenium atom is a nitrogen-containing heteroaryl ( _{NH aryl} ). Preferable _{NH aryl} compounds include, for example, acridine, carbazole, β-carboline, cinnoline, imidazole, indazole, indole, indolizine, isoindole, isoquinoline, isothiazole, oxazole, isoxazole, naphthyridine, perimidine. , Phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, and thiazole It is done.

  Reference to “epoxide” is intended to indicate a cyclic organic compound consisting of an oxygen atom bonded to two other atoms, preferably carbon, which are bonded together.

  For example

の場合のように共有結合を交差する

Crossing covalent bonds as in

の記号の使用は、置換基の結合点を示すことが意図される。同様に、例えば^＊−アルケニル−ＣＯＯＨの場合のようにアステリスクの使用もまた、置換基の結合点を示している。

The use of the symbol is intended to indicate the point of attachment of the substituent. Similarly, the use of an asterisk, such as in the case of ^* -alkenyl-COOH, also indicates the point of attachment of the substituent.

When multiple groups combine to form a substituent (eg, dialkylaminocarbonyl), the point of attachment is the group indicated at the end of the phrase (eg, carbonyl in the examples above). Not all of the substituents (eg, arylsulfonylalkyloxycarbonylamino) having multiple group combinations described in the examples are explicitly defined below, but their individual components are defined; these ranges are in the described example ^{(e.g., * -NH-C (O)} -O- alkyl -SO ₂ - aryl) as the sum of their individual components, will be apparent to those skilled in the art.

  The phrase “alkyl” refers to an alkyl group that does not contain a heteroatom. Thus, this phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. This phrase is also given by way of example, but not limited to:

などを含む直鎖アルキル基の分枝鎖異性体を含む。したがって、語句非置換アルキル基は、第一級アルキル基、第二級アルキル基、および第三級アルキル基を含む。非置換アルキル基は、親化合物中で、１つ以上の炭素原子、酸素原子、窒素原子、および／または硫黄原子と結合し得る。好ましい非置換アルキル基としては、１〜２０個の炭素原子を有する直鎖および分枝鎖のアルキル基および環状アルキル基が挙げられる。より好ましいそのような非置換アルキル基は、１〜１０個の炭素原子を有し、さらにより好ましいそのような基は、１〜５個の炭素原子を有する。最も好ましい非置換アルキル基としては、１〜３個の炭素原子を有する直鎖および分枝鎖アルキル基が挙げられ、メチル、エチル、プロピル、および−ＣＨ（ＣＨ_３）_２が含まれる。

Branched chain isomers of straight chain alkyl groups including Thus, the phrase unsubstituted alkyl group includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. An unsubstituted alkyl group can be bonded to one or more carbon, oxygen, nitrogen, and / or sulfur atoms in a parent compound. Preferred unsubstituted alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 20 carbon atoms. More preferred such unsubstituted alkyl groups have 1 to 10 carbon atoms, and even more preferred such groups have 1 to 5 carbon atoms. Most preferred unsubstituted alkyl groups include straight and branched chain alkyl groups having 1 to 3 carbon atoms, including methyl, ethyl, propyl, and —CH (CH ₃ ) ₂ .

  The phrase “substituted alkyl” includes, but is not limited to, one or more bonds to carbon or hydrogen, for example, a halogen atom in a halide (eg, F, Cl, Br, and I); Atoms (eg, phosphates, and dialkyl alkylphosphonates); oxygen atoms in groups (eg, hydroxyl groups, alkoxy groups, aryloxy groups and ester groups); sulfur atoms in groups (eg, thiol groups, alkyls and Aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups); nitrogen atoms in groups (eg, amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and Enamine); silicon atoms in the group (eg trialkylsilyl groups, di In arylalkylsilyl, alkyldiarylsilyl, and triarylsilyl groups); and substituted by bonds with non-hydrogen and non-carbon atoms, such as other heteroatoms in various other groups, above Represents an unsubstituted alkyl group as defined. Substituted alkyl groups also have one or more bonds with carbon or hydrogen atoms, for example, oxygen in carbonyl, carboxyl and ester groups; in groups such as imine, oxime, hydrazone and nitrile groups. A group substituted by a bond with a heteroatom such as nitrogen. Preferred substituted alkyl groups include, in particular, alkyl groups in which one or more bonds with a carbon atom or hydrogen atom are replaced by a bond with one or more fluorine atoms. An example of a substituted alkyl group is a trifluoromethyl group and other alkyl groups including a trifluoromethyl group. Another example is a carbonylalkyl, or -alkyl-COOH group. Other alkyl groups have one or more bonds with a carbon atom or hydrogen atom replaced by a bond with an oxygen atom such that the substituted alkyl group includes a hydroxyl group, an alkoxy group, an aryloxy group, or a heterocyclyloxy group Containing alkyl groups. Still other alkyl groups are amine, alkylamine, dialkylamine, arylamine, (alkyl) (aryl) amine, diarylamine, heterocyclylamine, (alkyl) (heterocyclyl) amine, (aryl) (heterocyclyl) amine, or di- Including an alkyl group having a heterocyclylamine group.

  The term “halogen” represents iodine, bromine, chlorine, or fluorine; “halo” as used herein represents iodo, bromo, chloro, or fluoro.

  The term “haloalkyl” as used herein refers to an alkyl radical having at least one halogen substituent, such as chloromethyl, fluoroethyl, or trifluoromethyl, as defined above. To express.

The term “amino” represents —NH ₂ when located terminally and —NH— when two groups are attached.

The term “nitro” refers to a —NO ₂ substituent.

  The term “cyano” refers to —CN.

  The term “carboxylic acid” refers to —COOH.

  The term “alkoxy” as used herein represents RO—, where R is, for example, alkyl as defined above. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy and the like.

The term “substituted alkoxy”, as used herein, represents RO—, where R is, for example, alkyl substituted with, for example, halogen. RO is, for example, OCF ₃ or is further substituted with an aryl such as (2-chlorophenyl) methoxy.

The term “alkoxyalkyl” as used herein refers to (alkyl) -O— (
Alkyl), wherein each alkyl group may be further substituted as defined below for an optionally substituted group.

  References to “malonate” include:

で示すように、置換アルコキシを示すことが意図される。

It is intended to indicate substituted alkoxy as shown in

  The term “alkenyl” as used herein is a branched or straight chain group containing from 2 to 20 carbon atoms and containing one or more carbon-carbon double bonds. Represents. Representative alkenyl groups include prenyl, 2-propenyl (ie allyl), 3-methyl-2-butenyl, 3,7-dimethyl-2,6-octadienyl, 4,8-dimethyl-3,7-nonadienyl. 3,7,11-trimethyl-2,6,10-dodecatrienyl and the like.

The term “substituted alkenyl” as used herein is substituted with an alkyl or substituted alkyl group (eg, dialkyl phosphoric acid), or an ester (eg, acetate), eg, ^* -alkenyl- Represents an alkenyl group that is carbonyl-oxy-( ^* -alkenyl-C (O) -O-), diethyl-hex-5-enylphosphonate or the like.

  The term “alkynyl” as used herein refers to a branched or straight chain group containing 2 to 20 carbon atoms and containing one or more carbon-carbon triple bonds. To express. Exemplary alkynyl groups include propargyl and butynyl.

  The term “substituted alkynyl” as used herein is substituted with an alkyl or substituted alkyl group (eg, dialkyl phosphate), or an ester (eg, acetate), eg, propargylamine, and the like. Represents a certain alkynyl group.

  The term “alkylamino” as used herein refers to an amino group substituted with one alkyl group (eg, a C1-20 alkyl group).

  The term “substituted alkylamino” as used herein refers to alkylamino substituted with, for example, carboxylic acid, ester, hydroxy, or alkoxy.

  The term “dialkylamino” as used herein refers to an amino group substituted with two alkyl groups (eg, a C1-20 alkyl group).

  The term “substituted dialkylamino” as used herein refers to a dialkylamino substituted with, for example, a carboxylic acid, ester, hydroxy, or alkoxy.

  The term “aminoalkyl” refers to an alkyl group substituted with an amino group.

The term “alkylaminoalkyl” refers to an alkyl group substituted with an aminoalkyl group (eg, ^* —CH ₂ NHCH (CH ₃ ) ₂ ).

The term “hydroxyalkylthio” as used herein refers to a thio radical to which a hydroxyalkyl group is attached, where the alkyl is, for example, ethyl. Examples are hydroxyethylthio, —SCH ₂ CH ₂ OH.

The term “N-alkylsulfonamido” as used herein represents a group —SO ₂ NHalkyl wherein alkyl is, for example, octyl.

“Aminosulfonyl” refers herein to the group —S (O) ₂ —NH ₂ . “Substituted aminosulfonyl” refers herein to the group —S (O) ₂ —NRR ′, where R is alkyl and R ′ is hydrogen or alkyl. The term “alkylaminosulfonyl” refers herein to the group —S (O) ₂ —NH-alkyl. The term “aralkylaminosulfonylaryl” refers herein to the group -aryl-S (O) ₂ —NH-aralkyl.

  “Carbonyl” represents the divalent group —C (O) —.

  “Carbonyloxy” generally represents the group —C (O) —O—. Such groups include esters, —C (O) —O—R, where R is alkyl, cycloalkyl, aryl, or aralkyl. The term “carbonyloxycycloalkyl” as used herein generally represents both “carbonyloxycarbocycloalkyl” and “carbonyloxyheterocycloalkyl”, ie where R is carbocycloalkyl or Heterocycloalkyl. The term “arylcarbonyloxy” refers herein to the group —C (O) —O-aryl, where aryl is monocyclic or polycyclic carbocycloaryl or heterocycloaryl. The term “aralkylcarbonyloxy” refers herein to the group —C (O) —O-aralkyl, where aralkyl is aralkyl.

The term “sulfonyl” refers herein to the group —S (O) ₂ —, where the unsubstituted sulfonyl group is —SO ₂ H. “Alkylsulfonyl” refers to a substituted sulfonyl of the structure ^* —SO ₂ R—, wherein R is alkyl. The alkylsulfonyl group used in the compounds of the present invention is typically an alkylsulfonyl group having 1 to 6 carbon atoms in its backbone structure. Thus, typical alkylsulfonyl groups used in the compounds of the invention include, for example, methylsulfonyl (ie, where R is methyl), ethylsulfonyl (ie, where R is ethyl), propylsulfonyl (ie, Where R is propyl). The term “arylsulfonyl” refers herein to the group —SO ₂ -aryl, and “heteroarylsulfonyl” refers to the group —SO ₂ -heteroaryl herein. The term “aralkylsulfonyl” refers herein to the group —SO ₂ -aralkyl, or, specifically, ^* —SO ₂ -alkyl-aryl. “Heteroaralkylsulfonyl” represents the same as aralkylsulfonyl, except having a heteroaryl substituent in place of aryl.
As used herein, the term “carbonylamino” refers to the divalent group —NH—C (O) —, wherein the hydrogen atom of the amide nitrogen of the carbonylamino group is an alkyl group, an aryl group, Or it can substitute for an aralkyl group. Such groups include carbamic acid esters ( ^* -NH-C (O) -O-R), amides ^* -NH-C (O) -O-R, etc., where R is Examples include a chain or branched alkyl, cycloalkyl, or a moiety that is aryl or aralkyl. The term “alkylcarbonylamino” refers to alkylcarbonylamino where R is an alkyl having from 1 to about 6 carbon atoms in its backbone structure. The term “arylcarbonylamino” refers to the group —NH—C (O) —R, where R is aryl. Similarly, the term “aralkylcarbonylamino” refers to carbonylamino where R is aralkyl.
As used herein, the term “guanidino” or “guanidyl” refers to a moiety derived from guanidine, H ₂ N—C (═NH) —NH ₂ . Such a moiety includes a moiety bound by a nitrogen atom having a formal double bond (the “2” position of guanidine, eg, diaminomethyleneamino, (H ₂ N) ₂ C═NH— ^* ), And a moiety bonded to any one of the nitrogen atoms having a formal single bond (the “1” position and / or “3” position of guanidine, eg, H ₂ N—C (═NH) —NH—) Is mentioned. The hydrogen atom at any nitrogen can be substituted with a suitable substituent (eg, alkyl, aryl, or aralkyl).
The term “arylthiourea” refers to an aryl-NC (S) N— ^* group where nitrogen is the point of attachment. Preferred examples of substituted aryl-NC (S) N-alkylamino groups are:

である。

It is.

  Representative substituted alkylcarbonylamino groups, alkyloxycarbonylamino groups, aminoalkyloxycarbonylamino groups, and arylcarbonylamino groups include, for example, the groups shown below. These groups can be further substituted as will be apparent to those skilled in the art of organic and medicinal chemistry in connection with the disclosure herein.

代表的な置換アミノカルボニル基としては、例えば、以下に示す基が挙げられる。これらのヘテロシクロ基は、本明細書中の開示と関連して有機および薬化学の技術分野の当業者には明らかであるように、さらに置換され得る。

Typical examples of the substituted aminocarbonyl group include the following groups. These heterocyclo groups can be further substituted as will be apparent to those skilled in the art of organic and medicinal chemistry in connection with the disclosure herein.

好ましい置換アミノカルボニルアミノ基（または尿素）としては、アニソール基で置換される：

Preferred substituted aminocarbonylamino groups (or ureas) are substituted with anisole groups:

が挙げられる。

Is mentioned.

  Representative substituted alkoxycarbonyl groups include, for example, the groups shown below. These alkoxycarbonyl groups can be further substituted as will be apparent to those skilled in the art of organic and medicinal chemistry in connection with the disclosure herein.

語句「カルボシクリル」は、環状アルキル基（例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロへプチル、およびシクロオクチル）、ならびに上記に定義されるような直鎖および分枝鎖のアルキル基で置換された環を含む。この語句はまた、多環式アルキル基（これらに限定されないが、例えば、アダマンチル、ノルボルニル、およびビシクロ［２．２．２］オクチル）、および本明細書中で規定されるような必要に応じて置換される環も含む。

The phrase “carbocyclyl” is substituted with a cyclic alkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl), and straight and branched chain alkyl groups as defined above. Including ring. The phrase also includes polycyclic alkyl groups such as, but not limited to, adamantyl, norbornyl, and bicyclo [2.2.2] octyl, and as required herein. Includes substituted rings.

  The phrase “aryl” refers to an aryl group that does not contain heteroatoms. The term thus includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl, by way of example. As used herein, an aryl group such as tolyl is considered to be a substituted aryl group as described below, so the phrase “unsubstituted aryl” includes groups that contain fused rings (eg, naphthalene). Does not include aryl groups that link other groups (eg, alkyl or halo groups) to one of the ring members. A preferred unsubstituted aryl group is phenyl. However, an unsubstituted aryl group can be attached to one or more carbon, oxygen, nitrogen, and / or sulfur atoms in the parent compound.

  The phrase “substituted aryl group” has the same meaning with respect to aryl groups that the substituted alkyl group had with respect to alkyl groups. However, a substituted aryl group also includes an aryl group in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above, and one or more aromatics of the aryl group. A group carbon includes an aryl group bonded to a substituted and / or unsubstituted alkyl group, a substituted and / or unsubstituted alkenyl group, or a substituted and / or unsubstituted alkynyl group as defined herein . This is a bonding arrangement in which two carbon atoms of an aryl group are bonded to two atoms of an alkyl, alkenyl, or alkynyl group to define a fused ring system (eg, dihydronaphthyl or tetrahydronaphthyl). )including. Thus, the phrase “substituted aryl” includes, but is not limited to, tolyl, and hydroxyphenyl in particular.

Fused arylaryl groups and non-fused arylaryl groups are included within the definition of aryl groups. The term “non-fused arylaryl” refers to a group or substituent to which two aryl groups that are not fused to each other are attached. Exemplary non-fused arylaryl compounds include, for example, phenylbenzene, diphenyldiazene, 4-methylthio-1-phenylbenzene, phenoxybenzene, (2-phenylethynyl) benzene, diphenylketone, (4-phenylbuta-1 , 3-diynyl) benzene, phenylbenzylamine, (phenylmethoxy) benzene and the like. Preferred substituted non-fused arylaryl groups include: 2- (phenylamino) -N- [4- (2-phenylethynyl) phenyl] acetamide, 1,4-diphenylbenzene, N- [4- (2-phenylethynyl) ) Phenyl] -2- [benzylamino] acetamide, 2-amino-N- [4- (2-phenylethynyl) phenyl] propanamide, 2-amino-N- [4- (2-phenylethynyl) phenyl] acetamide 2- (cyclopropylamino) -N- [4- (2-phenylethynyl) phenyl] acetamide, 2- (ethylamino) -N- [4- (2-phenylethynyl) phenyl] acetamide, 2-[( 2-Methylpropyl) amino] -N- [4- (2-phenylethynyl) phenyl] acetamide, 5-phenyl-2H- Nzo [d] 1,3-dioxolene, 2-chloro-1-methoxy-4-phenylbenzene, 2-[(imidazolylmethyl) amino] -N- [4- (2-phenylethynyl) phenyl] acetamide, 4 -Phenyl-1-phenoxybenzene, N- (2-aminoethyl) [4- (2-phenylethynyl) phenyl] carboxamide, 2-{[(4-fluorophenyl) methyl] amino} -N- [4- ( 2-phenylethynyl) phenyl] acetamide, 2-{[(4-methylphenyl) methyl] amino} -N- [4- (2-phenylethynyl) phenyl] acetamide, 4-phenyl-1- (trifluoromethyl) Benzene, 1-butyl-4-phenylbenzene, 2- (cyclohexylamino) -N- [4- (2-phenylethynyl) phenyl Acetamide, 2- (ethylmethylamino) -N- [4- (2-phenylethynyl) phenyl] acetamide, 2- (butylamino) -N- [4- (2-phenylethynyl) phenyl] acetamide, N- [ 4- (2-phenylethynyl) phenyl] -2- (4-pyridylamino) acetamide, N- [4- (2-phenylethynyl) phenyl] -2- (quinuclidin-3-ylamino) acetamide, N- [4- (2-phenylethynyl) phenyl] pyrrolidin-2-ylcarboxamide, 2-amino-3-methyl-N- [4- (2-phenylethynyl) phenyl] butanamide, 4- (4-phenylbuta-1,3- Diynyl) phenylamine, 2- (dimethylamino) -N- [4- (4-phenylbuta-1,3-diynyl) phenyl] a Cetamide, 2- (ethylamino) -N- [4- (4-phenylbuta-1,3-diynyl) phenyl] acetamide, 4-ethyl-1-phenylbenzene, 1- [4- (2-phenylethynyl) Phenyl] ethane-1-one, N- (1-carbamoyl-2-hydroxypropyl) [4- (4-phenylbuta-1,3-diynyl) phenyl] carboxamide, N- [4- (2-phenylethynyl) Phenyl] propanamide, 4-methoxyphenyl phenyl ketone, phenyl-N-benzamide, (tert-butoxy) -N- [4-phenylphenyl) methyl] carboxamide, 2- (3-phenylphenoxy) ethanehydroxamic acid, 3- Phenylphenylpropanoate, 1- (4-ethoxyphenyl) -4-methoxybenzene, and 4- (2-phenylethynyl) phenyl] pyrrole and the like. The term “fused arylaryl” as used herein represents an aryl group as defined above which is fused and fully conjugated to one aryl group. Representative fused arylaryl groups include biphenyl, 4- (1-naphthyl) phenyl, 4- (2-naphthyl) phenyl, and the like.

  The term “aralkyl”, as used herein, represents an alkyl radical to which one aryl group is added. Representative aralkyl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl and the like.

  The term “heteroaralkyl”, as used herein, represents an alkyl radical to which one heteroaryl group is added. Representative heteroaralkyl groups include methylpyridine, 4-sec-butylpyrimidine and the like.

  The term “heterocyclylalkyl” as used herein refers to an alkyl radical to which one heterocyclyl group is added. Representative heterocyclylalkyl groups include methylpiperidine, epichlorohydrin, sec-butylpiperidine and the like.

  The term “carbocyclylalkyl” as used herein refers to an alkyl radical to which one carbocyclyl group is added. Representative carbocyclylalkyl groups include isopropylcyclohexane, 1-ethyl-2-fluorocyclopentane, and the like.

  The term “arylalkenyl”, as used herein, represents an alkenyl radical to which one aryl group is added. Representative arylalkenyl groups include styrene, 1-((Z) -prop-1-enyl) benzene, and the like.

  The term “heteroarylalkenyl” as used herein refers to an alkenyl radical to which one heteroaryl group is added. Representative heteroarylalkenyl groups include 4-vinylpyrimidine, 4-((Z) -prop-1-enyl) pyridine, and the like.

  The term “heterocyclylalkenyl”, as used herein, represents an alkenyl radical to which one heterocyclyl group is added. Representative heterocyclylalkenyl groups include vinylpiperidine, 4-((E) -prop-1-enyl) piperidine and the like.

  The term “carbocyclylalkenyl” as used herein refers to an alkenyl radical to which one carbocyclyl group is added. Representative carbocyclylalkenyl groups include vinylcyclohexane, (prop-1-en-2-yl) cyclohexane, and the like.

  The term “aryloxy” as used herein represents RO— wherein R is an aryl group. Representative aryloxy groups include benzyloxy, biphenyloxy and the like.

  The term “heteroaryloxy”, as used herein, represents RO—, where R is a heteroaryl group.

  The term “arylalkoxy”, as used herein, represents an alkoxy radical to which one aryl group is added. Representative arylalkoxy groups include benzylmethoxy, phenylethoxy and the like.

  As used herein, typical heterocyclyl groups or heterocyclo groups include, for example, the groups listed below (the point of attachment of this substituent and other substituents shown below): Is via the upper left bond). These heterocyclyl groups can be further substituted and can be attached at various positions as will be apparent to those skilled in the art of organic and medicinal chemistry in connection with the disclosure herein. Examples of these heterocyclyl groups include pyrrolidine, piperidine, methylpyrrolidine, pyrrolidin-3-ylamine, dimethylpyrrolidin-3-ylamine, 2-aminoquinuclidine, pyrrolidin-2-one, tetrahydrofuranyl, pyrrolidin-3-ol. 4-piperidylpiperidine, 1-benzyl-4-piperidylamine, homopiperidine, homopiperidine, homomorpholine, methylpyrrolidine,

が挙げられる。

Is mentioned.

  Representative heteroaryl groups include, for example, acridine, carbazole, β-carboline, cinnoline, furan, imidazole, indazole, indole, indolizine, isoindole, isoquinoline, isothiazole, isoxazole, isoxazole, naphthyridine, perimidine, phenanthate Lysine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolidine, quinoxaline, thiazole, 4H-pyran-4-one, and the groups shown below Can be mentioned. These heteroaryl groups can be further substituted and can be attached at various positions, as will be apparent to those skilled in the art of organic and medicinal chemistry in connection with the disclosure herein.

縮合および非縮合のアリールヘテロアリール基、ヘテロアリールアリール基、およびヘテロアリールヘテロアリール基は、ヘテロアリール基の定義内に含まれる。用語「非縮合ヘテロアリールアリール」は、アリール基のうちの１つがヘテロアリール基である非縮合アリールアリール基を表す。例示的なヘテロアリールアリール基としては、例えば、２−フェニルピリジン、フェニルピロール、３−（２−フェニルエチニル）ピリジン、フェニルピラゾール、５−（２−フェニルエチニル）−１，３−ジヒドロピリミジン−２，４−ジオン、４−フェニル−１，２，３−チアジアゾール、２−（２−フェニルエチニル）ピラジン、２−フェニルチオフェン、フェニルイミダゾール、３−（２−ピペラジニルフェニル）フラン、３−（２，４−ジクロロフェニル）−４−メチルピロールなどが挙げられる。好ましい置換の非縮合ヘテロアリールアリール基としては：５−（２−フェニルエチニル）ピリミジン−２−イルアミン、１−メトキシ−４−（２−チエニル）ベンゼン、１−メトキシ−３−（２−チエニル）ベンゼン、５−メチル−２−フェニルピリジン、５−メチル−３−フェニルイソキサゾール、２−［３−（トリフルオロメチル）フェニル］フラン、３−フルオロ−５−（２−フリル）−２−メトキシ−１−プロプ−２−エニルベンゼン、（ヒドロキシイミノ）（５−フェニル（２−チエニル））メタン、５−［（４−メチルピペラジニル）メチル］−２−フェニルチオフェン、２−（４−エチルフェニル）チオフェン、４−メチルチオ−１−（２−チエニル）ベンゼン、２−（３−ニトロフェニル）チオフェン、（ｔｅｒｔ−ブトキシ）−Ｎ−［（５−フェニル（３−ピリジル））メチル］カルボキサミド、ヒドロキシ−Ｎ−［（５−フェニル（３−ピリジル））メチル］アミド、２−（フェニルメチルチオ）ピリジン、およびベンジルイミダゾールが含まれる。

Fused and non-fused arylheteroaryl, heteroarylaryl, and heteroarylheteroaryl groups are included within the definition of heteroaryl groups. The term “non-fused heteroarylaryl” refers to a non-fused arylaryl group in which one of the aryl groups is a heteroaryl group. Exemplary heteroarylaryl groups include, for example, 2-phenylpyridine, phenylpyrrole, 3- (2-phenylethynyl) pyridine, phenylpyrazole, 5- (2-phenylethynyl) -1,3-dihydropyrimidine-2 , 4-dione, 4-phenyl-1,2,3-thiadiazole, 2- (2-phenylethynyl) pyrazine, 2-phenylthiophene, phenylimidazole, 3- (2-piperazinylphenyl) furan, 3- ( 2,4-dichlorophenyl) -4-methylpyrrole and the like. Preferred substituted non-fused heteroarylaryl groups include: 5- (2-phenylethynyl) pyrimidin-2-ylamine, 1-methoxy-4- (2-thienyl) benzene, 1-methoxy-3- (2-thienyl) Benzene, 5-methyl-2-phenylpyridine, 5-methyl-3-phenylisoxazole, 2- [3- (trifluoromethyl) phenyl] furan, 3-fluoro-5- (2-furyl) -2- Methoxy-1-prop-2-enylbenzene, (hydroxyimino) (5-phenyl (2-thienyl)) methane, 5-[(4-methylpiperazinyl) methyl] -2-phenylthiophene, 2- (4 -Ethylphenyl) thiophene, 4-methylthio-1- (2-thienyl) benzene, 2- (3-nitrophenyl) thiophene, (tert-buto C) -N-[(5-phenyl (3-pyridyl)) methyl] carboxamide, hydroxy-N-[(5-phenyl (3-pyridyl)) methyl] amide, 2- (phenylmethylthio) pyridine, and benzylimidazole Is included.

  The term “non-fused heteroarylheteroaryl” refers to a non-fused arylaryl group in which both aryl groups are heteroaryl groups. Illustrative heteroarylheteroaryl groups include, for example, 3-pyridylimidazole, 2-imidazolylpyrazine, and the like. Preferred substituted non-fused heteroarylheteroaryl groups include: 2- (4-piperazinyl-3-pyridyl) furan, diethyl (3-pyrazin-2-yl (4-piperazinyl-3-pyridyl) furan, diethyl (3- Examples include pyrazin-2-yl (4-pyridyl) amine and dimethyl {2- [2- (5-methylpyrazin-2-yl) ethynyl] (4-pyridyl)} amine.

  The term “fused heteroarylaryl”, as used herein, represents an aryl group as defined above that is fused and fully conjugated to one heteroaryl group. Representative fused heteroarylaryl groups include quinoline, quinazoline and the like.

  The term “fused heteroarylheteroaryl” as used herein refers to a heteroaryl group as defined above which is fused and fully conjugated to another heteroaryl group. Representative fused heteroarylheteroaryl groups include pyrazalopyrimidine, imidazoquinoline, and the like.

  The term “imine heterocyclyl” refers to a moiety having an imine substituent attached distally to a heterocyclyl group (relative to its point of attachment). An example of an imine heterocyclyl is N- (piperazin-1-yl) ethanimine.

  The term “fused polycycle” refers to a polycyclic group having at least three linked rings. Typical fused polycyclic groups include anthrazine, phenanthroline, perimidine, tritanthrin and the like.

“Substitution” represents a limited substitution of hydrogen with one or more monovalent or divalent radicals. Suitable substituents include those described herein for a particular group, and hydroxyl, nitro, amino, imino, cyano, halo, thio, thioamide, amidino, imidino, oxo, oxamidino, Methoxamidino, imidino, guanidino, sulfonamide, carboxyl, formyl, alkyl, substituted alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl , Alkylthio, aminoalkyl, cyanoalkyl, benzyl, pyridyl, pyrazolyl, pyrrole, thiophene, imidazolyl and the like. “Unsubstituted” refers to groups as defined without further substitution except for the appropriate number of H substituents, as will be apparent to those skilled in the art. For example, sulfonyl represents —SO ₂ — and represents unsubstituted sulfonyl-SO ₂ H.
The number of the carbon atom on the cyclic structure and the symbol on the lower right of the R group are for preventing degeneracy in the classification of the R group. It is not intended to represent anything other than a particular position with respect to a group. For example, “Rb in position 2 is ethyl”:

であることを意味する。

It means that.

The present invention also provides for the SMIP disclosed above, apart from the fact that one or more atoms are replaced by an atom having an atomic mass number or mass number different from the atomic mass number or mass number normally found in nature. It includes SMIP compounds labeled with isotopes that are structurally identical to the compounds. Examples of isotopes that may be incorporated into the compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes (eg, ² H, ³ H, ¹³ C, ¹⁴ C, respectively, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl). Within the scope of the invention are compounds of the invention, their prodrugs, and pharmaceutically acceptable salts of the prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms. is there. Certain isotopically-labeled compounds of the present invention, for example, compounds of the present invention that incorporate radioactive isotopes (eg, ³ H and ¹⁴ C), are useful in drug and / or substrate tissue distribution assays. Tritium isotopes (ie, ³ H) and carbon-14 isotopes (ie, ¹⁴ C) are particularly preferred because of their ease of preparation and high detectability. In addition, substitution with heavier isotopes such as deuterium (ie, ² H) provides certain therapeutic benefits (eg, increased in vivo half-life, or reduced dosage) due to increased metabolic stability. Can be provided and therefore may be preferred in certain situations. Isotopically-labeled compounds of the present invention and their prodrugs are generally prepared by performing known or referenced procedures and isotopically labeled reagents that are readily available. Can be prepared by replacing with a reagent not labeled with.

  Various compounds and their methods of synthesis are described in the following US patents, US patent application publications, and PCT publications:

第９０１４８２６号、第９１１７７５４号、第９１１９４９５号、第９３０８８０２号、および第９３１４７７１号で開示されており、本発明の文脈において免疫増強に有用であることが見出されている。これらの米国および国際公開の開示全体が、本明細書中で参考として援用される。本発明の関心の他の化合物または中間体は、次の方法を使用して、交易上利用可能な供給源から購入した：関心の化学構造を、ＡＣＤ−ＳＣデータベース（ＭＤＬ Ｉｎｆｏｒｍａｔｉｏｎ Ｓｙｓｔｅｍｓ製）に描いた。特に次の企業／機関：

9014826, 9117754, 9119495, 9308802, and 9314771, which have been found to be useful for immune enhancement in the context of the present invention. The entire disclosures of these US and international publications are incorporated herein by reference. Other compounds or intermediates of interest of the present invention were purchased from a commercially available source using the following method: The chemical structure of interest is depicted in the ACD-SC database (MDL Information Systems). It was. In particular, the following companies / institutions:

の検索により、同定された化合物の供給源および購買情報を引き出した。

The source of the identified compound and purchase information was retrieved by searching for.

  The compositions of the invention can be administered with one or more antigens for use in the therapeutic, prophylactic, or diagnostic methods of the invention. Preferred antigens include those listed below. In addition, the compositions of the invention can be used to treat or prevent infections caused by any of the microorganisms listed below.

  In addition to the combinations with antigens described below, the compositions of the invention can also be combined with the adjuvants described herein. Antigens for use with the present invention include, but are not limited to, one or more of the antigens subsequently presented below or from one or more pathogens presented below.

(A. Bacterial antigen)
Bacterial antigens suitable for use in the present invention include proteins, polysaccharides, lipopolysaccharides, and outer membrane vesicles that can be isolated, purified, or obtained from bacteria. In addition, bacterial antigens can include bacterial lysates and inactivated bacterial formulations. Bacterial antigens can be produced by recombinant expression. The bacterial antigen preferably comprises an epitope that is exposed on the surface of the bacterium during at least one stage of its life cycle. Bacterial antigens are preferably conserved across multiple serotypes. Bacterial antigens include antigens derived from one or more of the bacteria shown below and examples of specific antigens identified below.

  Neisseria meningitides: Meningitis antigens are serogroups A, C, W135, Y, and / or B. Proteins purified or obtained from meningitidis (eg, proteins identified in references 1-7), saccharides (including polysaccharides, oligosaccharides or lipopolysaccharides), or outer membrane vesicles (references) 8, 9, 10, 11). The meningitis protein antigen may be selected from adhesions, autotransporters, toxins, Fe capture proteins, and membrane associated proteins, preferably complete outer membrane proteins.

  Streptococcus pneumoniae: A Streptococcus pneumoniae antigen can include sugars (including polysaccharides or oligosaccharides) or proteins from Streptococcus pneumoniae. Saccharide antigens are serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, And 33F. The protein antigen is selected from the proteins identified in WO 98/18931, WO 98/18930, US Pat. Nos. 6,699,703, 6,800,744, WO 97/43303, and WO 97/37026 Can be done. Streptococcus pneumoniae protein is a polyhistidine triad family (PhtX), a choline binding protein family (CbpX), a CbpX abbreviation, a LytX family, a LytX abbreviation, a CbpX abbreviation-Lytmori synthase chimeric protein, Ply), PspA, PsaA, Sp128, Sp101, Sp130, Sp125 or Sp133.

  Streptococcus pyogenes (Group A streptococci): Group A streptococcal antigens are proteins identified in WO 02/34771 or WO 2005/032582, including GAS 40, fusions of fragments of GAS M protein (WO 02 / 094851, and Dale, Vaccine, (1999), 17: 193-200, and those described in Dale, Vaccine, 14 (10): 994-948) fibronectin binding protein (Sfb 1), streptococcal It may include heme related protein (Shp), and streptolysin S (SagA).

  Moraxella catarrhalis: Moraxella antigens include the antigens identified in WO 02/18595 and WO 99/58562, outer membrane protein antigens (HMW-OMP), C-antigens, and / or LPS.

  Bordetella pertussis: pertussis antigen is optionally combined with pertactin and / or agglutinin 2 and agglutinin 3 antigens, Pertussis derived pertussis holotoxin (PT) and fibrillar hemagglutinin (FHA).

Staphylococcus aureus: Staph aureus antigens are optionally conjugated to non-toxic recombinants. aureus type 5 and type 8 capsular polysaccharides, Pseudomonas aeruginosa exotoxin A (eg StaphVAX ^™ ) or antigens derived from surface proteins, invasin (leucosidine, kinase, hyaluronidase), surface factors that inhibit phagocytosis (飲 み 莢) Membrane, protein A), carotenoids, catalase production, protein A, clotting enzymes, clotting factors, and / or membrane-damaging toxins that lyse eukaryotic cell membranes (detoxified if necessary) (hemolysin, leukotoxin , Leukocidin).

  Staphylococcus epidermis: S. The epidermidis antigen includes mucus associated antigen (SAA).

  Tetanus: Tetanus antigen comprises tetanus toxoid (TT), preferably used as a carrier protein in combination / conjugation with the composition of the present invention.

  Diphtheria: Diphtheria antigens include diphtheria toxins (preferably detoxified) (eg CRM197) and can further regulate, inhibit or be associated with ADP ribosylation Are contemplated for combination / co-administration / conjugation with the compositions of the present invention, diphtheria toxoid is preferably used as a carrier protein.

  Haemophilus influenzae B (Hib): Hib antigens include Hib saccharide antigens.

  Pseudomonas aeruginosa: Pseudomonas antigens are endotoxin A, Wzz protein, P. aeruginosa LPS (more specifically, LPS isolated from PAO1 (O5 serotype)) and / or outer membrane protein F (OprF) (Infect Immun., May 2001; 69 (5): 3510-3515 ) Include outer membrane proteins.

  Legionella pneumophila (Legionellosis): The pneumophila antigen can optionally be obtained from a cell line with a disrupted asd gene (Infect Immun., May 1998; 66 (5): 1898).

  Streptococcus agalactiae (Group B Streptococcus): Group B Streptococcus antigens are proteins or saccharide antigens identified in WO 02/34771, WO 03/093306, WO 04/041157, or WO 2005/002619 (protein GBS 80, GBS). 104, GBS 276 and GBS 322, and saccharide antigens derived from serotypes Ia, Ib, Ia / c, II, III, IV, V, VI, VII and VIII).

  Neiserria gonorrhoeae: Gonorrhoeae antigen is a Por (ie, porin) protein (eg, PorB (see Zhu et al., Vaccine, (2004), 22: 660-669), translocating binding proteins (eg, TbpA and TbpB ( Price et al., Infection and Immunity, (2004), 71 (1): 277-283), turbid protein (eg, Opa), reducible-modifiable protein (Rmp), and outer membrane vesicle (OMV) preparation (Plante) Et al., J. Infectious Disease, (2000), 182: 848-855) (eg, W099 / 24578, W099 / 36544, W099 / 57280, W002 / 07). 243 also includes a thing) of reference.

Chlamydia trachomatis: Chlamydia trachomatis antigens are serotypes A, B, Ba and C (factors of trachoma (cause of blindness)), serotypes L ₁ , L ₂ and L ₃ (associated with gender-associated lymphoblastoma) As well as antigens derived from serotypes DK. Chlamydia trachomas antigens can also include the antigens identified in WO 00/37494, WO 03/049762, WO 03/068811, or WO 05/002619.

  Treponema pallidum: syphilis antigens include the TmpA antigen.

  Haemophilus ducreyi (causes soft lower arm): Ducreyi antigen contains outer membrane protein (DsrA).

  Enterococcus faecalis or Enterococcus faecium: Antigens include trisaccharide repeats or other antigens from Enterococcus provided in other US Pat. No. 6,756,361.

  Helicobacter pylori: H pylori antigens include Cag, Vac, Nap, HopX, HopY and / or urease antigens.

  Staphylococcus saprophyticus: Antigen Contains the 160 kDa hemagglutinin of the saprophyticus antigen.

  Yersinia enterocolitica: Antigen includes LPS (Infect Immun., August 2002; 70 (8): 4414).

  E. E. coli: E. coli. The E. coli antigen is E. coli (ETEC), cohesive adhesion E. coli. E. coli (EAggEC), dispersive adhesion E. coli. E. coli (DAEC), enteropathogenic E. coli. E. coli (EPEC) and / or enterohemorrhagic E. coli. E. coli (EHEC).

  Bacillus anthracis: Anthracis antigens are detoxified as needed, and A component (lethal factor (LF) and edema factor (EF), both of which can share a common B component known as protective antigen (PA)) )).

  Yersinia pestis (Pest): The plague antigen is F1 capsule antigen (Infect Immun., June 2003; 71 (1): 374-383), LPS (Infect Immun., October 1999; 67 (10)) Yersinia pestis V antigen (Infect Immun, November 1997; 65 (11): 4476-4482).

  Mycobacterium tuberculosis: Tuberculosis antigen is a lipoprotein, LPS, BCG antigen, antigen 85B (Ag85B) and / or ESAT-6 fusion protein (Infect Immun., 2004) formulated in cationic lipid vesicles as needed. 72 (10): 6148), Mycobacterium tuberculosis (Mtb) isocitrate dehydrogenase-related antigen (Proc Natl Aeaed Sci USA., August 24, 2004; 101 (34): 12652), and / or MPT51 antigen (Infect Immun , July 2004; 72 (7): 3829).

  Rickettsia: Antigens include outer membrane proteins, including outer membrane protein A and / or outer membrane protein B (OmpB) (BiochimBiophys Acta., Nov. 1, 2004; 1702 (2): 145), LPS, and surface proteins Antigen (SPA) (J Autoimmun., June 1989; Second Addendum: 81).

  Listeria monocytogenes: Antigens derived from nonocytogenes are preferably used as carriers / vectors for intracytoplasmic delivery of the conjugates / related compositions of the invention.

  Chlamydia pneumoniae: Antigens include those identified in WO 02/02606.

  Vibrio cholerae: Antigens include proteinase antigen, LPS (especially lipopolysaccharide of Vibrio cholerae II), O1 Inaba O specific polysaccharide, V. cholera 0139, antigens of the IEM108 vaccine (Infect Immun., October 2003; 71 (10): 5498-504), and / or zona toxin (Zot).

  Salmonella typhi (typhoid fever): The antigen comprises a capsular polysaccharide, preferably a conjugate (Vi, ie, vax-TyVi).

  Borrelia burgdorferi (Lyme disease): Antigens are lipoproteins (eg, OspA, OspB, OspC and OspD), other surface proteins (eg, OspE related proteins (Erps), decorin binding proteins (eg, DbpA), and antigenicity Variable VI proteins (eg, antigens associated with P39 and P13 (complete membrane protein, Infect Immun., May 2001; 69 (5): 3323-3334)), VIsE antigen mutant protein (J Clin Microbiol., 1999). December; 37 (12): 3997).

  Porphyromonas gingivalis: Antigen gingivalis outer membrane protein (OMP).

  Klebsiella: Antigens include OMPs, including OMP A, or polysaccharides conjugated to tetanus toxoid as needed.

  Unless otherwise stated, the additional bacterial antigen of the present invention may be any of the capsule antigens, polysaccharide antigens or protein antigens described above. Additional bacterial antigens can also include outer membrane vesicle (OMV) preparations. In addition, antigens include live variations, attenuated variations, split variations, and / or purified variations of any of the bacteria described above. The bacterial or microbial antigens of the present invention can be gram negative or gram positive and aerobic or anaerobic.

In addition, any of the above bacterium-derived saccharides (polysaccharide, LPS, LOS or oligosaccharide) is conjugated to another factor or antigen (eg, carrier protein (eg, CRM197)). Such conjugation is described in US Pat. No. 5,360,897 and Can J
Biochem Cell Biol. May 1984; 62 (5): 270-5, with direct conjugation achieved by reductive amination of the carbonyl moiety on the saccharide to the amino group on the protein. possible. Alternatively, these saccharides can be conjugated by linkers using, for example, succinimide linkages or other linkages provided in Biocoijugate Technologies, 1996 and CRC, Chemistry of Protein Conjugation and Cross-Linking, 1993.

(B. Viral antigen)
Viral antigens suitable for use in the present invention include inactivated (or killed) viruses, attenuated viruses, split virus formulations, purified subunit formulations, can be isolated from viruses Viral proteins that can be purified or obtained, and virus-like particles (VLPs). Viral antigens can be derived from viruses grown in cell culture or recombinantly expressed. Viral antigens preferably include epitopes that are exposed on the surface of the virus during at least one stage of its life cycle. Viral antigens are preferably conserved across multiple serotypes. Viral antigens include antigens derived from one or more of the viruses shown below and examples of specific antigens identified below.

  Orthomyxovirus: Viral antigens can be derived from orthomyxoviruses (eg, influenza A, influenza B and influenza C). Orthomyxovirus antigens include one or more of hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix protein (M1), membrane protein (M2), and transcriptase components (PB1, PB2 and PA). May be selected from one or more of the viral proteins to be obtained. Preferred antigens include HA and NA.

  Influenza antigens can be derived from flu strains between epidemics (annual). Alternatively, the influenza antigen is pathogenic in strains that have the potential to cause epidemic infections (ie, influenza strains that have new hemagglutinin compared to hemagglutinin in currently spreading strains, or avian subjects, and Influenza strains that have the potential to spread horizontally to the human population, or influenza strains that are pathogenic to humans).

  Paramyxoviridae viruses: Viral antigens can be derived from Paramyxoviridae viruses such as pneumonia virus (RSV), paramyxovirus (PIV) and measles virus (measles).

  Pneumonia virus: Viral antigens can be derived from pneumonia viruses such as RS virus (RSV), bovine RS virus, mouse pneumonia virus, and turkey rhinotracheitis virus. Preferably, the pneumonia virus is RSV. The pneumonia virus antigen may be selected from one or more of the following proteins: surface protein fusion (F), glycoprotein (G) and small molecule hydrophobic protein (SH), matrix proteins M and M2, nucleocapsid protein N, P and L and nonstructural proteins NS1 and NS2. Preferred pneumonia virus antigens include F, G and M. For example, J Gen Virol. 2004, November; 85 (Pt 11): 3229. The pneumonia virus antigen may also be formulated in or derived from a chimeric virus. For example, a chimeric RSV / PIV virus can include both RSV and PIV components.

  Paramyxovirus: Viral antigens can be derived from paramyxoviruses such as parainfluenza virus types 1 to 4 (PIV), mumps, Sendai virus, simian virus 5, bovine parainfluenza virus, and Newcastle disease virus. Preferably, the paramyxovirus is PIV or mumps. The paramyxovirus antigen may be selected from one or more of the following proteins: hemagglutinin-neuraminidase (HN), fusion proteins F1 and F2, nucleoprotein (NP), phosphoprotein (P), large protein (L ), And matrix protein (M). Preferred paramyxovirus proteins include HN, F1 and F2. Paramyxovirus antigens may also be formulated in or derived from a chimeric virus. For example, a chimeric RSV / PIV virus can include both RSV and PIV components. Commercially available mumps vaccines contain live attenuated mumps virus (MMR), either in monovalent form or in combination with measles-rubella vaccine.

  Measles virus: Viral antigens can be derived from measles virus (eg, measles). The measles virus antigen may be selected from one or more of the following proteins: hemagglutinin (H), glycoprotein (G), fusion factor (F), large protein (L), nucleoprotein (NP), polymerase phosphoprotein ( P), and matrix (M). Commercially available measles vaccines typically contain live attenuated measles virus (MMR) in combination with mumps and rubella.

  Picornavirus: Viral antigens can be derived from picornaviruses such as enteroviruses, rhinoviruses, heparnaviruses, cardioviruses and aphtoviruses. Antigens derived from enteroviruses (eg, poliovirus) are preferred.

  Enterovirus: Virus antigens are enteroviruses (eg, poliovirus type 1, type 2 or type 3, Cossackie A virus type 1 to type 22 and type 24, Cossackie B virus type 1 to type 6, type Echo virus (ECHO virus) type 1 ~ 9, Echovirus 11-27 and Echovirus 29-34 and Enterovirus 68-71). Preferably, the enterovirus is a poliovirus. The enterovirus antigen is preferably selected from one or more of capsid proteins VP1, VP2, VP3 and VP4. Commercially available polio vaccines include inactivated poliovirus vaccine (IPV) and / or oral poliovirus vaccine (OPV).

  Heparnavirus: The viral antigen may be derived from a heparnavirus (eg, hepatitis A virus (HAV)). Commercially available HAV vaccines include inactivated HAV vaccines.

  Togavirus: The viral antigen can be derived from a togavirus (eg, rubivirus, alphavirus, or arterivirus). Antigens derived from ruby virus (eg rubella virus) are preferred. Togavirus antigens can be selected from E1, E2, E3, C, NSP-1, NSPO-2, NSP-3 or NSP-4. Togavirus antigens are preferably selected from E1, E2 or E3. Commercially available rubella vaccines typically include live cold-adapted virus (MMR) combined with mumps and measles vaccines.

  Flavivirus: Viral antigens are flaviviruses (eg tick-borne encephalitis (TBE), dengue fever (type 1, type 2, type 3 or type 4), yellow fever, Japanese encephalitis, West Nile encephalitis, St. Louis encephalitis, Russian spring and summer Encephalitis, Powassan encephalitis). The flavivirus antigen may be selected from PrM, M, C, E, NS-1, NS-2a, NS2b, NS3, NS4a, NS4b, and NS5. The flavivirus antigen is preferably selected from PrM, M and E. Commercially available TBE vaccines include inactivated virus vaccines.

  Pestivirus: Viral antigens can be derived from pestiviruses such as bovine viral diarrhea (BVDV), classic swine fever (CSFV) or border disease (BDV).

  Hepadnavirus: The viral antigen may be derived from a hepadnavirus (eg, hepatitis B virus). The hepadnavirus antigen can be selected from surface antigens (L, M and S), core antigens (HBc, HBe). Commercially available HBV vaccines include subunit vaccines that contain surface antigen S protein.

  Hepatitis C virus: Viral antigens can be derived from hepatitis C virus (HCV). HCV antigen is a peptide derived from E1, E2, E1 / E2, NS345 polyprotein, NS 345-core polyprotein, core, and / or non-structural regions (Houghton et al., Hepatology, (1991), 14: 381). More than one can be selected.

  Rhabdovirus: Viral antigens can be derived from rhabdoviruses such as Lissa virus (rabies virus) and vesiculovirus (VSV). The rhabdovirus antigen may be selected from glycoprotein (G), nucleoprotein (N), large protein (L), nonstructural protein (NS). Commercially available rabies virus vaccines contain killed virus that grows in human diploid cells or fetal rhesus lung cells.

  Caliciviridae; Viral antigens can be derived from Caliciviridae (eg, Norwalk virus).

  Coronavirus: Viral antigens are coronavirus, SARS, human respiratory coronavirus, avian infectious bronchitis (IBV), mouse hepatitis virus (MHV), and swine infectious gastroenteritis virus (TGEV). The coronavirus antigen can be selected from spike (S), envelope (E), matrix (M), nucleocapsid (N), and hemagglutinin-esterase glycoprotein (HE). Preferably, the coronavirus antigen is derived from SARS virus. SARS virus antigens are described in WO 04/92360.

Retrovirus: Viral antigens can be derived from retroviruses (eg, oncoviruses, lentiviruses or spumaviruses). Oncovirus antigens can be derived from HTLV-1, HTLV-2 or HTLV-5. The lentiviral antigen can be derived from HIV-1 or HIV-2. The retroviral antigen can be selected from gag, pol, env, tax, tat, rex, rev, nef, vif, vpu, and vpr. The HIV antigen may be selected from gag (p24gag and p55gag), env (gp160 and gp41), pol, tat, nef, rev, vpu, small proteins (preferably p55 gag and gp140v deletions). HIV antigens may be derived from one or more of the following _{strains: HIV IIIb, HIV SF2, HIV} LAV, HIV LAI, HIVMN, HIV-1 CM235, HIV-1 US4.

  Reovirus: Viral antigens can be derived from reovirus (eg, ortho-reovirus, rotavirus, orbivirus, or cortivirus). The reovirus antigen may be selected from the nonstructural proteins λ1, λ2, λ3, μ1, μ2, σ1, σ2, or σ3, or the nonstructural proteins σNS, μNS, or σ1s. Preferred reovirus antigens can be derived from rotavirus. The rotavirus antigen may be selected from VP1, VP2, VP3, VP4 (or degradation products VP5 and VP8), NSP1, VP6, NSP3, NSP2, VP7, NSP4, or NSP5. Preferred rotavirus antigens include VP4 (or degradation products VP5 and VP8), and VP7.

  Parvovirus: The viral antigen can be derived from a parvovirus (eg, parvovirus B19). The parvovirus antigen can be selected from VP-1, VP-2, VP-3, NS-1 and NS-2. Preferably, the parvovirus antigen is capsid protein VP-2.

  Hepatitis D virus (HDV): Viral antigens can be derived from HDV (particularly HDV-derived δ-antigen) (see, eg, US Pat. No. 5,378,814).

  Hepatitis E virus (HEV): Viral antigens can be derived from HEV.

  Hepatitis G virus (HGV): Viral antigens can be derived from HGV.

  Human herpesvirus: Viral antigens include human herpesviruses (eg herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 ( HHV6), human herpesvirus 7 (HHV7), and human herpesvirus 8 (HHV8)). The human herpesvirus antigen may be selected from an early protein (α), an early protein (β), and a late protein (γ). HSV antigens can be derived from HSV-1 or HSV-2 strains. HSV antigens can be selected from glycoproteins gB, gC, gD and gH, fusion proteins (gB), or immune escape proteins (gC, gE, or gI). The VZV antigen can be selected from a core protein, nucleocapsid protein, coat protein, or envelope protein. Attenuated live VZV vaccines are commercially available. The EBV antigen can be selected from early antigen (EA) protein, viral capsid antigen (VCA), and membrane antigen (MA) glycoprotein. The CMV antigen can be selected from capsid proteins, envelope glycoproteins (eg, gB and gH), and coat proteins.

  Papovavirus: The antigen can be derived from a papovavirus (eg, papillomavirus and polyomavirus). Papillomaviruses are HPV serotypes 1, 2, 4, 5, 6, 8, 11, 13, 16, 18, 31, 33, 35, 39, 41, 42, 47, 51, 57, 58, 63 and 65. including. Preferably, the HPV antigen is derived from serotype 6, 11, 16 or 18. The HPV antigen may be selected from capsid proteins (L1) and (L2), or capsid proteins E1-E7, or fusions thereof. HPV antigens are preferably formulated in virus-like particles (VLPs). Polyomavirus (Polyomavirus viruses) includes BK virus and JK virus. The polyomavirus antigen can be selected from VP1, VP2 or VP3.

  Vaccines, 4th edition (Plotkin and Orenstein, 2004); Medical Microbiology, 4th edition (Murray et al., 2002); Virology, 3rd edition (WK Joklik, 1988); Fundamental Virology (1988); Further provided are antigens, compositions, methods, and microorganisms included in BN Fields and DM Knipe, 1991), which are contemplated in connection with the compositions of the present invention.

(Fungal antigen)
In some embodiments, the composition of the present invention is combined with a fungal antigen for use in the methods of the present invention comprising the treatment or prevention of mycosis. With respect to vaccines, fungal antigens for use herein include those described below: US Pat. No. 4,229,434 for the prevention and treatment of trichophytosis caused by Trichophyton mentagrophytes. No. 4,368,191; US Pat. No. 5,277, relating to a broad spectrum dermatophyte vaccine for the prevention of dermatophyte infection in animals such as guinea pigs, cats, rabbits, horses and lambs. 904 and 5,284,652 (these antigens are killed T. equiuin, T. mentagrophytes (var. Granulare), M. canis and / or optionally combined with an adjuvant if necessary. U.S. Pat. No. 5,453,273 and No. 1 for a ringworm vaccine (ie, Microsporum canis culture in a carrier) containing an effective amount of a homogenized and formaldehyde killed fungus. No. 6,132,733; U.S. Pat. No. 5,948,413 for extracellular and intracellular proteins for pythosis. Additional antigens identified within antifungal vaccines include Ringvac bovis LTF-130 and Bioveta.

  In addition, fungal antigens for use herein can be derived from Dermatophytes, including:

本発明の組成物と共に、抗原としてか、または抗原の誘導体化において使用するための真菌病原体は、以下を含む：

Fungal pathogens for use with the compositions of the present invention as antigens or in derivatization of antigens include:

抗原が得られる他の真菌としては、Ａｌｔｅｒｎａｒｉａ ｓｐｐ．、Ｃｕｒｖｕｌａｒｉａ ｓｐｐ．、Ｈｅｌｍｉｎｔｈｏｓｐｏｒｉｕｍ ｓｐｐ．、Ｆｕｓａｒｉｕｍ ｓｐｐ．、Ａｓｐｅｒｇｉｌｌｕｓ ｓｐｐ．、Ｐｅｎｉｃｉｌｌｉｕｍ ｓｐｐ．、Ｍｏｎｏｌｉｎｉａ ｓｐｐ．、Ｒｈｉｚｏｃｔｏｎｉａ ｓｐｐ．、Ｐａｅｃｉｌｏｍｙｃｅｓ ｓｐｐ．、Ｐｉｔｈｏｍｙｃｅｓ ｓｐｐ．、およびＣｌａｄｏｓｐｏｒｉｕｍ
ｓｐｐ．が挙げられる。

Other fungi from which antigens can be obtained include Alternaria spp. Curvularia spp. Helminthosporium spp. Fusarium spp. Aspergillus spp. , Penicillium spp. Monolinia spp. Rhizoctonia spp. Paecilomyces spp. Pithymyces spp. , And Cladosporium
spp. Is mentioned.

  Processes for producing fungal antigens are well known in the art (see US Pat. No. 6,333,164). In a preferred method, the solubilized fraction extracted and separated from the insoluble fraction available from fungal cells whose cell wall has been substantially removed or at least partially removed comprises the following steps: To obtain a live fungal cell; obtaining a fungal cell whose cell wall has been substantially removed or at least partially removed; whether the cell wall has been substantially removed or at least Rupturing partially removed fungal cells; obtaining an insoluble fraction; and extracting and separating a solubilized fraction from the insoluble fraction.

(STD antigen)
Embodiments of the invention relate to compositions and methods relating to prophylactic and therapeutic treatments for microorganisms that can be neutralized prior to infection of cells. In certain embodiments, the microorganism (bacteria, virus and / or fungus) in which the compositions and methods of the invention can be practiced is a microorganism causing sexually transmitted disease (STD) and / or a target or antigen composition of the invention. Included are microorganisms that display possible antigens on their surface. In a preferred embodiment of the invention, the composition is combined with an antigen derived from a viral STD or a bacterial STD. Antigens derived from bacteria or viruses may be administered with the compositions of the present invention to provide protection against, among other things, at least one of the following STDs: Chlamydia, genital herpes, hepatitis (especially HCV), genital warts, mania Syphilis and / or soft varieties (see WO 00/15255).

  In another embodiment, the composition of the invention is co-administered with an antigen for the prevention or treatment of STD.

  Antigens from the following viruses associated with STD, which are described in more detail above, are preferred for co-administration with the compositions of the invention: hepatitis (especially HCV), HPV, HIV, or HSV.

  In addition, antigens from the following bacteria associated with STD, which are described in more detail above, are preferred for co-administration with the compositions of the invention: Neisereria gonorrzoeae, Chlamydia pneumoniae, Chlamydia trachomatis, Trepona. Pallidum, or Haemophilus ducreyi.

(Respiratory antigen)
The present invention specifically relates to viruses, bacteria, or fungi (eg, RS virus (RSV), PIV, SARS virus) by reducing or preventing one or more symptoms of infection and / or respiratory viral infection. , Influenza, Bacillus anthracis), and methods for preventing and / or treating infection by respiratory pathogens. Compositions containing the antigens described herein (eg, antigens derived from respiratory viruses, bacteria, or fungi) can be used in individuals at risk of being exposed to certain respiratory microorganisms. Administered with the compositions of the present invention to individuals exposed to microorganisms or to individuals infected with respiratory viruses, bacteria or fungi. The composition of the present invention is preferably co-administered with the antigen of the respiratory pathogen at the same time or in the same formulation. Administration of this composition results in a decrease in the incidence of respiratory infection and / or one or more severity.

(Tumor antigen)
One embodiment of the invention includes a tumor or cancer antigen associated with the composition of the invention. The tumor antigen can be, for example, a peptide-containing tumor antigen (eg, a polypeptide tumor antigen or a glycoprotein tumor antigen). The tumor antigen can also be, for example, a saccharide-containing tumor antigen (eg, a glycolipid tumor antigen or a ganglioside tumor antigen). In addition, the tumor antigen can be, for example, a polynucleotide-containing tumor antigen that expresses a polypeptide-containing tumor antigen (eg, an RNA construct or a DNA vector construct (eg, plasmid DNA)).

  Tumor antigens suitable for the practice of the present invention include a wide variety of molecules (eg, (a) can range, for example, 8-20 amino acids long, but lengths outside this range are also common) Polypeptides, including peptide, lipopolypeptide and glycoprotein-containing tumor antigens, (b) saccharide-containing tumor antigens including polysaccharides, mucins, gangliosides, glycolipids and glycoproteins, and (c) polys, including antigenic polypeptides Nucleotides).

  The tumor antigen includes, for example, (a) a full-length molecule associated with a cancer cell, (b) a full-length molecule associated with a cancer cell, including a molecule having a deletion portion, an addition portion and / or a substitution portion. Homologues and modified forms, and (c) fragments of full-length molecules associated with cancer cells. Tumor antigens can be provided in recombinant form. Tumor antigens include, for example, class I restricted antigens recognized by CD8 + lymphocytes or class II restricted antigens recognized by CD4 + lymphocytes.

Many tumor antigens are known in the art and include: (a) cancer-testis antigens (eg, NY-ESO-1, SSX2, SCP1), and RAGE family, BAGE family, GAGE family and MAGE family polypeptides (eg, GAGE-1, GAGE-2, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12) (these Can be used, for example, to address tumors in melanoma, lung, head and neck, NSCLC, breast, gastrointestinal, and bladder), (b) mutant antigens (eg, p53 (various solid tumors (eg, Associated with colorectal cancer, lung cancer, head and neck cancer), p21 / Ras (eg, melanoma, pancreatic cancer and tuberculosis) Associated with rectal cancer), CDK4 (eg associated with melanoma), MUM1 (eg associated with melanoma), caspase-8 (eg associated with head and neck cancer), CIA 0205 ( For example, related to bladder cancer), HLA-A2-R1701, β-catenin (eg related to melanoma), TCR (eg related to T cell non-Hodgkin lymphoma), BCR-abl (eg chronic myeloid) Leukemia related), triose phosphate isomerase, KIA 0205, CDC-27, and LDLR-FUT, (c) overexpressed antigen (eg galectin 4 (eg related to colorectal cancer), galectin 9 (eg , Associated with Hodgkin's disease), proteinase 3 (eg associated with chronic myeloid leukemia), WT 1 (eg various leukemias) ), Carbonic anhydrase (eg, associated with kidney cancer), aldolase A (eg, associated with lung cancer), PRAME (eg, associated with melanoma), HER-2 / neu (eg, breast cancer) , Associated with colon cancer, lung cancer and ovarian cancer), alpha-fetoprotein (eg associated with hepatocellular carcinoma), KSA (eg associated with colorectal cancer), gastrin (eg associated with pancreatic cancer and gastric cancer) Telomerase catalytic protein, MUC-1 (eg, associated with breast and ovarian cancer), G-250 (eg, associated with renal cell carcinoma), p53 (eg, associated with breast cancer, colon cancer), and Carcinoembryonic antigen (eg, breast cancer, lung cancer, and cancer of the gastrointestinal tract (eg, colorectal cancer), (d) a common antigen (eg, melanoma-melanocyte differentiation antigen ( (E) prostate Antigens (eg, PAP, PSA, PSMA, PSH-P1, PSM-P1, PSM-P2 (eg, associated with prostate cancer), (f) immunoglobulin idiotypes (eg, myeloma and B cell lymphoma) And (g) (i) glycoproteins (eg, sialyl Tn and sialyl Le ^x (eg, associated with breast cancer and colorectal cancer) and various mucins; glycoproteins bind to carrier proteins Obtain (eg, MUC-1 binds to KLH (Ii) a lipopolypeptide (eg, MUC-1 linked to a lipid moiety); (iii) a polysaccharide (eg, a Globo H synthetic hexasaccharide) that can bind to a carrier protein (eg, KLH); iv) Other tumor antigens (eg, polypeptides, including gangliosides (eg, GM2, GM12, GD2, GD3 (eg, associated with brain cancer, lung cancer, melanoma)) that can also bind to carrier proteins (eg, KLH) -Containing antigen and saccharide-containing antigen. Additional tumor antigens known in the art include p15, Hom / Mel-40, H-Ras, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein-Barr virus antigen, EBNA, human papillomavirus (HPV) antigens (including E6 and E7), hepatitis B virus antigen and hepatitis C virus antigen, human T cell lymphotropic virus antigen, TSP-180, p185erbB2, p180erbB-3, c-met, mn-23HI TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, p16, TAG, PSCA, CT7, 43-9F, 5T4, 791 Tgp72, β-HCG, BCA225 , BTAA, CA 125, CA 15-3 (CA 27.2 / BCAA), CA 195, CA 242, CA-50, CAM43, CD68 / KPI, CO-029, FGF-5, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB / 70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein / protein related to cyclophilin C), TAAL6, TAG72, TLP, TPS and the like. These cellular components and other cellular components are described, for example, in US Patent Application No. 20020007173 and the references listed therein.

  Polynucleotide-containing antigens according to the present invention typically include a polynucleotide encoding a polypeptide cancer antigen (eg, those listed above). Preferred polynucleotide-containing antigens include DNA vector constructs or RNA vector constructs (eg, plasmid vectors (eg, pCMV)) that can express polypeptide cancer antigens in vivo.

  Tumor antigens can be derived, for example, from mutated or altered cell components. After change, the cellular components no longer perform their regulatory functions, and therefore the cells can face uncontrolled proliferation. Representative examples of altered cellular components include ras, p53, Rb, altered protein encoded by Wilms oncogene, ubiquitin, mucin, DCC gene, protein encoded by APC gene, and MCC gene, and receptor Or receptor-like structures (eg, neu, thyroid hormone receptor, platelet derived growth factor (PDGF) receptor, insulin receptor, epidermal growth factor (EGF) receptor, and colony stimulating factor (CSF) receptor). These and other cellular components are described, for example, in US Pat. No. 5,693,522 and references listed therein.

  In addition, bacterial and viral antigens can be used with the compositions of the present invention for the treatment of cancer. In particular, carrier proteins (eg, CRM197, tetanus toxoid, or Salmonella typhimurium antigen) can be used for conjugation / conjugation with compounds of the invention for the treatment of cancer. Cancer antigen combination therapies show increased efficacy and bioavailability compared to both existing ones.

  More information about cancer antigens or tumor antigens can be found, for example, in:

。

.

(Antigens of children / old people)
In one embodiment, the compositions of the invention are used with an antigen, such as a pediatric antigen, for the treatment of a pediatric population. In more specific embodiments, the pediatric population is less than about 3 years old, or less than about 2 years old, or less than about 1 year old. In another embodiment, the pediatric antigen (with the composition of the invention) is administered multiple times over at least 1 year, 2 years, or 3 years.

  In another embodiment, the compositions of the invention are used with an antigen, such as an elderly antigen, for the treatment of the elderly population.

(Other antigens)
Other antigens for use with the compositions of the present invention include those associated with hospital outbreaks (in-hospital).

  In another embodiment, parasitic antigens are contemplated in connection with the compositions of the present invention. Examples of parasitic antigens include those derived from organisms that cause malaria and / or Lyme disease.

  In another embodiment, the antigen associated with the composition of the invention is associated with or effective in a mosquito born illness. In another embodiment, the antigen associated with the composition of the invention is associated with or effective in encephalitis. In another embodiment, the antigen associated with the composition of the invention is associated with or effective in infection of the nervous system.

  In another embodiment, the antigen associated with the composition of the invention is capable of transmitting the antigen via blood or body fluid.

(Antigen formulation)
In another aspect of the invention, a method for producing microparticles with adsorbed antigen is provided. The process includes the following: (a) (i) water, (ii) surfactant, (iii) organic solvent, and (iv) poly (α-hydroxy acid), polyhydroxybutyric acid, polycaprolactone, poly Providing an emulsion by dispersing a mixture containing a biodegradable polymer selected from the group consisting of orthoesters, polyanhydrides, and polycyanoacrylates (this polymer is typically against the organic solvent). While present in the mixture at a level of about 1% to about 30%, the surfactant is typically about 0.00001: 1 to about 0.1: 1 (more typically About 0.0001: 1 to about 0.1: 1, about 0.001: 1 to about 0.1: 1, or about 0.005: 1 to about 0.1: 1) surfactant to polymer Present in this mixture at a weight ratio of (B) removing the organic solvent from the emulsion; and (c) adsorbing the antigen onto the surface of the microparticles. In certain embodiments, the biodegradable polymer is present at a level of about 3% to about 10% relative to the organic solvent.

  Microparticles for use herein are formed from materials that are sterilizable, non-toxic, and biodegradable. Such materials include, but are not limited to, poly (α-hydroxy acid), polyhydroxybutyric acid, polycaprolactone, polyorthoester, polyanhydride, PACA and polycyanoacrylate. Preferably, the microparticles for use in the present invention are poly (α-hydroxy acids) (particularly poly (lactide) (“PLA”)) or copolymers of D, L-lactide and glycolide or glycolic acid (eg, poly (lactide)). (D, L-lactide-co-glycolide) (“PLG” or “PLGA”), or a copolymer of D, L-lactide and caprolactone, which has a variety of molecular weights and copolymers (eg, PLG ), Which can be derived from any of a variety of polymer starting materials having various lactide: glycolide ratios (the majority of this choice is a matter of preference), and are partially co-administered macromolecules. These parameters are discussed more fully below.

  Additional antigens can also include outer membrane vesicle (OMV) preparations.

  Additional formulation methods and antigens, particularly tumor antigens, are provided in US patent application Ser. No. 09 / 581,772.

(References on antigens)
The following references contain useful antigens for the compounds and methods of the present invention.

上記に引用した全ての特許、特許出願、および雑誌論文の内容が、本明細書中で十分に提示されたものとして、参考として援用される。

The contents of all patents, patent applications, and journal articles cited above are hereby incorporated by reference as if fully set forth herein.

  The names for the compounds in the examples are from Advanced Chemistry Development, Inc. Provided using the ACD Name version 5.07 software available from (November 14, 2001). Some of the compounds and starting materials were named using standard IUPAC nomenclature.

  The foregoing may be better understood by reference to the examples, methods, and schemes that follow, which are presented for purposes of illustration and are not intended to limit the scope of the inventive concept. Absent. Compound groups for which there are no experimental procedures for synthesis are either commercially available, described by procedures incorporated herein by reference, or readily synthesized by those skilled in the art from commercially available starting materials that are readily recognizable. Either.

  All patents, patent applications, and publications referenced herein are incorporated by reference in their entirety.

(I. Synthesis)
Unless otherwise specified, the numbers given to the R groups in the Examples section are not intended to correspond to the numbers used throughout the rest of the specification. Reference to a specific reaction by name will be apparent to the skilled person and / or: Name Reactions and Reagents in Organic by Mundy et al. (1988).
Synthesis, which is incorporated herein by reference. In addition, certain reagents may be added or the reaction may be modified, which will be apparent // and will be apparent to those skilled in the art and / or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure No. 5 It is described in the edition.

(Synthesis of Example 83)
An attempt was made to synthesize analogs of 5'-modified derivatives of bredinin, 5'-phosphate 2, 5'-deoxy derivative 3, and 5'-o- (3-aminopropyl) carbamate 4 (FIG. 1).

ｏ−キシリレンＮ，Ｎ−ジエチルホスホラミダイト（ＸＥＰＡ）^１３を用いたホスホラミダイト法が、このシステムにおいて有効である（スキーム２）。ＣＨ_２Ｃｌ_２中でＸＥＰＡおよびテトラゾールで１７を処置し、続いてＩ_２水を用いた酸化により、収率７０％で、対応する５’−ホスホトリエステル１９を得る。１９のイソプロピリデンおよびＢｏｃ基を、９０％のＴＦＡ水で同時に除去し、そして得られる生成物を、精製せずにＤＭＦ中の（ＥｔＯ）_３ＣＨと共に９０℃で加熱することにより、１９から収率４７％でブレジニン５’−ホスフェート誘導体２０を得る。Ｐｄ−炭素を用いてＭｅＯＨ中で２０を水素化し、ブレジニン５’−ホスフェート２を得、Ｄｏｗｅｘ５０（Ｈ＋）およびＤｉａｉｏｎ ＷＫ−２０（Ｎａ^＋）樹脂で連続して処置した後、収率８９％で二ナトリウム塩として単離する。

The phosphoramidite method using o-xylylene N, N-diethyl phosphoramidite (XEPA) ¹³ is effective in this system (Scheme 2). Treatment of 17 with XEPA and tetrazole in CH ₂ Cl ₂ followed by oxidation with I ₂ water gives the corresponding 5′-phosphotriester 19 in 70% yield. The 19 isopropylidene and Boc groups were removed simultaneously with 90% TFA water and the resulting product was recovered from 19 by heating at 90 ° C. with (EtO) ₃ CH in DMF without purification. Bredinin 5′-phosphate derivative 20 is obtained at a rate of 47%. Hydrogenation of 20 in MeOH using Pd-carbon to give bredinin 5′-phosphate 2 and after successive treatment with Dowex 50 (H +) and Diaion WK-20 (Na ⁺ ) resin, yield 89% Isolate as disodium salt.

。

.

  (Synthesis of Example 102)

。

.

(Synthesis of cyclosporine Example (111 to 115))
Most of the naturally occurring cyclosporine being studied contains the majority of N-desMe analogs, and Tolypocladum infatum Gam (NRRL
8044), but some other fungi are cyclosporine analogues such as Cylindrochricholigospermum (SDZ 214-103 and its [Thr ² , D-Hiv ⁸ , Leu ¹⁰ ] -CsA family All of the body) or a specific cyclosporine (eg, Acremonium luzulae (Fuckel) W. Gam ([Thr ² , Leu ⁵ , Ala ¹⁰ ] -CsA), Tolypocladum tericola ([Leu ⁴ ] umolFlaR ^{8044 ([Thr 2, Leu 10} ] -CsA) mutant strain of, Hypoderma eucalyptii Cooke and Harkn Lep of most other analogs can be obtained by precursor-directed biosynthesis, and other analogs can be obtained by chemical modification. For the synthesis of cyclosporine, the peptide bond between L-alanine at position 7 and D-alanine at position 8 is selected for the cyclization step for two main reasons: between the amide groups of the linear peptide The H bond in the chain acts to stabilize the open chain in the folded conformation and to approximate the cyclic structure of cyclosporine, thus assisting cyclization between N-methylated amino acid residues. Bond formation presents more difficulties than for non-N-methylated derivatives, so the N-terminus of the undecapeptide and Strategies for eliminating N-methylated amino acids at the termini are also specifically selected, so bond formation only between consecutive pairs of non-N methylated amino acids in cyclosporine is a cyclization step. Is a logical choice for.

  Using this synthetic approach, potentially any amino acid in the peptide chain of cyclosporine (FIG. 1a) can be modified and specific aspects of the structure-activity relationship can be examined in turn.

図１．ａは、固体の状態のシクロスポリンの構造および立体配座の概略図である。ｂ．無極性溶媒中のシクロスポリンの構造および立体配座の概略図である。この２つのペプチド立体配座は非常に良く似ている。主要な違いはＭｅＢｍｔアミノ酸の炭素鎖の配向（ｏｒｉｅｎｔａｔｉｏｎ）にあり、軽微な違いは溶液中の三中心水素結合の存在である。

FIG. a is a schematic diagram of the structure and conformation of cyclosporine in a solid state. b. 1 is a schematic diagram of the structure and conformation of cyclosporine in a nonpolar solvent. The two peptide conformations are very similar. The main difference is in the orientation of the MeBmt amino acid carbon chain, and the minor difference is the presence of a three-center hydrogen bond in solution.

For the synthesis of undecapeptides, fragment condensation techniques are used that introduce the amino acid MeBmt at the end of the synthesis. In this way, the number of steps after introduction of this amino acid is minimized. Peptide fragments are generated using the numerical sequence of steps in the direction indicated by the arrows in FIG. The amino group of the amino acid to be reacted and the amino group of the peptide are protected with a tert-butoxycarbonyl group (Boc), and the carboxy group is protected with a benzyloxy group (benzyl ester; OBzl). In general, a modification of the mixed pivalic anhydride method reported by Zaoral [14] and adapted by the inventors for N-methyl-amino acid derivatives was used to activate the carboxy group. After slowly forming an anhydride in CHCl ₃ at −20 ° C. with pivaloyl chloride (= trimethylacetyl chloride) in the presence of an equivalent amount of a tertiary base (eg N-methylmorpholine), the amino acid or peptide ester To bind as the free base. The Boc protecting group of the peptide intermediate is removed with CF ₃ COOH at −20 ° C., the acid is neutralized with NaHCO ₃ and the peptide base is isolated. Benzyloxy protecting group of the peptide intermediate is removed by C supported Pd in H ₂ and ethanol. The tetrapeptide Boc-D-Ala-MeLeu-MeLeu-MeVal-OBzl was made from left to right by forming bonds 1, 2 and 3 (FIG. 3). Bond 4 is created and the dipeptide Boc-Abu-Sar-OBzl is synthesized. The tetrapeptide Boc-MeLeu-Val-MeLeu-Ala-OBzl is synthesized from left to right by forming bonds 5, 6 and 7 in this order. The hexapeptide Boc-Abu-Sar-MeLeu-VaI-MeLeu-Ala-OBzl is then prepared by forming bond 8. To prepare protected heptapeptides from protected MeBmt amino acids and hexapeptides, a dicyclohexylcarbodiimide (DCCI) coupling method is used in the presence of N-hydroxybenztriazole (BtOH). Reagent (1H-benzo [d] [1,2,3] triazol-1-yloxy) -tris- (dimethylamino) developed by Castro et al. In CH ₂ Cl ₂ at room temperature in the presence of N-methylmorpholine. ) By using phosphonium hexafluorophosphate, Boc-D-Ala-MeLeu-MeLeu-MeVal-OH was coupled with heptapeptide to undecapeptide Boc-D-Ala-MeLeu-MeLeu-MeVal- MeBmt-Abu-Sar-MeLeu-Val-MeLeu-Ala-Obzl is generated and the final amide bond 10 is made. The ester group of the undecapeptide is removed by hydrolysis with NaOH at 0 ° C., the Boc group is removed with CF ₃ COOH at −20 ° C. and then unprotected HD-Ala-MeLeu-MeLeu. the -MeVal-MeBmt-Abu-Sar- MeLeu-Val-MeLeu-Ala-OH, 5 the presence of equivalent amount of 4-dimethylaminopyridine, using 4 equivalents of anhydrous propanephosphonic acid _{(CH 3 CH 2 CH 2 PO} ) Cyclization in CH ₂ Cl ₂ (0.0002M) (1 day at room temperature) gives crystalline cyclosporine isolated in 65% yield. Using this fragment condensation technique, it is now possible to synthesize cyclosporine very efficiently with a yield of 30% for the amino acid MeBmt. Thus, since the molecular weight increases during this synthesis, starting with 1 g of the amino acid MeBmt, 1.7 g of cyclosporine can be produced.

図２．アミノ酸（４Ｒ）−４−［（Ｅ）−２−ブテニル］−４，Ｎ−ジメチル−Ｌ−トレオニン（ＭｅＢｍｔ）の合成。（１）第１過程：ＭｅＢｍｔアミノ酸の不斉中心Ｃ−３およびＣ−４の形成。（ａ）Ｃ_２Ｈ_３ＯＨ／ＨＣｌ（エステル化）；（ｂ）Ｃ_６Ｈ_５ＣＨＯ／ＨＣ（ＯＣ_２Ｈ_３）_３／ＴｓＯＨ・Ｈ_２Ｏ（ＯＨ−保護）；（ｃ）ＬｉＡｌＨ_４（エステルの還元）；（ｄ）Ｃ_６Ｈ_５ＣＨ_２Ｂｒ／ＫＯＨ（ＯＨ−ベンジル化）；（ｅ）Ｎ−ブロモコハク酸イミド；（ｆ）ＫＯＨ／Ｃ_２Ｈ_５ＯＨ（ｅ＋ｆ．エポキシ化）；（ｇ）２ＣＨ_３Ｌｉ／Ｃｕｌ（メチル化）；（ｈ）Ｐｄ／Ｈ_２（脱ベンジル化）。（２）第２過程：トランス二重結合を含む炭素鎖の導入。（ｉ）（ＣＨ_３）_２Ｃ（ＯＣＨ_３）_２／ＴｓＯＨ・Ｈ_２Ｏ（ビシナルＯＨ基の保護）；（ｋ）ＴｓＣｌ／Ｐｙ（トシラート形成）；（ｌ）ＫＣＮ／ＤＭＳＯ（ニトリル形成）；（ｍ）ＤＩＢＡＨ（アルデヒドの還元）；（ｎ）（Ｃ_６Ｈ_５）_３Ｐ^＋−Ｃ_２Ｈ_５Ｂｒ⁻／ＢｕＬｉ（ウィッティヒ反応）；（ｏ）ＴＨＦ／Ｈ_２Ｏ中の１．１当量０．１Ｎ ＨＣｌ（ＯＨ基の脱保護）。（３）第３過程：メチルアミノ基およびカルボキシ基の導入。（ｐ）ＤＣＣｌ／ＤＭＳＯ／Ｃ_２Ｈ_６／Ｐｙ／ＴＦＡ（モファット酸化）；（ｑ）ＫＣＮ／ＣＨ_３ＮＨ_２−ＨＣｌ／ＣＨ_３ＯＨ−Ｈ_２Ｏ（シアンアミン形成）；（ｒ）１，１’カルボニルジイミダゾール／ＣＨ_２Ｃｌ_２（オキサゾリジン−２−オン形成）；（ｓ）Ｋ_２ＣＯ_３／Ｃ_２Ｈ_５ＯＨ（エチルカルボキシミダート（ｅｔｈｙｌｃａｒｂｏｘｉｍｉｄａｔｅ）への転化）；（ｔ）Ｃ_２Ｈ_５ＯＨ中の１Ｎ ＨＣｌ（Ｎ，Ｏ−カルボニル−ＭｅＢｍｔ−ＯＣ_２Ｈ_５への加水分解）；（ｕ）２Ｎ ＫＯＨ／Ｈ_２Ｏ／８０℃、次いでＨＣｌ（Ｈ−ＭｅＢｍｔ−ＯＨアミノ酸の脱保護および単離）。

FIG. Synthesis of amino acid (4R) -4-[(E) -2-butenyl] -4, N-dimethyl-L-threonine (MeBmt). (1) First step: formation of asymmetric centers C-3 and C-4 of MeBmt amino acids. (A) C ₂ H ₃ OH / HCl (esterification); (b) C ₆ H ₅ CHO / HC (OC ₂ H ₃ ) ₃ / TsOH · H ₂ O (OH-protected); (c) LiAlH ₄ ( reduction of the _{ester); (d) C 6 H} 5 CH 2 Br / KOH (OH- benzylated); (e) _{N-bromosuccinimide;. (f) KOH / C} 2 H 5 OH (e + f epoxidation); (G) 2CH ₃ Li / Cul (methylation); (h) Pd / H ₂ (debenzylation). (2) Second process: introduction of a carbon chain containing a trans double bond. (I) (CH ₃ ) ₂ C (OCH ₃ ) ₂ /TsOH.H ₂ O (protection of vicinal OH group); (k) TsCl / Py (tosylate formation); (l) KCN / DMSO (nitrile formation); (M) DIBAH (aldehyde reduction); (n) (C ₆ H ₅ ) ₃ P ⁺ —C ₂ H ₅ Br ⁻ / BuLi (Wittig reaction); (o) 1.1 equivalents in THF / H ₂ O 0.1N HCl (deprotection of OH groups). (3) Third step: introduction of a methylamino group and a carboxy group. _{(P) DCCl / DMSO / C} 2 H 6 / Py / TFA ( Moffat _{oxidation); (q) KCN / CH} 3 NH 2 -HCl / CH 3 OH-H 2 O ( cyan amine form); (r) 1, 1 'carbonyldiimidazole / CH ₂ Cl ₂ (oxazolidine-2-one formation); (s) K ₂ CO ₃ / C ₂ H ₅ OH (conversion to ethyl carboxyboximidate); (t) C ₂ 1N HCl in H ₅ OH (hydrolysis to N, O-carbonyl-MeBmt-OC ₂ H ₅ ); (u) 2N KOH / H ₂ O / 80 ° C., then HCl (dehydration of H-MeBmt-OH amino acid) Protection and isolation).

。

.

  (Synthesis of Example 129)

試薬をＭｅＯＨ（またはＣＨ_２Ｃｌ_２もしくはＴＨＦ）に一緒に加え、室温で少なくとも０．５時間攪拌する。この反応を促進するために、溶液を加熱し得る。ＴＬＣおよびＨＰＬＣにより、進行をモニタリングする。後処理は、水溶液でクエンチすることおよびＣＨ_２Ｃｌ_２中に生成物を抽出することを含む。

The reagents are added together in MeOH (or CH ₂ Cl ₂ or THF) and stirred at room temperature for at least 0.5 hours. To promote this reaction, the solution can be heated. Progress is monitored by TLC and HPLC. The work-up involves quenching with an aqueous solution and extracting the product into CH ₂ Cl ₂ .

(Synthesis of Example 130)
The synthesis of compounds (4a, 5a-d) is outlined in Scheme 7. 5-Substituted 2-mercapto-1H-benzimidazole (2a, b) is synthesized from the corresponding acetanilide derivative (1a, b). [10] Purchase 4-substituted 2- (chloromethyl) pyridine (3a-c) or from the corresponding picoline-1-oxide by Pummerer-like rearrangement and chlorination with thionyl chloride in chloroform. Induce. The coupling reaction of 3a-c with 2a or 2b is carried out under aqueous basic conditions to give the sulfenyl derivative (4a-d), followed by selection of the benzimidazolyl sulfur atom using m-chloroperbenzoic acid. Oxidize to give sulfoxides 5a-d.

。

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(Synthesis of Example 133)
The synthesis of (alkylimino) -1,4-dihydroquinoline is shown in Scheme 8. A key synthetic precursor, 4-chloroquinoline 12, is prepared from commercially available aniline by the well-established route of Price and Roberts. Conversion to the hexyl ether analog 13 is achieved by treating 4-chloroquinoline with hexanol in the presence of base and phase transfer catalyst tris [2- (2-methoxyethoxy) -ethylamine, TDA-1. . The alkylamine group is installed using a Surrey method modification procedure whereby the 4-chloroquinoline derivative 12 is heated with excess alkylamine to give 4- (alkylamino) quinoline 14. Alkylation of the quinoline nitrogen by treatment of the 4-substituted quinolines 13 and 14 with the appropriate alkyl halide or benzylic halide gave the target molecule.

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  (Synthesis of Example 145)

実施例１４５の（＋）−２−メチルアラキドニル−２’−フルオロエチルアミド（４）（スキーム９）を、ヨウ化メチルを用いたｏ−アルキル化により、アラキドン酸メチルから合成し、エステル（＋）−１を得、これを加水分解して酸（＋）−３を得る。得られた酸（＋）−３をその酸塩化物に転化し、過剰なフルオロエチルアミンで処理して最終生成物を得る。

The (+)-2-methylarachidonyl-2′-fluoroethylamide (4) of Example 145 (Scheme 9) was synthesized from methyl arachidonic acid by o-alkylation with methyl iodide to give the ester ( +)-1 is obtained and hydrolyzed to give acid (+)-3. The resulting acid (+)-3 is converted to its acid chloride and treated with excess fluoroethylamine to give the final product.

  The current purpose is achieved by carrying out the decomposition of the acid precursor and then converting it to the product of the enantiomer. To decompose the acid (+)-3, it is converted to its acid chloride and then treated with (S)-(+)-2-phenylglycinol 20 to give the amide as a diastereomeric mixture. Get 2. This is easily separated by flash chromatography, diastereomer 2a (87%; Rf 0.37 (50% ethyl acetate / hexane); [o] 21D + 54 ° (c 0.14, MeOH)), and 2b (75% Rf 0.19 (50% ethyl acetate / hexane); led 21 [> + 28 ° (c 0.15, MeOH)] 21 Hydrolyzing each amide to give the corresponding enantiomer acids 3a (62%) and 3b In order to check the purity of the enantiomers of acids 3a and 3b (ie to verify that no racemization has occurred during hydrolysis of the amide), they are again reconstituted with their respective diastereoisomers. Converted to Meramide 2 and analyzed by HPLC eluting with 55% ethyl acetate / hexane. Omer 2a showed a single peak eluting at 7.69 minutes at room temperature and showed> 98 ° kde, the optical purity of 3b determined similarly, regenerated 2b (room temperature, 15.82 minutes) HPLC analysis of shows 98% ee (ie 1% diastereomer 2a is detected).

The enantiomeric acids 3a and 3b are then converted to the target fluoroethylamides (+)-4a, and (−)-4b as described above for the racemate. Enantiomer (+)-4a is obtained in 82% yield; [o] 21D + 19.9 ° (c0.99, MeOH); MS rrdz 364 (M + 1). Similarly, the enantiomer (−)-4b is obtained in 89% yield; [O] 21D-17.1 ° (c0.98, MeOH); MS m / z.
364 (M + 1). Finally, assuming no further racemization during the conversion of acid 3a / 3b to fluoroethylamide 4a / 4b (considering using the same reaction procedure when regenerating amide 2a / 2b) (Reasonable assumption), amide 4a is assumed to be> 98% ee and amide 4b was assumed to be 98% ee, which corresponds to the ee of the regenerated amide 2a / 2b and is within 4 a And the optical rotation of 4b.

(Synthesis of Examples 134-136)
The approach described in Scheme 10 is chosen primarily because it allows the use of either (−) or (+) a-pinene as a starting point. This optically active pinene is then converted to berbenol 8a and 8b resulting in optically active 9-ketocannabinoids (6a and 6b). Similarly, selection of (f) -a-pinene as the starting material gives the desired racemate. In the preparation of 6a, the early synthesis of the 10a ring junction trans prevents the separation of isomers, which can be detrimental. The appropriate berbenol 8a or 8b is converted to AB isomer 9a or 9b by reaction with resorcinol ( ₁ ) in a similar manner reported for the synthesis of A8-THC. Photolysis following acetylation to 10a or 10b provides isomer 11a or 11b. During photolysis, the 1-acetate group is removed and the isomer must be reacetylated and the resulting 12a or 12b is subsequently ozonated to give ketoacetic acid 13a or 13b. Hydrolysis of 1-acetate gives the desired optically active ketone 6a or 6b. From (−)-a-pinene, isomer 6a is obtained; from (+)-a-pinene, isomer 6b is obtained. The assignment of absolute stereochemistry is based on the fact that (-)-berbenol was converted to (-)-A9-THC, where the absolute stereochemistry was shown to be 6aR, lOaR.

。

.

(Synthesis of Example 143)
A microorganism belonging to the genus Myrothecium and capable of producing TAN-1140 (e.g., IT-121 strain) is cultured in potato / glucose agar medium at pH 4-10 at 20-30 ° C for 2 weeks, The resulting compound of Example 143 can be further derivatized.

  (Synthesis of Example 152)

。

.

  (Analog synthesis of Example 161)

構造的に、オバリシン（ｏｖａｌｉｃｉｎ）（１）は、合成され十分に説明されている抗体のフマギリン（２）と非常に良く似ている。本明細書中では、オバリシンの簡単な立体制御合成を報告する。２，４−ジヒドロキシ安息香酸から、（１）２．５当量のヨウ化メチルおよび２当量の炭酸カリウムと、１６時間、還流にてアセトン中で反応させ、抽出分離およびシリカゲル（ｓｇ）クロマトグラフィーにより、２−ヒドロキシ−４−メトキシ安息香酸メチル（８３％）を得、（２）続いて３０分間、還流にてエーテル中の１．８当量のビス（２−メトキシエトキシ）アルミニウム二水素化物ナトリウムで還元することにより、フェノール３を調製する（収率９７％）。３と過ヨウ素酸ナトリウム水溶液４（０．３Ｍ）とのテトラヒドロフラン（ＴＨＦ）中、２３℃で１．５時間の反応により、抽出分離および中性アルミナ（１：１ヘキサン：酢酸エチル）に通す濾過により、収率６１％でジエノン（ｄｉｅｎｏｎｅ）エポキシド４が得られる。多種多様な条件の下での接触水素化により、４の二重結合の還元によりフェノール３を形成させる。しかしながら、ジイミドを使用した還元は、ＤＭＥ中４５℃にて４およびアゾジカルボン酸カリウム（１８当量）の攪拌混合物に、酢酸溶液（ジメトキシエタン（ＤＭＥ）１２当量中１Ｍ）を２４時間かけて加えた後、濾過し、中性アルミナ（１：１ヘキサン：酢酸エチル）を用いたクロマトグラフィーにより、所望のエポキシエノン５（７７％）が得られる。

Structurally, ovalicin (1) is very similar to the synthetic and well-described antibody fumagillin (2). Here we report a simple stereocontrolled synthesis of ovalicin. From 2,4-dihydroxybenzoic acid, (1) reaction with 2.5 equivalents of methyl iodide and 2 equivalents of potassium carbonate in acetone for 16 hours at reflux, extraction separation and silica gel (sg) chromatography. To give methyl 2-hydroxy-4-methoxybenzoate (83%), (2) with 1.8 equivalents of sodium bis (2-methoxyethoxy) aluminum dihydride in ether at reflux followed by 30 minutes. Phenol 3 is prepared by reduction (yield 97%). 3 and reaction with sodium periodate aqueous solution 4 (0.3 M) in tetrahydrofuran (THF) at 23 ° C. for 1.5 hours, extraction separation and filtration through neutral alumina (1: 1 hexane: ethyl acetate) Gives the dioneone epoxide 4 in a yield of 61%. Phenol 3 is formed by reduction of 4 double bonds by catalytic hydrogenation under a wide variety of conditions. However, reduction using diimide added an acetic acid solution (1M in 12 equivalents of dimethoxyethane (DME)) over 24 hours to a stirred mixture of 4 and potassium azodicarboxylate (18 equivalents) at 45 ° C. in DME. Subsequent filtration and chromatography using neutral alumina (1: 1 hexane: ethyl acetate) gives the desired epoxy enone 5 (77%).

Vinyl lithium reagent 6a is prepared stereospecifically from vinyl iodide 6b synthesized by the 90% overall yield method from acetone (2,4,6-triisopropylbenzyl) sulfonyl-hydrazone as follows. To this hydrazone solution in DME at −78 ° C. was added n-butyllithium (2.15 eq). The mixture is warmed to −66 ° C. over 20 minutes and recooled to −78 ° C. before 1-bromo-3-methyl-2-butene (1.2 eq) is added. The solution is warmed to -66 ° C over 20 minutes, stirred at -66 ° C for 1 hour, and re-cooled to -78 ° C. Following the addition of N, N, -N ′, N′-tetramethylethylenediamine (3.3 eq) and n-butyllithium (1.1 eq), the reaction mixture was warmed to −3 ° C. over 2 h, Recool to −78 ° C. and treat with tri-n-butyltin chloride (1.25 equivalents) at −78 ° C. for 35 minutes, at −35 ° C. for 1 hour, and finally at room temperature for 45 minutes. . Extraction separation and chromatography with triethylamine inactive sg (hexane eluent) gives 6c as a single isomer with a small amount of tetra-n-butyltin by-product (purity by ¹ H NMR analysis> 90%). Vinyltin 6c is treated with iodine (1.2 eq) in methylene chloride at room temperature for 1 hour, and post-extraction treatment and chromatography using sg (pentane eluent) provides 6b.

A solution of 6b in ether at −78 ° C. was stirred with tert-butyllithium (1.6 eq) for 3.25 hours, then epoxy enone 5 (0.8 eq) in toluene was obtained. Add to vinyllithium reagent 6a. After stirring for 1.25 hours at −78 ° C. and post-extraction treatment, diastereomers 7 and 8 (sgTLC Rf values with 1: 1 hexane-ethyl acetate are 0.58 and 0.72 respectively) and A 17: 1 mixture of (by ¹ H NMR analysis) is isolated. Separation of this mixture is accomplished using an inert sg of triethylamine (4: 1 hexane-ethyl acetate co-solvent containing 1% triethylamine) to give pure 7 in 83% yield. Reaction of 7 with N-bromosuccinimide (1.12 equivalents) in methanol at 0 ° C. to give the corresponding bromoketal 9 and the corresponding a-bromo a′-enol ether (4: 1 hexane-ethyl acetate). A 3: 1 mixture with sgTLC Rf values of 0.33 and 0.44), respectively, is efficiently obtained in quantitative yield. This mixture was stirred in acetone-water (1.5: 1) together with a catalytic amount of p-toluenesulfonic acid at room temperature for 24 hours. After the post-extraction treatment, bromoketone was obtained with good purity by ¹ H NMR analysis. 10 (94%) is obtained. Chromatography with sg (4: 1 hexane-ethyl acetate) at 4 ° C. gives pure 10 (7 to 55% overall). A reaction product of bromoketone 10 and hydroxylamine hydrochloride (3.56 equivalents) in acetic acid was buffered to pH 6 with potassium acetate (1: 1 equivalents) at room temperature for 1 hour, and after extraction, bromooxime 11 (Quantitative). 11 in methanol was treated with triethylamine (5 equivalents) for 2 hours at room temperature and 24 hours at 48 ° C., and after extraction, a-methoxyoxime 12 was obtained after separation (quantitative recovery, ¹ Purity by H NMR analysis> 90%). Hydrolysis of the oxime was carried out at room temperature for 2.5 hours with aqueous titanium trichloride solution (4 equivalents) in methanol buffered with aqueous ammonia acetate solution (pH 6; 18 equivalents). After extraction and separation, diastereomer 13 A 1: 1 mixture of and is obtained. The mixture was treated with potassium carbonate (2 eq) in methanol for 2 hours at 0 ° C. to fully isomerize 14 to 13 which was converted to an inert sg of triethylamine (3: 1 hexanes). Isolate in the pure state by chromatography with (ethyl acetate) (12 to 63%). Conversion of 13 to ovalicin (1) is performed as follows. A solution of 13 in benzene was treated with vanadyl acetylacetonate (0.14 equivalents) followed by a solution of dry tert-butyl hydroperoxide (2 equivalents) in toluene for 2 hours at room temperature. Specific (by TLC and ¹ H NMR analysis) gave ( ^* )-ovalkin (1), chromatographed with inactive sg of triethylamine (3: 1 hexane-ethyl acetate), yield 89% Isolate with ( ^* )-1 of the synthesis is ¹ H NMR analysis, IR analysis, mass spectral analysis, 13C
It cannot be distinguished from the reference sample by NMR analysis and the mobility of the chromatography with sg in several solvent systems. Further derivatization can take place by reaction and opening of the epoxide.

  (Synthesis of Example 162)

ここでＲ７７は、詳細な説明において規定されるような基である。

Here, R77 is a group as defined in the detailed description.

ここでＲ７７は、詳細な説明において規定されるような基である。

Here, R77 is a group as defined in the detailed description.

（ＩＩ．機構）
（方法１：ＳＭＩＳイミダゾキノリンを作製するためのＳＭＩＰイミダゾキノリンの誘導体化）

(II. Mechanism)
(Method 1: Derivatization of SMIL imidazoquinoline to make SMIS imidazoquinoline)

（方法２：ＳＭＩＳ縮合テトラシクロピリミジノン（ｔｅｔｒａｃｙｃｌｏｐｙｒｍｉｄｉｎｏｎｅ）を作製するためのＳＭＩＰ縮合テトラシクロピリミジノンへの誘導体化）

Method 2: Derivatization to SMIP-fused tetracyclopyrimidinone to make SMIS-fused tetracyclopyrimidinone

（表２：新規ＳＭＩＰ化合物およびそれらのＳＭＩＳアナログ）

Table 2: New SMIP compounds and their SMIS analogs

実施例の化合物に対する命名は、Ａｄｖａｎｃｅｄ Ｃｈｅｍｉｓｔｒｙ Ｄｅｖｅｌｏｐｍｅｎｔ，Ｉｎｃ．から入手可能なＡＣＤ Ｎａｍｅ ｖｅｒｓｉｏｎ ５．０７ ソフトウェア（２００１年１１月１４日）を使用して提供した。化合物および出発物質のいくつかは、スタンダードＩＵＰＡＣ命名法を使用して命名した。

The nomenclature for the example compounds is given in Advanced Chemistry Development, Inc. Provided using the ACD Name version 5.07 software available from (November 14, 2001). Some of the compounds and starting materials were named using standard IUPAC nomenclature.

Examples 2 to 67 in Table 3 were synthesized according to the synthetic methods described in the above Examples and Schemes and screened according to the methods immediately following the table below. Precursors can be readily recognized by those skilled in the art, such as Aldrich (Milwaukee, Wis.) Or Acros.
Commercially available from Organics (Pittsburgh, PA).

表４の化合物の好ましいアナログは、

Preferred analogs of the compounds in Table 4 are

によって包含される化合物のアナログを含む。

Including analogs of compounds encompassed by

(Biological Example)
(Example 174)
Candidate small molecule enhancers can be identified in vitro. Compounds are screened for the ability to activate immune cells in vitro. One indicator of such activation is induction of cytokine production (eg, TNF-α production). Small molecules that induce apoptosis can be identified as having this activity. These small molecule immune enhancing factors have potential utility as adjuvants and immunotherapeutic agents.

In an assay procedure for small molecule immune enhancing factor (SMIP) (High Throughput Screening (HTS)), human peripheral blood mononuclear cells (PBMC) (500,000 per mL in RPMI 1640 medium containing 10% FCS were already added to DMSO. Distribute into 96-well plates containing 5 μM of compound (100,000 per well) Incubate this PBMC in 5% CO ₂ for 18 hours at 37 ° C. Produce cytokines in response to small molecule compounds Their ability to do is determined using a modified sandwich ELISA, or Luminex Technology can be used.

  Briefly, supernatants from PBMC cultures were assayed for secreted TNF using a primary plate-binding antibody for capture and then a secondary biotinylated anti-TNF antibody forming a sandwich. . This biotinylated second antibody was then detected using streptavidin-europium and the amount of bound europium was measured by fluorescence that disappeared over time. SMIP compounds are confirmed by the TNF-induced activity measured in this assay as increased europium values for cells incubated in their RPMI medium alone. “Hits” were selected based on their TNF-inducing activity against the optimal dose of lipopolysaccharide (LPS) (1 μg / ml) (a potent TNF-inducing agent). The stringency and low background of this assay allowed the conventional selection of hits with about 10% LPS activity, usually between 5 and 10 times background (cells only). The selected hits are then subjected to confirmation of their ability to induce cytokines from multiple donors at reduced levels. Those compounds with consistent activity at 5 μM or less are examined and confirmed for the purpose of this assay. This assay is readily modified to screen for compounds that are effective at higher or lower levels.

(Example 175)
Each of Examples 2-67 induced TNF-α production in human peripheral blood mononuclear cells. Many of the compounds showed activity at less than 20 μM for TNF-α production. Many of these compounds showed activity at less than 5 μM for TNF-α production. Many of these compounds showed activity at less than 1.5 μM for TNF-α production.

  For this reason, each of the R groups of any of the compounds listed in Table 3 is preferred. In addition, due to the superior activity and mechanistic correlation of each of the compounds, each of these compounds in Tables 3 and 4 is individually preferred and is a group comprising any or all of the other compounds. Each compound is preferred in methods of modulating immune enhancement and methods of treating biological conditions associated therewith, eg, used as a vaccine adjuvant. Each of these compounds is also preferred for use in the preparation of pharmaceuticals for vaccines, immune enhancement, reduction of tumor growth and treatment of biological conditions mediated by tumor growth.

  In addition to the above procedures, methods for measuring other cytokines (eg, IL1-β, IL-12, IL-6, IFN-γ, IL-10, etc.) are well known in the art and Can be used to find active SMIP compounds of the invention.

  In the assays described herein, compounds that result in production of TNF-α at higher levels (eg, 100 μM, 200 μM or 300 μM) may be useful. For example, loxoribine leads to the useful production of TNF-α at 300 μM (Pope et al., Immunostimulatory Compound 7-Allyl-8-Oxogenoline 3 (Loxorivine) Induces a Distinc Subsine. checking).

(Example 176)
A combinatorial library is constructed (e.g., using conventional mixed / split synthesis on a suitable resin bead support), which generally comprises about 2 to 500 compounds, and preferably about 2O to Contains a number of sub-library mixtures, each containing 100 compounds. The bead carrier is preferably high-loading beads (providing> 1 nanomole of compound per bead). It is also preferred that the bead carrier has a substantially uniform diameter. The use of a substantially uniform population of bead carriers in the method of the present invention provides the additional benefit that the final reaction volume of the compound that is cleaved from the bead carrier has a substantially uniform compound level. Thus, preferably, the bead carrier has a dispersion with a diameter of about 40%, preferably about 30%, more preferably about 20%, and most preferably less than about 5-10%. The actual number of individual compounds in each sub-library is not critical or limiting in the present invention, and the method can be used with any size sub-library selected by user preference. Can be implemented. Prior to detaching the compound from the resin bead carrier, each sublibrary is divided into an archive sample and a screening sample, where the screening sample generally consists of about 10-30% of the total volume of the sublibrary. Is done.

  Small aliquots of archive samples can be used for post-synthesis statistical analysis, using the methods and devices of the present invention, single in a suitable reaction vessel (preferably a multi-well plate or a fixed array of reaction vials). Of the beads so that each bead can be chemically analyzed or screened independently. This statistical analysis can be used to determine the amount of different compounds present in the archive sample and / or to identify these compounds. The rest of the archive sample remains in bound form (unbroken) but is processed to remove the solvent and dried appropriately, then as an intact archive sample or as individual beads, small collections of beads Stored either in the body or in multiple replica samples that may contain a pool of the entire sub-library of beads. Storage of archive samples in dry, unbroken form allows the library to be stored indefinitely, with compound loss and / or reduced incidence of degradation.

  The screening sample is dispensed into a reaction vessel (eg, a fixed array of multi-well plates or reaction vials) to establish a screening aliquot. The screening aliquot is then processed in an appropriate fragmentation step to remove and separate the bead carrier from the fragmented compound, and the fragmented compound is screened for a desired activity in a representative primary screen. For example, a fragmented compound can be subjected to evaporation to remove the solvent, lyophilized, labeled (if desired), and subjected to lysis. Thereafter, the sub-library containing the active ingredient is subjected to the following non-synthetic analysis method.

  A dried archive sample corresponding to the sub-library identified as active in the primary screening of the analytical sample is then recovered. The probability that a sample is reconstituted in a suitable solvent (preferably a solvent having a density of at least about 1.1 g / ml) and each compound in the sub-library is represented using a suitable bead sorter Distribute one bead per well in a multi-well reaction plate or reaction vessel array in multiple excesses (eg, in a 5-fold excess) such that is greater than 95%. If desired, the bead sorter is used to dispense any number of beads per well (eg, when a combination of compounds is evaluated for activity in the screening method).

After dispensing the desired number of beads, the non-synthetic analysis method of the present invention is then performed. As discussed above, each sub-library typically contains about 20-100 compounds each, so about 100-500 different beads can be dispensed from the archive sample to display the appropriate compounds. A screening array can be provided. These compounds are cleaved from the bead carrier using a suitable cleaving reagent and these compounds are reconstituted in a suitable reaction solvent (eg DMSO). This portion of the fragmented compound is delivered into a further array that mimics the screening array. The replica array is then contacted with cells (eg, HPMC) and immunologically active compounds are identified using the high throughput assay of the present invention. A sample preparation (eg, 10%) of the preliminary portion of the screening array is then used to provide direct chemical identification and characterization of the active compound using conventional chemical analytics (eg, liquid chromatography (eg, (For HPLC analysis, mass spectrometry (MS) and / or nitrogen (N ₂ ) analysis) As can be seen, the non-synthetic analysis described above is performed in a mixture of compounds synthesized by the method of mixing and resolving. Avoid repetitive analysis by resynthesis, which is usually required to identify single compounds involved in chemical and / or chemical activity, if desired, individual compounds can be chemically tagged Appropriate labeling (eg, mass tags, enzyme labels, etc.) can facilitate sample identification, but such labeling can be performed using MS data. Since the active sub-library construction can readily be used as a "tag" for the component, providing only a margin in non-synthetic analysis method of the present invention.

本発明は、本発明の実施に関して現在好ましい形態を含む特定の実施例に関して記載されてきたが、本発明の精神および範囲内にある上記に記載されるシステムおよび技術に関して多数のバリエーションおよび変更があることは、当業者に理解される。

Although the invention has been described with reference to specific embodiments, including presently preferred forms of implementing the invention, there are numerous variations and modifications with respect to the systems and techniques described above that are within the spirit and scope of the invention. This will be understood by those skilled in the art.

  Each of the following US provisional patent applications is hereby incorporated by reference in its entirety: 60 / 599,717 filed on August 5, 2004; 60 filed on August 5, 2004. No./599,592; 60 / 600,850 filed on Aug. 11, 2004; 60 / 603,001 filed on Aug. 19, 2004; filed on Aug. 23, 2004 60 / 603,867; 60 / 612,070 filed on September 21, 2004; 60 / 582,654 filed on June 24, 2004; filed on September 21, 2004 60 / 614,963; and 60 / 590,459 filed on July 22, 2004.

(Incorporation as a reference)
The contents of all patents, patent applications and journal articles cited throughout this document are incorporated by reference as if fully set forth herein.

Claims (23)

An immunogenic composition for eliciting an immune response in a patient comprising an antigen and formula (IV):

Small molecule immune enhancer ( SMIP ) compounds , wherein R ₁₁ is hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and Unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxy Alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted hetero From aralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted arylamino, substituted and unsubstituted heteroarylamino, substituted and unsubstituted heterocyclylamino, and substituted and unsubstituted carbocyclylamino Selected from the group consisting of;
R ₁₂ and R ₁₃ are joined together to form a diagram (IV _a ):

Forming a heterocyclyl group as shown in
R _12a is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy Selected from the group consisting of: substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted alkoxyalkyl;
R _13a is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl;
R _b is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy , substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substitution and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and Unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted Selected from the group consisting of substituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl
An immunogenic composition. The immunogenic composition of claim 1 , wherein R ₁₁ is of the formula (R _11a ):

Wherein R ₁₄ and R ₁₅ are H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted And unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted Independently from the group consisting of telocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, substituted and unsubstituted heteroaralkenyl, substituted and unsubstituted heterocyclylalkenyl, and substituted and unsubstituted carbocyclylalkenyl or selected Te; or R ₁₄ and R ₁₅ form a substituted or unsubstituted heteroaryl group together immunogenic composition. An immunogenic composition according to claim 2, as R _11a is a DNA base to form a substituted heteroaryl group R ₁₄ and R ₁₅ together form an immunogenic composition. An immunogenic composition according to claim 3, wherein the DNA base is adenine, immunogenic compositions. An immunogenic composition according to claim 2, R ₁₄ is aminocarbonyl, immunogenic compositions. An immunogenic composition according to claim 2, R ₁₄ is hydroxy, immunogenic compositions. An immunogenic composition according to any one of claims 1 to 6, wherein the SMIP compound, characterized in that it is administered in a dose may increase the TNF-alpha levels, immunogenic compositions. The immunogenic composition according to any one of claims 1 to 6 , wherein the SMIP compound is a glucocorticoid receptor, DNA alkylation, calcineurin, JNK, p38 kinase, cyclin kinase cascade, PDE IV, IMPDH, DHOD. , Lck, and an immunogenic composition that modulates the activity of at least one target selected from the group consisting of thymidylate synthase. An immunogenic composition according to any one of claims 1 to 6, wherein the immune response involved in the production of cytokines, the immunogenic composition. An immunogenic composition according to any one of claims 1 to 6, wherein the immune response involved in increased production of TNF-alpha, the immunogenic composition. An immunogenic composition according to any one of claims 1 to 6, wherein the patient is suffering from a viral infection, the immunogenic composition. An immunogenic composition according to claim 11, wherein the viral infection is HCV, immunogenic compositions. An immunogenic composition according to any one of claims 1 to 6, wherein the patient is suffering from cell proliferation or cancer progression, immunogenic compositions. An immunogenic composition according to any one of claims 1 to 6, wherein the patient is suffering from allergic diseases, the immunogenic composition. An immunogenic composition according to any one of claims 1 to 6, wherein the patient is suffering from asthma, immunogenic compositions. An immunogenic composition according to claim 11, you wherein SMIP compound is coadministered with another agent, the immunogenic composition. An immunogenic composition according to claim 12, you wherein SMIP compound is coadministered with another agent, the immunogenic composition. An immunogenic composition according to claim 13, you wherein SMIP compound is coadministered with another agent, the immunogenic composition. An immunogenic composition according to claim 14, you wherein SMIP compound is coadministered with another agent, the immunogenic composition. An immunogenic composition according to claim 15, you wherein SMIP compound is coadministered with another agent, the immunogenic composition. An immunogenic composition according to any one of claims 1 to 6, wherein the SMIP compound you characterized in that it is co-administered with another agent, the immunogenic composition. An immunogenic composition according to any one of claims 1 to 6 when the SMIP compound is present at a concentration of less than 20 [mu] M, that give to induce the production of TNF-alpha, the immunogenic composition . Formula (IV):

A small molecule immune enhancer (SMIP) compound, wherein
R ₁₁ Is hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted alkoxy Carbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted carbocyclyl, substituted and Unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted Unsubstituted carbocyclylalkyl, substituted and unsubstituted arylamino, substituted and unsubstituted heteroarylamino, is selected from the group consisting of substituted and unsubstituted heterocyclylaminoalkyl, and substituted and unsubstituted carbocyclylalkyl amino;
R ₁₂ Is H, halogen, hydroxy, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted And selected from the group consisting of unsubstituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxy, and substituted and unsubstituted alkoxyalkyl; and
R ₁₃ Is selected from the group consisting of H, hydroxyl, alkoxy, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heteroaryl; or
R ₁₂ And R ₁₃ Are joined together to form a substituted or unsubstituted heterocyclyl group; and
R _b H, halogen, amino, nitro, cyano, carboxylic acid, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylamino, substituted and unsubstituted carbonyloxy, substituted and unsubstituted Substituted alkoxycarbonyl, substituted and unsubstituted aminocarbonyl, substituted and unsubstituted carbonylamino, substituted and unsubstituted sulfonyl, substituted and unsubstituted alkoxyalkyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted And unsubstituted heteroaryl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted heterocyclylalkyl, substituted and unsubstituted carbocyclylalkyl, substituted and unsubstituted aralkenyl, Conversion and unsubstituted heteroaralkenyl, is selected from the group consisting of substituted and unsubstituted heterocyclylalkyl, and substituted and unsubstituted carbocyclylalkyl alkenyl
Small molecule immune enhancer (SMIP) compounds.