JP2007538081A - Synthesis of amino acid ketoepoxides. - Google Patents

Abstract

The present invention relates to a process for the preparation of amino acid keto epoxides according to scheme (I). Specifically, allyl ketone is stereoselectively converted to the desired keto epoxide. In a typical procedure, allyl ketone is stereoselectively reduced by a reducing agent such as sodium borohydride with cerium trichloride, lithium tri-tert-butoxyaluminum hydride, or L-Selectride, and then m-chloroperoxide. Stereoselectively epoxidized with an oxidant such as benzoic acid or VO (acac) ₂ with t-BuOOH, followed by Swern oxidation, or oxidant such as Dess-Martin periodinane, or 4-methylmorpholine-N-oxide Oxidized by tetrapropyl perruthenate (TPAP) with (NMO).

Description

(Background of the Invention)
Many compounds have been identified that are generally useful as inhibitors of enzymes with a nucleophilic group at the N-terminus that are structurally related to epoxomicin (Non-patent Document 1).

These compounds are disclosed in U.S. patent application Ser. Nos. 09/559748, 60/562340, and 11 / 106,879, and PCT applications filed May 9, 2005. Are incorporated herein by reference.
Hanada, M .; Et al. Antibiotics, 1992, Vol. 45, No. 11, pp. 1746-1752

  There remains a need for improved processes for producing these compounds in an efficient manner.

(Summary of the Invention)
The present invention relates to a method for synthesizing amino acid keto epoxide according to scheme (I),

ここで
Ｒ^１は、保護基またはアミノ酸のさらなる鎖より選択され、該保護基またはアミノ酸のさらなる鎖は、それ自体必要に応じて置換されていてもよく、好ましくは保護基、最も好ましくは電子吸引性保護基であり；
Ｒ^２は、水素およびＣ_１〜６アルキルより選択されるか；または
Ｒ^１およびＲ^２は、一緒になってＣ（Ｏ）−アリール−Ｃ（Ｏ）またはＣ（Ｏ）Ｃ_１〜６アルケニルＣ（Ｏ）であって、それにより環を形成し；
Ｒ^３は、水素、Ｃ_１〜６アルキル、Ｃ_１〜６アルコキシアルキル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６ヘテロアラルキル、およびＣ_１〜６アラルキルより選択され；
Ａは、還元条件下での立体選択的還元であり、好ましくは、三塩化セリウムを伴う水素化ホウ素ナトリウム、水素化リチウムトリ−ｔｅｒｔ−ブトキシアルミニウム、またはＬ−Ｓｅｌｅｃｔｒｉｄｅ、最も好ましくは三塩化セリウムを伴う水素化ホウ素ナトリウム；
Ｂは、エポキシ化条件下での立体選択的エポキシ化であり、好ましくはｍ−クロロ過安息香酸、またはｔ−ＢｕＯＯＨを伴うＶＯ（ａｃａｃ）_２であり、最も好ましくはｔ−ＢｕＯＯＨを伴うＶＯ（ａｃａｃ）_２であり；そして
Ｃは、酸化条件下での酸化であり、好ましくはＤｅｓｓ−Ｍａｒｔｉｎペルヨージナンなど、Ｓｗｅｒｎ酸化、または４−メチルモルホリン−Ｎ−オキシドを伴う過ルテニウム酸テトラプロピルである。

Wherein R ¹ is selected from a protecting group or a further chain of amino acids, which further chain of the protecting group or amino acid may itself be optionally substituted, preferably a protecting group, most preferably electron withdrawing A protective group;
R ² is selected from hydrogen and C _1-6 alkyl; or R ¹ and R ² together are C (O) -aryl-C (O) or C (O) C _1-6 alkenyl. C (O) thereby forming a ring;
R ³ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxyalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 heteroaralkyl, and C _1-6 aralkyl;
A is a stereoselective reduction under reducing conditions, preferably sodium borohydride with cerium trichloride, lithium tri-tert-butoxyaluminum hydride, or L-Selectride, most preferably cerium trichloride. Accompanying sodium borohydride;
B is a stereoselective epoxidation under epoxidation conditions, preferably m-chloroperbenzoic acid, or VO (acac) ₂ with t-BuOOH, most preferably VO with t-BuOOH ( acac) ₂ ; and C is oxidation under oxidizing conditions, preferably Swern oxidation, such as Dess-Martin periodinane, or tetrapropyl perruthenate with 4-methylmorpholine-N-oxide.

  Other features and advantages of the invention will be apparent from the following detailed description and from the claims.

(Detailed description of the invention)
A number of compounds have been identified that are generally useful as inhibitors of enzymes having a nucleophilic group at the N-terminus. The present invention describes an efficient method for producing these compounds. More specifically, described herein are methods for the stereoselective synthesis of amino acid keto epoxides.

  These keto epoxides may optionally contain a group attached to the α ′ carbon, the stereochemistry of which the α ′ carbon (which forms part of the epoxide or aziridine ring) is (R) Or (S). Preferred compounds have the indicated top-bottom (or β-α; where β is above the face of the page) or (R)-(S) relationship shown. Note that it can have many stereocenters (ie it is not necessary for every stereocenter in the compound to take the described preferred configuration). In some preferred embodiments, the α-carbon stereochemistry is (R), ie the X atom is β, ie above the face of the molecule. Regarding stereochemistry, Cahn-Ingold-Prelog rules for determining absolute stereochemistry are followed. These rules are described, for example, in Organic Chemistry, Fox, and Whitesell; Jones and Bartlett Publishers, Boston, MA (1994); Is incorporated by reference.

  The present invention relates to a method for synthesizing an amino acid ketoepoxide according to scheme (I),

ここで
Ｒ^１は、保護基またはアミノ酸のさらなる鎖より選択され、この保護基またはアミノ酸のさらなる鎖は、それ自体必要に応じて置換されていてもよく、好ましくは、保護基、最も好ましくは電子吸引性保護基であり；
Ｒ^２は、水素およびＣ_１〜６アルキルより選択されるか；または
Ｒ^１およびＲ^２は、一緒になって、Ｃ（Ｏ）−アリール−Ｃ（Ｏ）またはＣ（Ｏ）Ｃ_１〜６アルケニルＣ（Ｏ）、それにより環を形成し；
Ｒ^１は、水素、Ｃ_１〜６アルキル、Ｃ_１〜６アルコキシアルキル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６ヘテロアラルキル、およびＣ_１〜６アラルキルより選択され；
Ａは、還元条件下での立体選択的還元であり、好ましくはここでこの還元剤は、三塩化セリウムを伴う水素化ホウ素ナトリウム、水素化リチウムトリ−ｔｅｒｔ−ブトキシアルミニウム、またはＬ−Ｓｅｌｅｃｔｒｉｄｅ、最も好ましくは三塩化セリウムを伴う水素化ホウ素ナトリウムであり；
Ｂは、エポキシ化条件下での立体選択的エポキシ化であり、好ましくはここでこの酸化剤は、ｍ−クロロ過安息香酸、またはｔ−ＢｕＯＯＨを伴うＶＯ（ａｃａｃ）_２、最も好ましくはｔ−ＢｕＯＯＨを伴うＶＯ（ａｃａｃ）_２であり；そして
Ｃは、酸化条件下での酸化であり、好ましくはＳｗｅｒｎ酸化、または酸化剤がＤｅｓｓ−Ｍａｒｔｉｎペルヨージナンなど、または４−メチルモルホリン−Ｎ−オキシド（ＮＭＯ）を伴う過ルテニウム酸テトラプロピル（ＴＰＡＰ）である酸化であり、最も好ましくはＳｗｅｒｎ酸化である。

Wherein R ¹ is selected from a protecting group or an additional chain of amino acids, which further chain of amino acids may optionally be substituted per se, preferably a protecting group, most preferably an electron An attractive protective group;
R ² is selected from hydrogen and C _1-6 alkyl; or R ¹ and R ^{2 taken} together are C (O) -aryl-C (O) or C (O) C _1-6. Alkenyl C (O), thereby forming a ring;
R ¹ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxyalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 heteroaralkyl, and C _1-6 aralkyl;
A is a stereoselective reduction under reducing conditions, preferably where the reducing agent is sodium borohydride with cerium trichloride, lithium tri-tert-butoxyaluminum hydride, or L-Selectride, most Preferably sodium borohydride with cerium trichloride;
B is a stereoselective epoxidation under epoxidation conditions, preferably where the oxidant is m-chloroperbenzoic acid, or VO (acac) ₂ with t-BuOOH, most preferably t- VO (acac) ₂ with BuOOH; and C is oxidation under oxidizing conditions, preferably Swern oxidation, or the oxidizing agent is Dess-Martin periodinane, or 4-methylmorpholine-N-oxide (NMO ), Which is tetrapropyl perruthenate (TPAP), most preferably Swern oxidation.

  Various N-protecting groups (for example, benzyloxycarbonyl group or t-butyloxycarbonyl group (Boc)), various coupling agents (for example, dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), 1 -(3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), N-hydroxyazabenzotriazole (HATU), carbonyldiimidazole, or 1-hydroxybenzotriazole monohydrate (HOBT)) and various Cleavage conditions (eg, trifluoroacetic acid (TFA), HCl in dioxane, hydrogenation with Pd—C in organic solvents (eg, methanol or ethyl acetate), boron tris (trifluoroacetate) (triflu (triflu) reaction in solution with isolation and purification of intermediates and intermediates are well known in the field of peptide synthesis and are equally applicable to the preparation of the above target compounds (Greene, TW). Wuts, PGM Protective Groups in Organic Synthesis, 3rd edition; Wiley: New York, 1999).

In certain embodiments, R ¹ is selected from a protecting group or additional chain of amino acids, which protecting group or additional chain of amino acids may itself be optionally substituted. In a preferred embodiment, R ¹ is a protecting group. In a more preferred embodiment, R ¹ is an electron withdrawing protecting group. In certain such embodiments, R ¹ is t-butoxycarbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), and benzyloxycarbonyl (Cbz). ) Is selected. In a more preferred embodiment, R ¹ is Cbz.

In certain embodiments, R ¹ and R ^{2 taken} together are C (O) -aryl-C (O) or C (O) C _1-6 alkenyl C (O), thereby forming a ring Form. In preferred such embodiments, R ¹ and R ¹ together are phthaloyl.

In certain embodiments, R ³ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxyalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 heteroaralkyl and C _1-6 aralkyl. In a preferred embodiment, R ³ is C _1-6 alkyl. In the most preferred embodiment, R ³ is isobutyl.

  A is a stereoselective reduction under reducing conditions. In a preferred embodiment, the reducing agent of A is selected from sodium borohydride with cerium trichloride, lithium tri-tert-butoxyaluminum hydride or L-Selectride. In a more preferred embodiment, the reducing agent is sodium borohydride with cerium trichloride. Other suitable reagents include achiral reducing agents such as lithium aluminum hydride, trimethoxy lithium aluminum hydride, K-Selectride, KS-Selectride, LS-Selectride, and diisobutylaluminum hydride (R) or ( S) -2-methyl-CBS-oxaborolidine and (R) or (S) -alpine borane, chiral oxazaborolidine, (R, R or S, S) lithium dimethylborolane and chiral hydrogenated alkoxy These include chiral reducing agents such as (acyloxy) boron, or achiral reducing agents in the presence of chiral additives such as achiral lithium aluminum hydride in the presence of quinine or ephedrine. Not limited to

B is a stereoselective epoxidation under epoxidation conditions. In preferred embodiments, the conditions include m-chloroperbenzoic acid (or another suitable peracid), or VO (acac) 2 with t-BuOOH. In a preferred embodiment, B is VO (acac) ₂ with t-BuOOH. Other suitable epoxidation conditions include, but are not limited to, Sharpless asymmetric epoxidation, Shi asymmetric epoxidation, Jacobsen epoxidation, dimethyldioxolane and trifluoromethylmethyloxolane.

  C is oxidation under oxidizing conditions. In preferred embodiments, C is Swern oxidation or Moffat oxidation, or employs TPAP with Dess-Martin periodinane or NMO. In the most preferred embodiment, C is Swern oxidation. Other suitable oxidizing agents include, but are not limited to, ruthenium dioxide, pyridinium chlorochromate (PCC), IBX, and pyridinium dichromate (PDC).

  In certain embodiments, the present invention provides the above reaction sequence as a separate stage in which the products of each reaction (A, B, and C) are isolated and purified. In another embodiment, the present invention provides a reaction sequence in which the product of at least one reaction is used in the next reaction without isolation and / or purification. Furthermore, the present invention relates to reaction sequences (A, B, and C), each individual reaction (A, B, and C) and some combinations thereof. Accordingly, the present invention provides scheme (II):

に従うアリルアルコールの合成に関し、ここで
Ｒ^１は、保護基またはアミノ酸のさらなる鎖より選択され、この保護基またはアミノ酸のさらなる鎖はそれ自体必要に応じて置換されていてもよく、好ましくは保護基であり、最も好ましくは電子吸引性保護基であり；
Ｒ^２は、水素およびＣ_１〜６アルキルより選択されるか；または
Ｒ^１およびＲ^２は、一緒になって、Ｃ（Ｏ）−アリール−Ｃ（Ｏ）またはＣ（Ｏ）Ｃ_１〜６アルケニルＣ（Ｏ）であり、それにより環を形成し；
Ｒ^３は、水素、Ｃ_１〜６アルキル、Ｃ_１〜６アルコキシアルキル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６ヘテロアラルキル、およびＣ_１〜６アラルキルより選択され；そして
Ａは、還元条件下での立体選択的還元であり、好ましくはこの還元剤は、三塩化セリウムを伴う水素化ホウ素ナトリウム、水素化リチウムトリ−ｔｅｒｔ−ブトキシアルミニウム、またはＬ−Ｓｅｌｅｃｔｒｉｄｅであり、最も好ましくは、三塩化セリウムを伴う水素化ホウ素ナトリウムである。

Wherein R ¹ is selected from a protecting group or a further chain of amino acids, which protecting group or further chain of amino acids may itself be optionally substituted, preferably a protecting group And most preferably an electron-withdrawing protecting group;
R ² is selected from hydrogen and C _1-6 alkyl; or R ¹ and R ^{2 taken} together are C (O) -aryl-C (O) or C (O) C _1-6. Alkenyl C (O), thereby forming a ring;
R ³ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxyalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 heteroaralkyl, and C _1-6 aralkyl; and A is under reducing conditions Preferably, the reducing agent is sodium borohydride with cerium trichloride, lithium tri-tert-butoxyaluminum hydride, or L-Selectride, most preferably cerium trichloride. Sodium borohydride with

  The present invention further provides Scheme (III):

に従うエポキシドの合成に関し、ここで
Ｒ^１は、保護基またはアミノ酸のさらなる鎖より選択され、この保護基またはアミノ酸のさらなる鎖は、それ自体必要に応じて置換されていてもよく、好ましくは保護基であり、最も好ましくは電子吸引性保護基であり；
Ｒ^２は、水素およびＣ_１〜６アルキルより選択されるか；または
Ｒ^１およびＲ^２は、一緒になって、Ｃ（Ｏ）−アリール−Ｃ（Ｏ）またはＣ（Ｏ）Ｃ_１〜６アルケニルＣ（Ｏ）であり、それにより環を形成し；
Ｒ^３は、水素、Ｃ_１〜６アルキル、Ｃ_１〜６アルコキシアルキル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６ヘテロアラルキル、およびＣ_１〜６アラルキルより選択され；そして
Ｂは、エポキシ化条件下での立体選択的エポキシ化であり、好ましくはこの酸化剤は、ｍ−クロロ過安息香酸、またはＶＯ（ａｃａｃ）_２であり、最も好ましくはｔ−ＢｕＯＯＨを伴うＶＯ（ａｃａｃ）_２である。

Wherein R ¹ is selected from a protecting group or a further chain of amino acids, which protecting group or further chain of amino acids may itself be optionally substituted, preferably a protecting group And most preferably an electron-withdrawing protecting group;
R ² is selected from hydrogen and C _1-6 alkyl; or R ¹ and R ^{2 taken} together are C (O) -aryl-C (O) or C (O) C _1-6. Alkenyl C (O), thereby forming a ring;
R ³ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxyalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 heteroaralkyl, and C _1-6 aralkyl; and B is an epoxidation condition Stereoselective epoxidation below, preferably the oxidant is m-chloroperbenzoic acid, or VO (acac) ₂ , most preferably VO (acac) ₂ with t-BuOOH.

  Furthermore, the present invention provides a scheme (IV):

に従うアミノ酸ケトエポキシドの合成に関し、ここで
Ｒ^１は、保護基またはアミノ酸のさらなる鎖より選択され、この保護基またはアミノ酸のさらなる鎖はそれ自体必要に応じて置換されていてもよく、好ましくは保護基であり、最も好ましくは電子吸引性保護基であり；
Ｒ^２は、水素およびＣ_１〜６アルキルより選択されるか；または
Ｒ^１およびＲ^２は、一緒になって、Ｃ（Ｏ）−アリール−Ｃ（Ｏ）またはＣ（Ｏ）Ｃ_１〜６アルケニルＣ（Ｏ）であり、それにより環を形成し；
Ｒ^３は、水素、Ｃ_１〜６アルキル、Ｃ_１〜６アルコキシアルキル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６ヘテロアラルキル、およびＣ_１〜６アラルキルより選択され；そして
Ｃは、酸化条件下での酸化、好ましくはＳｗｅｒｎ酸化、または上記酸化剤がＤｅｓｓ−Ｍａｒｔｉｎペルヨージナン、または４−メチルモルホリン−Ｎ−オキシド（ＮＭＯ）を伴う過ルテニウム酸テトラプロピル（ＴＰＡＰ）である酸化であり、最も好ましくはＳｗｅｒｎ酸化である。

Wherein R ¹ is selected from a protecting group or an additional chain of amino acids, which protecting group or further chain of amino acids may itself be optionally substituted, preferably protected A group, most preferably an electron-withdrawing protecting group;
R ² is selected from hydrogen and C _1-6 alkyl; or R ¹ and R ^{2 taken} together are C (O) -aryl-C (O) or C (O) C _1-6. Alkenyl C (O), thereby forming a ring;
R ³ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxyalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 heteroaralkyl, and C _1-6 aralkyl; and C is under oxidizing conditions Oxidation, preferably Swern oxidation, or oxidation wherein the oxidant is Dess-Martin periodinane, or tetrapropyl perruthenate (TPAP) with 4-methylmorpholine-N-oxide (NMO), most preferably Swern oxidation.

  In another embodiment, the reduction is performed in Scheme (V):

に示されるようなアルデヒドへの有機金属の付加およびそれに続くエポキシ化、酸化の順序で置き換えられ得る。

Can be replaced by the addition of an organometallic to the aldehyde followed by epoxidation and oxidation as shown in

  Alternatively, the epoxidation may be performed according to scheme (VI):

に示されるように、不斉ジヒドロキシル化、選択的シリル化またはトシル化、エポキシ化順序で置き換えられ得、所望のアミノ酸ケトエポキシドに到達される。

Can be replaced with an asymmetric dihydroxylation, selective silylation or tosylation, epoxidation sequence to arrive at the desired amino acid ketoepoxide.

  In some embodiments, the amino acid keto epoxide is optionally a four-step procedure (Wipf, P. et al., 1998, J. Org. Chem., 63: 6089-6090) or a one-step procedure (Shao, H. et al., 1995, J. Org. Chem., 60: 790-791), leading to the formation of the corresponding aziridine.

  In certain embodiments, the compound of Scheme I has the following stereochemistry:

を有する。

Have

  In certain embodiments, the amino acid ketoepoxide or ketoaziridine can be further modified by deprotection of the amine and coupling with a chain of amino acids, if applicable. Methods for coupling such fragments are well known in the art (Elofsson, M. et al. (1999) Chemistry & Biology, 6: 811-822). In a preferred embodiment, the amino acid chain comprises 1 to 3 amino acids.

  In certain embodiments, the chain of amino acids has the structure of formula (I):

を有するか、またはその薬学的に受容可能な塩であり、ここで
各Ａは、独立に、Ｃ＝Ｏ、Ｃ＝Ｓ、およびＳＯ_２より選択され、好ましくはＣ＝Ｏであるか；または
Ａは、Ｚの存在に隣接している場合、必要に応じて共有結合であり；
Ｌは、存在しないか、またはＣ＝Ｏ、Ｃ＝Ｓ、およびＳＯ_２より選択され、好ましくは、Ｌは存在しないかまたはＣ＝Ｏであり；
Ｍは、存在しないか、Ｃ_１〜１２アルキル、好ましくはＣ_１〜８アルキルであり；
Ｑは、存在しないか、またはＯ、ＮＨ、およびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＱ は、存在しないか、ＯまたはＮＨであり、最も好ましくはＱは、存在しないかＯであり；
Ｘは、ＣＯＯＨまたはその活性化形態であり、好ましくはＸはＣＯＯＨ、ＣＯＣｌ、またはＣＯＮ（Ｍｅ）（ＯＭｅ）であり、最も好ましくは、ＸはＣＯＯＨまたはＣＯＣｌであり；
Ｙは、存在しないか、Ｏ、ＮＨ、Ｎ−Ｃ_１〜６アルキル、Ｓ、ＳＯ、ＳＯ_２、ＣＨＯＲ^１７およびＣＨＣＯ_２Ｒ^１７より選択され；
各Ｚは、独立に、Ｏ、Ｓ、ＮＨ、およびＮ−Ｃ_１〜６アルキルより選択されるか、好ましくはＯであり；または
Ｚは、Ａの存在に隣接している場合、必要に応じて共有結合であり；
Ｒ^５、Ｒ^６およびＲ^７は、各々独立にＣ_１〜６アルキル、Ｃ_１〜６ヒドロキシアルキル、Ｃ_１〜６アルコキシアルキル、アリール、およびＣ_１〜６アラルキルより選択され、これらの基のいずれも、必要に応じて、アミド、アミン、カルボン酸（またはその塩）、エステル（Ｃ_１〜６アルキルおよびＣ_１〜５アルキルエステルおよびアリールエステルを含む）、チオールまたはチオエステル置換基の１つ以上で置換され；
Ｒ^９は、Ｎ（Ｒ^１０）ＬＱＲ^１１であり；
Ｒ^１０、Ｒ^１２、およびＲ^１３は、独立に、水素、ＯＨ、Ｃ_１〜６アルキル、および式ＩＩ：

Or a pharmaceutically acceptable salt thereof, wherein each A is independently selected from C═O, C═S, and SO ₂ , preferably C═O; or A is optionally a covalent bond when adjacent to the presence of Z;
L is absent or selected from C═O, C═S, and SO ₂ , preferably L is absent or C═O;
M is absent or C _1-12 alkyl, preferably C _1-8 alkyl;
Q is absent or selected from O, NH, and N—C _1-6 alkyl, preferably Q is absent, O or NH, most preferably Q is absent or O Yes;
X is COOH or an activated form thereof, preferably X is COOH, COCl, or CON (Me) (OMe), most preferably X is COOH or COCl;
Y is absent or selected from O, NH, N—C _1-6 alkyl, S, SO, SO ₂ , CHOR ¹⁷ and CHCO ₂ R ¹⁷ ;
Each Z is independently selected from O, S, NH, and N—C _1-6 alkyl, preferably O; or Z is optionally adjacent to the presence of A A covalent bond;
R ⁵ , R ⁶ and R ⁷ are each independently selected from C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxyalkyl, aryl, and C _1-6 aralkyl, and any of these groups Optionally with one or more of an amide, amine, carboxylic acid (or salt thereof), ester (including C _1-6 alkyl and C _1-5 alkyl ester and aryl ester), thiol or thioester substituent Replaced;
R ⁹ is N (R ¹⁰ ) LQR ¹¹ ;
R ¹⁰ , R ¹² , and R ¹³ are independently hydrogen, OH, C _1-6 alkyl, and Formula II:

の基より選択され；好ましくは、Ｒ^１０は、水素、ＯＨ、およびＣ_１〜６アルキルより選択され、そしてＲ^１２およびＲ^１３は、独立に水素およびＣ_１〜６アルキルより選択され、好ましくは水素であり；
Ｒ^１１は、水素、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、アリール、Ｃ_１〜６アラルキル、ヘテロアリール、Ｃ_１〜６ヘテロアラルキル、Ｒ^１５ＺＡＺ−Ｃ_１〜８アルキル−、Ｒ^１８Ｚ−Ｃ_１〜８アルキル−、（Ｒ^１５Ｏ）（Ｒ^１６Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−ＺＡＺ−Ｃ_１〜８アルキル−、Ｒ^１５ＺＡＺ−Ｃ_１〜８アルキル−ＺＡＺ−Ｃ_１〜８アルキル−、ヘテロシクリルＭＺＡＺ−Ｃ_１〜８アルキル−、（Ｒ^１５Ｏ）（Ｒ^１６Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−、（Ｒ^１７）_２Ｎ−Ｃ_１〜１２アルキル−、（Ｒ^１７）_３Ｎ^＋−Ｃ_１〜１２アルキル−、ヘテロシクリルＭ−、カルボシクリルＭ−、Ｒ^１８ＳＯ_２Ｃ_１〜８アルキル−、およびＲ^１８ＳＯ_２ＮＨより選択され；好ましくは、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、アリール、Ｃ_１〜６アラルキル、ヘテロアリール、Ｃ_１〜６ヘテロアラルキル、Ｒ^１５ＺＡ−Ｃ_１〜８アルキル−、Ｒ^１８Ｚ−Ｃ_１〜８アルキル−、（Ｒ^１５Ｏ）（Ｒ^１６Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−ＺＡＺ−Ｃ_１〜８アルキル−、（Ｒ^１５Ｏ）（Ｒ^１６Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−Ｚ−Ｃ_１〜８アルキル−、Ｒ^１５ＺＡ−Ｃ_１〜８アルキル−ＺＡＺ−Ｃ_１〜８アルキル−、ヘテロシクリルＭＺＡＺ−Ｃ_１〜８アルキル−、（Ｒ^１５Ｏ）（Ｒ^１６Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−、（Ｒ^１７）_２Ｎ−Ｃ_１〜８アルキル−、（Ｒ^１７）_３Ｎ^＋−Ｃ_１〜８アルキル−、ヘテロシクリルＭ−、カルボシクリルＭ−、Ｒ^１８ＳＯ_２Ｃ_１〜８アルキル−、およびＲ^１８ＳＯ_２ＮＨであり、ここでＺおよびＡの各出現は、独立に、共有結合以外であるか；または
Ｒ^１０およびＲ^１１は、一緒になってＣ_１〜６アルキル−Ｙ−Ｃ_１〜６アルキル、Ｃ_１〜６アルキル−ＺＡＺ−Ｃ_１〜６アルキル、ＺＡＺ−Ｃ_１〜６アルキル−ＺＡＺ−Ｃ_１〜６アルキル、ＺＡＺ−Ｃ_１〜６アルキル−ＺＡＺまたはＣ_１〜６アルキル−Ａであり、それにより環を形成し；好ましくは Ｃ_１〜２アルキル−Ｙ−Ｃ_１〜２アルキル、Ｃ_１〜２アルキル−ＺＡ−Ｃ_１〜２アルキル、Ａ−Ｃ_１〜２アルキル−ＺＡ−Ｃ_１〜２アルキル、Ａ−Ｃ_１〜３アルキル−Ａ、またはＣ_１〜４アルキル−Ａであり、ここでＺおよびＡの各出現は、独立に、共有結合以外であり；
Ｒ^１５およびＲ^１６は、独立に、水素、金属カチオン、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、アリール、ヘテロアリール、Ｃ_１〜６アラルキル、およびＣ_１〜６ヘテロアラルキルより選択され、好ましくは水素、金属カチオンおよびＣ_１〜６アルキルより選択されるか、またはＲ^１５およびＲ^１６は、一緒になってＣ_１〜６アルキルであり、それにより環を形成し；
各Ｒ^１７は、独立に、水素およびＣ_１〜６アルキルより選択され、好ましくはＣ_１〜６アルキルであり；
Ｒ^１８は、独立に、水素、ＯＨ、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６アラルキル、およびＣ_１〜６ヘテロアラルキルより選択され；
Ｒ^１９およびＲ^２０は、独立に、水素およびＣ_１〜６アルキルより選択されるか、またはＲ^１９およびＲ^２０は、一緒になって、３〜６員の炭素環式環または複素環式環を形成し；そして
Ｒ^２１およびＲ^２２は、独立に、水素、金属カチオン、Ｃ_１〜６アルキル、およびＣ_１〜６アラルキルより選択されるか、またはＲ^２１およびＲ^２２は、一緒になってＣ_１〜６アルキルを表し、それにより環を形成し；
ただし一連のＺＡＺの任意の出現において、この一連の少なくとも１つのメンバーは、共有結合以外のものでなければならなない。

Preferably, R ¹⁰ is selected from hydrogen, OH, and C _1-6 alkyl, and R ¹² and R ¹³ are independently selected from hydrogen and C _1-6 alkyl, preferably Hydrogen;
R ¹¹ is hydrogen, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, aryl, C _1-6 aralkyl, heteroaryl, C _1-6 heteroaralkyl, R ¹⁵ ZAZ-C _1-8 Alkyl-, R ¹⁸ Z-C _1-8 alkyl-, (R ¹⁵ O) (R ¹⁶ O) P (═O) O—C _1-8 alkyl-ZAZ-C _1-8 alkyl-, R ¹⁵ ZAZ- C _1-8 alkyl-ZAZ-C _1-8 alkyl-, heterocyclyl MZAZ-C _1-8 alkyl-, (R ¹⁵ O) (R ¹⁶ O) P (═O) O—C _1-8 alkyl-, ( R ¹⁷ ) ₂ N—C _1-12 alkyl-, (R ¹⁷ ) ₃ N ⁺ —C _1-12 alkyl-, heterocyclyl M-, carbocyclyl M-, R ¹⁸ SO ₂ C _1-8 alkyl-, and R ¹⁸ Selected from SO ₂ NH Preferably, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, aryl, C _1-6 aralkyl, heteroaryl, C _1-6 heteroaralkyl, R ¹⁵ ZA-C _1-8 Alkyl-, R ¹⁸ Z—C _1-8 alkyl-, (R ¹⁵ O) (R ¹⁶ O) P (═O) O—C _1-8 alkyl-ZAZ-C _1-8 alkyl-, (R ¹⁵ O ) (R ¹⁶ O) P (═O) O—C _1-8 alkyl-Z—C _1-8 alkyl-, R ¹⁵ ZA-C _1-8 alkyl-ZAZ-C _1-8 alkyl-, heterocyclyl MZAZ— C _1-8 alkyl-, (R ¹⁵ O) (R ¹⁶ O) P (═O) O—C _1-8 alkyl-, (R ¹⁷ ) ₂ N—C _1-8 alkyl-, (R ¹⁷ ) ₃ N ⁺ -C _{1 to 8} alkyl -, heterocyclyl M-, carbo Krill _^M-, R ₁₈ SO _{2 C} ^1~8 alkyl -, and a ^R 18 _SO 2 NH, wherein either each occurrence of Z and A is independently other than a covalent bond; or R ¹⁰ and ^{R 11} is, _{C 1 to 6} alkyl _{-Y-C 1 to 6} alkyl taken _{together, C 1 to 6} alkyl _{-ZAZ-C 1~6} alkyl, _{ZAZ-C 1 to 6} alkyl _{-ZAZ-C 1~6} alkyl, _ZAZ-C is _1-6 alkyl -ZAZ or _{C 1-6} alkyl -A, thereby forming a ring; preferably C _{1 to 2} alkyl _{-Y-C 1 to 2 alkyl, C 1 to 2} alkyl -ZA -C _1-2 alkyl, AC _1-2 alkyl-ZA-C _1-2 alkyl, AC _1-3 alkyl-A, or C _1-4 alkyl-A, wherein Z and A Each occurrence is independently other than a covalent bond Ri;
R ¹⁵ and R ¹⁶ are independently hydrogen, metal cation, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, aryl, heteroaryl, C _1-6 aralkyl, and C _1-6 hetero Selected from aralkyl, preferably selected from hydrogen, metal cations and C _1-6 alkyl, or R ¹⁵ and R ^{16 taken} together are C _1-6 alkyl, thereby forming a ring;
Each R ¹⁷ is independently selected from hydrogen and C _1-6 alkyl, preferably C _1-6 alkyl;
R ¹⁸ is independently hydrogen, OH, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C _1-6 aralkyl, and C _1-6 hetero Selected from Aralkyl;
R ¹⁹ and R ²⁰ are independently selected from hydrogen and C _1-6 alkyl, or R ¹⁹ and R ^{20 taken} together are a 3-6 membered carbocyclic or heterocyclic ring And R ²¹ and R ²² are independently selected from hydrogen, metal cations, C _1-6 alkyl, and C _1-6 aralkyl, or R ²¹ and R ^{22 taken} together _Represents C _1-6 alkyl, thereby forming a ring;
However, at any occurrence of a series of ZAZs, the series of at least one member must be other than a covalent bond.

In some embodiments, R ⁵ , R ⁶ and R ⁷ are selected from C _1-6 alkyl or C _1-6 aralkyl. In a preferred embodiment, R ⁶ is C _1-6 alkyl and R ⁵ and R ⁷ are C _1-6 aralkyl. In the most preferred embodiment, R ⁶ is isobutyl, R ⁵ is 2-phenylethyl, and R ⁷ is phenylmethyl.

In certain embodiments, L and Q are absent and R ¹¹ is C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 aralkyl, and C _1-6 heteroaralkyl. More selected. In certain such embodiments, R ¹⁰ is C _1-6 alkyl and R ¹¹ is selected from butyl, allyl, propargyl, phenylmethyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.

In other embodiments, L is SO ₂ , Q is absent, and R ¹¹ is selected from C _1-6 alkyl and aryl. In certain such embodiments, R ¹¹ is selected from methyl and phenyl.

In certain embodiments, L is C═O and R ¹¹ is C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, aryl, C _1-6 aralkyl, heteroaryl, C _{1 6 ^{heteroaralkyl,}} R 15 _ZA-C ^1~8 alkyl _^-, R 18 _Z-C 1~8 alkyl ^{-, (R 15 O) (} R 16 O) P (= O) O-C 1~8 alkyl - , (R ¹⁵ O) (R ¹⁶ O) P (═O) O—C _1-8 alkyl-ZAZ-C _1-8 alkyl-, (R ¹⁵ O) (R ¹⁶ O) P (═O) O— C _1-8 alkyl-Z—C _1-8 alkyl-, R ¹⁵ ZA-C _1-8 alkyl-ZAZ-C _1-8 alkyl-, heterocyclyl MZAZ-C _1-8 alkyl-, (R ¹⁷ ) ₂ N -C _{1 to 8} alkyl _{^{-, (R l7) 3 N}} + -C 1~8 al Selected from kill-, heterocyclyl M-, carbocyclyl M-, R ¹⁸ SO ₂ C _1-8 alkyl- and R ¹⁸ SO ₂ NH-, wherein each occurrence of Z and A is independently other than a covalent bond. . In certain embodiments, L is C═O, Q is absent, and R ¹¹ is H.

In certain embodiments, R ¹⁰ is C _1-6 alkyl, R ¹¹ is C _1-6 alkyl, Q is absent, and L is C═O. In certain such embodiments, R ¹¹ is ethyl, isopropyl, 2,2,2-trifluoroethyl, or 2- (methylsulfonyl) ethyl.

In other embodiments, L is C═O, Q is absent, and R ¹¹ is C _1-6 aralkyl. In certain such embodiments, R ¹¹ is selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl) methyl, (4-chlorophenyl) methyl, and (4-fluorophenyl) methyl.

In other embodiments, L is C═O, Q is absent, R ¹⁰ is C _1-6 alkyl, and R ¹¹ is aryl. In certain such embodiments, R ¹¹ is substituted or unsubstituted phenyl.

In certain embodiments, L is C═O, Q is absent or O, n is 0 or 1, and R ¹¹ is — (CH ₂ ) _n carbocyclyl. In certain such embodiments, R ¹¹ is cyclopropyl or cyclohexyl.

In certain embodiments, L and A are C═O, Q is absent, Z is O, n is an integer from 1 to 8 (preferably 1), and R ¹¹ is R ^15. ZA-C _1-8 alkyl-, R ¹⁸ Z-C _1-8 alkyl-, R ¹⁵ ZA-C _1-8 alkyl-ZAZ-C _1-8 alkyl-, (R ¹⁵ O) (R ¹⁶ O) P (═O) O—C _1-8 alkyl-ZAZ-C _1-8 alkyl-, (R ¹⁵ O) (R ¹⁶ O) P (═O) O—C _1-8 alkyl-Z—C _1-8 alkyl -, and heterocyclyl _MZAZ-C 1~8 alkyl - is selected from each occurrence of wherein a is independently other than a covalent bond. In certain such embodiments, R ⁷ is heterocyclyl MZAZ-C _1-8 alkyl-, wherein N is a substituted or unsubstituted oxodioxorenyl, or N (R ¹² ) (R ¹³ ). In which case R ¹² and R ¹³ together are C _1-6 alkyl-Y—C _1-6 alkyl, preferably C _1-3 alkyl-Y—C _1-3 alkyl, This forms a ring.

In certain preferred embodiments, L is C═O, Q is absent, n is an integer from 1 to 8, and R ¹¹ is (R ¹⁵ O) (R ¹⁶ O) P (═O ) O—C _1-8 alkyl-, (R ¹⁷ ) ₂ NC _1-8 alkyl, (R ¹⁷ ) ₃ N ⁺ (CH ₂ ) _n and heterocyclyl-M-. In certain such embodiments, R ¹¹ is —C _1-8 alkyl N (R ¹⁷ ) ₂ or —C _1-8 alkyl N ⁺ (R ¹⁷ ) ₃ , wherein R ¹⁷ is C _{1- 6} alkyl. In certain other such embodiments, R ¹¹ is heterocyclyl M—, wherein the heterocyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino.

In certain embodiments, L is C═O, R ¹⁰ is C _1-6 alkyl, Q is selected from O and NH, and R ¹¹ is C _1-6 alkyl, cycloalkyl-M, Selected from C _1-6 aralkyl and C _1-6 heteroaralkyl. In other embodiments, L is C═O, R ¹⁰ is C _1-6 alkyl, Q is selected from O and NH, and R ¹⁰ is C _1-6 alkyl, wherein C _{1 6} alkyl is selected from methyl, ethyl and isopropyl. In a further embodiment, L is C═O, R ¹⁰ is C _1-6 alkyl, Q is selected from O and NH, and R ¹¹ is C _1-6 aralkyl, wherein aralkyl is Phenylmethyl. In other embodiments, L is C═O, R ¹⁰ is C _1-6 alkyl, Q is selected from O and NH, and R ¹¹ is C _1-6 heteroaralkyl, wherein hetero Aralkyl is (4-pyridyl) methyl.

In certain embodiments, L is absent or C═O and R ¹⁰ and R ¹¹ are taken together with C _1-6 alkyl-Y—C _1-6 alkyl, C _1-6 alkyl-ZA. -C _1-6 alkyl or C _1-6 alkyl-A, wherein each occurrence of Z and A is independently other than a covalent bond, thereby forming a ring. In certain preferred embodiments, L is C═O, Q and Y are absent, and R ¹⁰ and R ¹¹ together are C _1-3 alkyl-Y—C _1-3 alkyl. In another preferred embodiment, L and Q are absent and R ¹⁰ and R ¹¹ together are C _1-3 alkyl-Y—C _1-3 alkyl. In another preferred embodiment, L is C═O, Q is absent, Y is selected from NH and N—C _1-6 alkyl, and R ¹⁰ and R ^{11 taken} together are C _{1 ~ 3} alkyl-Y-C _1-3 alkyl. In another preferred embodiment, L is C═O, Y is absent, and R ¹⁰ and R ¹¹ together are C _1-3 alkyl-Y—C _1-3 alkyl. In another preferred embodiment, L and A are C═O and R ¹⁰ and R ^{11 taken} together are C _1-2 alkyl-ZA-C _1-2 alkyl. In another preferred embodiment, L and A are C═O and R ¹⁰ and R ¹¹ together are C _2-3 alkyl-A.

  In certain embodiments, the chain of amino acids has the structure of formula (III):

を有し、ここで
各Ａは、独立に、Ｃ＝Ｏ、Ｃ＝Ｓ、およびＳＯ_２より選択され、好ましくはＣ＝Ｏであるか；または
Ａは、Ｚの出現に隣接する場合は、必要に応じて共有結合であり；
各Ｂは、独立に、Ｃ＝Ｏ、Ｃ＝Ｓ、およびＳＯ_２より選択され、好ましくはＣ＝Ｏ；
Ｄは存在しないか、またはＣ_１〜８アルキル；
Ｇは、Ｏ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され；
Ｋは存在しないか、またはＣ＝Ｏ、Ｃ＝ＳおよびＳＯ_２より選択され、好ましくはＫは存在しないか、Ｃ＝Ｏであり；
Ｌは存在しないか、Ｃ＝Ｏ、Ｃ＝ＳおよびＳＯ_２より選択され、好ましくはＬは存在しないかまたはＣ＝Ｏであり；
Ｍは存在しないか、Ｃ_１〜８アルキルであり；
Ｑは存在しないか、Ｏ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＱは存在しないか、ＯまたはＮＨであり、最も好ましくはＱは存在せず；
ＸはＣＯＯＨまたはその活性化形態であり、好ましくはＸはＣＯＯＨ、ＣＯＣｌまたはＣＯＮ（Ｍｅ）（ＯＭｅ）であり、最も好ましくはＸはＣＯＯＨはＣＯＣｌであり；
各Ｖは、独立に、存在しないかＯ、Ｓ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＶは存在しないかＯであり；
Ｗは存在しないか、独立にＯ、Ｓ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＯであり；
Ｙは存在しないか、Ｏ、ＮＨ、Ｎ−Ｃ_１〜６アルキル、Ｓ、ＳＯ、ＳＯ_２、ＣＨＯＲ^１７、およびＣＨＣＯ_２Ｒ^１７より選択され；
各Ｚは、独立に、Ｏ、Ｓ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＯであるか；または
Ｚは、Ａの出現に隣接する場合、必要に応じて、共有結合であり；
Ｒ^５、Ｒ^６およびＲ^７は、各々、独立にＣ_１〜６アルキル、Ｃ_１〜６ヒドロキシアルキル、Ｃ_１〜６アルコキシアルキル、アリール、Ｃ_１〜６アラルキルおよびＲ^１６ＤＶＫＯＣ_１〜３アルキル−より選択され、ここでＲ^５およびＲ^７の少なくとも１つは、Ｒ^１６ＤＶＫＯＣ_１〜３アルキル−であり；
Ｒ^９は、Ｎ（Ｒ^１０）ＬＱＲ^１１であり；
Ｒ^１０は、水素、ＯＨおよびＣ_１〜６アルキルより選択され、好ましくは水素またはＣ_１〜６アルキルであり；
Ｒ^１１は、アミノ酸のさらなる鎖、水素、保護基、アリールまたはヘテロアリールであり、これらの基のいずれも、必要に応じて、ハロゲン、カルボニル、ニトロ、ヒドロキシ、アリール、Ｃ_１〜５アルキルで置換されるか；またはＲ^１１は、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、Ｃ_１〜６アラルキル、Ｃ_１〜６ヘテロアラルキル、Ｒ^１２ＺＡＺ−Ｃ_１〜８アルキル−、Ｒ^１５ＺＡＺ−Ｃ_１〜８アルキル−、（Ｒ^１２Ｏ）（Ｒ^１３Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−ＺＡＺ−Ｃ_１〜８アルキル−、Ｒ^１２ＺＡＺ−Ｃ_１〜８アルキル−ＺＡＺ−Ｃ_１〜８アルキル−、ヘテロシクリルＭＺＡＺ−Ｃ_１〜８アルキル−、（Ｒ^１２Ｏ）（Ｒ^１３Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−、（Ｒ^１４）_２Ｎ−Ｃ_１〜８アルキル−、（Ｒ^１４）_３Ｎ^＋−Ｃ_１〜８アルキル−、ヘテロシクリルＭ−、カルボシクリルＭ−、Ｒ^１５ＳＯ_２Ｃ_１〜８アルキル−、およびＲ^１５ＳＯ_２ＮＨより選択されるか；または
Ｒ^１０およびＲ^１１は、一緒になって、Ｃ_１〜６アルキル−Ｙ−Ｃ_１〜６アルキル、Ｃ_１〜６アルキル−ＺＡＺ−Ｃ_１〜６アルキル、ＺＡＺ−Ｃ_１〜６アルキル−ＺＡＺ−Ｃ_１〜６アルキル、ＺＡＺ−Ｃ_１〜６アルキル−ＺＡＺまたはＣ_１〜６アルキル−ＺＡＺであり；
Ｒ^１２およびＲ^１３は、独立に、水素、金属カチオン、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、アリール、ヘテロアリール、Ｃ_１〜６アラルキル、およびＣ_１〜６ヘテロアラルキルより選択され、好ましくは水素、金属カチオンおよびＣ_１〜６アルキルより選択されるか、またはＲ^１２およびＲ^１３は、一緒になって、Ｃ_１〜６アルキルであり、それにより環を形成し；
各Ｒ^１４は、独立に、水素およびＣ_１〜６アルキルより選択され、好ましくはＣ_１〜６アルキルであり；
各Ｒ^１５は、独立に、水素、ＯＲ^１４、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６アラルキル、およびＣ_１〜６ヘテロアラルキルより選択され；
Ｒ^１６は、水素、（Ｒ^１７Ｏ）（Ｒ^１８Ｏ）Ｐ（＝Ｏ）Ｗ−、Ｒ^１７ＧＢ−、ヘテロシクリル−、（Ｒ^１９）_２Ｎ−、（Ｒ^１９）_３Ｎ^＋−、Ｒ^１９ＳＯ_２ＧＢＧ−およびＲ^１７ＧＢＣ_１〜８アルキル−より選択され、ここでこのＣ_１〜８アルキル部分は、必要に応じてＯＨ、Ｃ_１〜８アルキルＷ（必要に応じてハロゲン、好ましくはフッ素で置換されている）、アリール、ヘテロアリール、カルボシクリル、ヘテロシクリルおよびＣ_１〜６アラルキルで置換されており、好ましくはＲ^１６の出現の少なくとも１つは、水素以外であり；
Ｒ^１７およびＲ^１８は、独立に、水素、金属カチオン、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、アリール、ヘテロアリール、Ｃ_１〜６アラルキルおよびＣ_１〜６ヘテロアラルキルより選択され、好ましくは水素、金属カチオンおよびＣ_１〜６アルキルより選択されるか、またはＲ^１７およびＲ^１８は、一緒になってＣ_１〜６アルキルであり、それにより環を形成し；そして
各Ｒ^１９は、独立に、水素、ＯＲ^１４、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６アラルキル、およびＣ_１〜６ヘテロアラルキルより選択され；そしてＤ、Ｇ、Ｖ、ＫおよびＷは、Ｏ−Ｏ結合、Ｎ−Ｏ結合、Ｓ−ＮまたはＳ−Ｏ結合が存在しないように選択される。

Where each A is independently selected from C═O, C═S, and SO ₂ , preferably C═O; or if A is adjacent to the occurrence of Z, A covalent bond if necessary;
Each B is independently selected from C═O, C═S, and SO ₂ , preferably C═O;
D is absent or C _1-8 alkyl;
G is selected from O, NH and N—C _1-6 alkyl;
K is absent or selected from C═O, C═S and SO ₂ , preferably K is absent or C═O;
L is absent or selected from C═O, C═S and SO ₂ , preferably L is absent or C═O;
M is absent or C _1-8 alkyl;
Q is absent or selected from O, NH and N—C _1-6 alkyl, preferably Q is absent, O or NH, most preferably Q is absent;
X is COOH or an activated form thereof, preferably X is COOH, COCl or CON (Me) (OMe), most preferably X is COOH COCO;
Each V is independently absent or selected from O, S, NH and N—C _1-6 alkyl, preferably V is absent or O;
W is absent or independently selected from O, S, NH and N—C _1-6 alkyl, preferably O;
Y is absent or selected from O, NH, N—C _1-6 alkyl, S, SO, SO ₂ , CHOR ¹⁷ , and CHCO ₂ R ¹⁷ ;
Each Z is independently selected from O, S, NH, and N—C _1-6 alkyl, preferably O; or, if Z is adjacent to the occurrence of A, optionally a covalent bond Is;
R ⁵ , R ⁶ and R ⁷ are each independently C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxyalkyl, aryl, C _1-6 aralkyl and R ¹⁶ DVKOC _1-3 alkyl- Wherein at least one of R ⁵ and R ⁷ is R ¹⁶ DVKOC _1-3 alkyl-;
R ⁹ is N (R ¹⁰ ) LQR ¹¹ ;
R ¹⁰ is selected from hydrogen, OH and C _1-6 alkyl, preferably hydrogen or C _1-6 alkyl;
R ¹¹ is an additional chain of amino acids, hydrogen, protecting group, aryl or heteroaryl, any of these groups optionally substituted with halogen, carbonyl, nitro, hydroxy, aryl, C _1-5 alkyl Or R ¹¹ is C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 aralkyl, C _1-6 heteroaralkyl, R ¹² ZAZ-C _1-8 alkyl- , R ¹⁵ ZAZ-C _1-8 alkyl-, (R ¹² O) (R ¹³ O) P (═O) O—C _1-8 alkyl-ZAZ-C _1-8 alkyl-, R ¹² ZAZ-C _{1 8} alkyl _-ZAZ-C 1~8 alkyl -, heterocyclyl _MZAZ-C 1~8 alkyl ^{-, (R 12 O) (} R 13 O) P (= O) O-C 1~8 alkyl -, ^{(R 14} _{2 N-C 1~8} alkyl ^{_{-, (R 14) 3 N}} + -C 1~8 alkyl -, heterocyclyl M-, carbocyclyl _^M-, R ₁₅ SO _{2 C 1~8} alkyl -, and ^R 15 _SO 2 NH more or selected; or R ¹⁰ and ^{R 11} _{together, C 1 to 6} alkyl _{-Y-C 1 to 6 alkyl, C 1 to 6} alkyl _{-ZAZ-C 1~6} alkyl, ZAZ-C _1-6 alkyl-ZAZ-C _1-6 alkyl, ZAZ-C _1-6 alkyl-ZAZ or C _1-6 alkyl-ZAZ;
R ¹² and R ¹³ are independently hydrogen, metal cation, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, aryl, heteroaryl, C _1-6 aralkyl, and C _1-6 hetero Selected from aralkyl, preferably selected from hydrogen, metal cation and C _1-6 alkyl, or R ¹² and R ^{13 taken} together are C _1-6 alkyl, thereby forming a ring ;
Each R ¹⁴ is independently selected from hydrogen and C _1-6 alkyl, preferably C _1-6 alkyl;
Each R ¹⁵ is independently hydrogen, OR ¹⁴ , C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C _1-6 aralkyl, and C _{1-6 .} Selected from ₆ heteroaralkyls;
R ¹⁶ is ^{hydrogen, (R 17 O) (R} 18 O) P (= O) W-, R 17 GB-, heterocyclyl ^{_{-, (R 19) 2 N}} -, (R 19) 3 N + -, R ¹⁹ SO ₂ GBG- and R ¹⁷ GBC _1-8 alkyl-, wherein the C _1-8 alkyl moiety is optionally OH, C _1-8 alkyl W (optionally halogen, preferably Substituted with fluorine), substituted with aryl, heteroaryl, carbocyclyl, heterocyclyl and C _1-6 aralkyl, preferably at least one occurrence of R ¹⁶ is other than hydrogen;
R ¹⁷ and R ¹⁸ are independently hydrogen, metal cation, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, aryl, heteroaryl, C _1-6 aralkyl and C _1-6 heteroaralkyl. More preferably selected from hydrogen, metal cations and C _1-6 alkyl, or R ¹⁷ and R ¹⁸ together are C _1-6 alkyl, thereby forming a ring; and Each R ¹⁹ is independently hydrogen, OR ¹⁴ , C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C _1-6 aralkyl, and C _{1-6 .} is selected from ₆ heteroaralkyl; and D, G, V, K and W, O-O bond, N-O bond, the S-N or S-O bonds It is selected so as not to standing.

In certain embodiments, R ⁵ , R ⁶ and R ⁷ are each independently C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxyalkyl, aryl, C _1-6 aralkyl and R ^16. DVKOC _1-3 alkyl-, wherein at least one of R ⁵ and R ⁷ is R ¹⁶ DVKOC _1-3 alkyl-. In preferred embodiments, one of R ⁵ and R ⁷ is C _1-6 aralkyl, the other is R ¹⁶ DVKOC _1-3 alkyl-, and R ⁶ is independently C _1-6 alkyl. It is. In the most preferred embodiment, one of R ⁵ and R ⁷ is 2-phenylethyl or phenylmethyl, the other is R ¹⁶ DVKOCH ₂ — or R ¹⁶ DVKO (CH ₃ ) CH—, and R ⁶ Is isobutyl.

In certain embodiments, each R ¹⁵ is independently hydrogen, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C _1-6 aralkyl, and Selected from C _1-6 heteroaralkyl.

In certain embodiments, each R ¹⁹ is independently hydrogen, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C _1-6 aralkyl and C _1. Selected from _{1 to 6} heteroaralkyls.

In certain embodiments, L and Q are absent and R ¹¹ is hydrogen, an additional chain of amino acids, C _1-6 acyl, protecting group, aryl, heteroaryl, C _1-6 alkyl, C _1-6 alkenyl. , C _1-6 alkynyl, C _1-6 aralkyl and C _1-6 heteroaralkyl. In certain such embodiments, R ¹⁰ is C _1-6 alkyl and R ¹¹ is selected from butyl, allyl, propargyl, phenylmethyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.

In other embodiments, L is SO ₂ , Q is absent, and R ¹¹ is selected from C _1-6 alkyl and aryl. In certain such embodiments, R ¹¹ is selected from methyl and phenyl.

In certain embodiments, L is C═O and R ¹¹ is C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, aryl, C _1-6 aralkyl, heteroaryl, C _1-6. Heteroaralkyl, R ¹² ZA—C _1-8 alkyl-, R ¹⁵ Z—C _1-8 alkyl-, (R ¹² O) (R ¹³ O) P (═O) O—C _1-8 alkyl-, ( R ¹² O) (R ¹³ O) P (═O) O—C _1-8 alkyl-ZAZ-C _1-8 alkyl-, (R ¹² O) (R ¹³ O) P (═O) O—C _{1 6} alkyl _{-Z-C 1 to 8} alkyl _^-, R 12 _ZA-C ^1~6 alkyl _-ZAZ-C 1~8 alkyl -, heterocyclyl _MZAZ-C 1~8 alkyl _{^{-, (R 14) 2 NC}} 1~ ₈ alkyl-, (R ¹⁴ ) ₃ N ⁺ -C _1-8 alkyl-, f Heterocyclyl M-, carbocyclyl _^M-, R ₁₅ SO _{2 C} ^1~8 alkyl -, is selected from the ^R 15 _SO 2 NH-. In certain embodiments, L is C═O, Q is absent, and R ¹¹ is H.

In certain embodiments, R ¹⁰ is C _1-6 alkyl, R ¹¹ is C _1-6 alkyl, Q is absent, and L is C═O. In certain such embodiments, R ¹¹ is ethyl, isopropyl, 2,2,2-trifluoroethyl, or 2- (methylsulfonyl) ethyl.

In other embodiments, L is C═O, Q is absent, and R ¹¹ is C _1-6 aralkyl. In certain such embodiments, R ¹¹ is selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl) methyl, (4-chlorophenyl) methyl and (4-fluorophenyl) methyl.

In other embodiments, L is C═O, Q is absent, R ¹⁰ is C _1-6 alkyl, and R ¹¹ is aryl. In certain such embodiments, R ¹¹ is substituted or unsubstituted phenyl.

In certain embodiments, L is C═O, Q is absent or O, and R ¹¹ is — (CH ₂ ) _n carbocyclyl. In certain such embodiments, R ¹¹ is cyclopropyl or cyclohexyl.

In certain embodiments, L and A are C═O, Q is absent, Z is O, and R ¹¹ is R ¹² ZA—C _1-8 alkyl-, R ¹⁵ Z—C _{1. 8} alkyl _^-, R 12 _{ZA-C 1~8} alkyl _-ZAZ-C 1~8 alkyl ^{-, (R 12 O) (} R 13 O) P (= O) O-C 1~8 alkyl -ZAZ-C _1-8 alkyl-, (R ¹² O) (R ¹³ O) P (═O) O—C _1-8 alkyl-Z—C _1-8 alkyl- and heterocyclyl MZAZ-C _1-8 alkyl- The In certain such embodiments, R ¹¹ is heterocyclyl MZAZ-C _1-8 alkyl-, wherein heterocyclyl is a substituted or unsubstituted oxodioxolenyl, or N (R ²⁰ ) (R ²¹ ). Where R ²⁰ and R ²¹ together are C _1-6 alkyl-Y—C _1-6 alkyl, preferably C _1-3 alkyl-Y—C _1-3 alkyl, thereby Form a ring.

In certain preferred embodiments, L is C═O, Q is absent, and R ¹¹ is (R ¹² O) (R ¹³ O) P (═O) O—C _1-8 alkyl-, (R ¹⁴ ) ₂ NC _1-8 alkyl, (R ¹⁴ ) ₃ N ⁺ (CH ₂ ) _n -and heterocyclyl-M-. In certain such ^{embodiments, R 11} is _{-C 1 to 8} alkyl ^{N (R} _{14) 2} or _{-C 1 to 8} alkyl ^N + ^(R _{l4) 3,} wherein ^{R 14} is _{C 1 to 6} Alkyl. In certain other such embodiments, R ¹¹ is heterocyclyl M-, wherein heterocyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino.

In certain embodiments, L is C═O, R ¹⁰ is C _1-6 alkyl, Q is selected from O and NH, and R ¹¹ is C _1-6 alkyl, cycloalkyl-M, C Selected from _1-6 aralkyl and _C1-6 heteroaralkyl. In other embodiments, L is C═O, R ¹⁰ is C _1-6 alkyl, Q is selected from O and NH, and R ¹¹ is C _1-6 alkyl, wherein C _{1 6} alkyl is selected from methyl, ethyl, and more isopropyl. In a further embodiment, L is C═O, R ¹⁰ is C _1-6 alkyl, Q is selected from O and NH, and R ¹¹ is C _1-6 aralkyl, wherein aralkyl is phenyl Methyl. In other embodiments, L is C═O, R ¹⁰ is C _1-6 alkyl, Q is selected from O and NH, and R ¹¹ is C _1-6 heteroaralkyl, wherein Heteroaralkyl is (4-pyridyl) methyl.

In certain embodiments, L is absent or C = O, and R ¹⁰ and R ^{11 taken} together are C _1-6 alkyl-Y—C _1-6 alkyl, C _1-6. Alkyl-ZA-C _1-6 alkyl or C _1-6 alkyl-A, thereby forming a ring. In certain preferred embodiments, L is C═O, Q and Y are absent, and R ¹⁰ and R ¹¹ together are C _3-8 alkyl-Y—C _1-3 alkyl. It is. In another preferred embodiment, L and Q are absent and R ¹⁰ and R ^{11 taken} together are C _1-3 alkyl-Y—C _1-3 alkyl. In another preferred embodiment, L is C═O, Q is absent, Y is selected from NH and N—C _1-6 alkyl, and R ¹⁰ and R ^{11 taken} together are C _{1 ~ 3} alkyl-Y-C _1-3 alkyl. In another preferred embodiment, L is C═O, Y is absent, and R ¹⁰ and R ^{11 taken} together are C _1-3 alkyl-Y—C _1-3 alkyl. In another preferred embodiment, L and A are C═O, and R ¹⁰ and R ¹¹ together are C _1-2 alkyl-ZA-C _1-2 alkyl. In another preferred embodiment, L and A are C═O and R ¹⁰ and R ¹¹ together are C _2-3 alkyl-A.

In certain embodiments, R ¹⁶ is (R ¹⁷ O) (R ¹⁸ O) P (═O) W—. In certain such embodiments, D, V, K, and W are absent. In other such embodiments, V and K are absent, D is C _1-8 alkyl, and W is O. In still other such embodiments, D is C _1-8 alkyl, K is C═O, and V and W are O.

In certain embodiments, R ¹⁶ is R ¹⁷ GB-. In preferred embodiments, B is C═O, G is O, D is C _1-8 alkyl, V is O, and K is C═O.

In certain embodiments, R ¹⁶ is heterocyclyl-. In preferred such embodiments, D is C _1-8 alkyl. In certain such embodiments, V is O, K is C═O, and the heterocyclyl is oxodioxorenyl. In other such embodiments, V is absent, K is absent or C = O, and the heterocyclyl is N (R ²⁰ ) (R ²¹ ), where R ²⁰ and R ²¹ Together are J-T-J, J-WB-J or B-J-T-J, T is absent or O, NR ¹⁷ , S, SO, SO _{2 ,} CHOR ¹⁹ , CHCO ₂ Selected from R ¹⁷ , C═O, CF ₂ and CHF, and J is absent or C _1-3 alkyl.

In certain embodiments, R ¹⁶ is (R ¹⁹ ) ₂ N- or (R ¹⁹ ) ₃ N ⁺ -, and preferably V is absent. In preferred such embodiments, D is C _1-8 alkyl and K is absent or C = O. In certain embodiments where V is not present and R ¹⁶ is (R ¹⁹ ) ₂ N—, D is not present, K is absent or C═O, preferably K is C═O. is there.

In certain embodiments, R ¹⁶ is R ¹⁹ SO ₂ GBG-. In preferred such embodiments, B is C = O, D, V and K are absent, and G is NH or NC _1-6 alkyl.

In certain embodiments, R ¹⁶ is R ¹⁷ GBC _1-8 alkyl-. In preferred embodiments, B is C═O, G is O, and the C _1-8 alkyl moiety is optionally OH, C _1-8 alkyl (optionally halogen, preferably fluorine. Substituted), C _1-8 alkyl W, aryl, heteroaryl, carbocyclyl, heterocyclyl and C _1-6 aralkyl. In certain such embodiments, the C _1-8 alkyl moiety is an unsubstituted, monosubstituted or disubstituted C ₁ alkyl.

  In certain embodiments, the product of the coupling reaction of the amino acid ketoepoxide or ketoaziridine with the compound of formula (III) has the structure of formula (IV):

を有する化合物であり、ここで
各Ａは、独立にＣ＝Ｏ、Ｃ＝ＳおよびＳＯ_２より選択され、好ましくはＣ＝Ｏであるか；
Ａは、Ｚの出現に隣接する場合は、必要に応じて共有結合であり；
各Ｂは、独立に、Ｃ＝Ｏ、Ｃ＝ＳおよびＳＯ_２より選択され、好ましくはＣ＝Ｏであり；
Ｄは存在しないか、またはＣ_１〜８アルキルであり；
Ｇは、Ｏ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され；
Ｋは、存在しないかまたはＣ＝Ｏ、Ｃ＝Ｓ、よびＳＯ_２より選択され、好ましくはＫは存在しないかＣ＝Ｏであり；
Ｌは存在しないか、またはＣ＝Ｏ、Ｃ＝ＳおよびＳＯ_２より選択され、好ましくはＬは存在しないかまたはＣ＝Ｏであり；
Ｍは存在しないか、またはＣ_１〜８アルキルであり；
Ｑは存在しないか、またはＯ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＱは存在しないか、Ｏ、ＮＨであり、最も好ましくはＱは存在せず；
ＸはＯ、Ｓ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＯであり；
各Ｖは、独立に、存在しないかまたはＯ、Ｓ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＶは存在しないかまたはＯであり；
Ｗは存在しないか、または独立に、Ｏ、Ｓ、ＮＨ、およびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＯであり；
Ｙは存在しないか、またはＯ、ＮＨ、Ｎ−Ｃ_１〜６アルキル、Ｓ、ＳＯ、ＳＯ_２、ＣＨＯＲ^１０およびＣＨＣＯ_２Ｒ^１０より選択され；
各Ｚは、独立に、Ｏ、Ｓ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＯであるか；または
Ｚは、Ａの出現に隣接する場合は、必要に応じて、共有結合であり；
Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、各々独立に、Ｃ_１〜６アルキル、Ｃ_１〜６ヒドロキシアルキル、Ｃ_１〜６アルコキシアルキル、アリール、Ｃ_１〜６アラルキル、およびＲ^１４ＤＶＫＯＣ_１〜３アルキル−より選択され、ここでＲ^１およびＲ^３のうちの少なくとも１つは、Ｒ^１４ＤＶＫＯＣ_１〜３アルキル−であり；
Ｒ^５はＮ（Ｒ^６）ＬＱＲ^７であり；
Ｒ^６は、水素、ＯＨおよびＣ_１〜６アルキルより選択され、好ましくはＣ_１〜６アルキルであり；
Ｒ^７は、アミノ酸のさらなる鎖、水素、保護基、アリールまたはヘテロアリールであり、これらの基のいずれも、必要に応じて、ハロゲン、カルボニル、ニトロ、ヒドロキシ、アリール、Ｃ_１〜５アルキルで置換されているか；またはＲ^７はＣ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、Ｃ_１〜６アラルキル、Ｃ_１〜６ヘテロアラルキル、Ｒ^８ＺＡＺ−Ｃ_１〜８アルキル−、Ｒ^１１Ｚ−Ｃ_１〜８アルキル−、（Ｒ^８Ｏ）（Ｒ^９Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−ＺＡＺ−Ｃ_１〜８アルキル−、Ｒ^８ＺＡＺ−Ｃ_１〜８アルキル−ＺＡＺ−Ｃ_１〜８アルキル−、ヘテロシクリルＭＺＡＺ−Ｃ_１〜８アルキル−、（Ｒ^８Ｏ）（Ｒ^９Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−、（Ｒ^１０）_２Ｎ−Ｃ_１〜８アルキル−、（Ｒ^１０）_３Ｎ^＋−Ｃ_１〜８アルキル−、ヘテロシクリルＭ−、カルボシクリルＭ−、Ｒ^１１ＳＯ_２Ｃ_１〜８アルキル−およびＲ^１１ＳＯ_２ＮＨより選択され、ここでＺおよびＡの各出現は、独立して、共有結合以外であるか；または
Ｒ^６およびＲ^７は、一緒になって、Ｃ_１〜６アルキル−Ｙ−Ｃ_１〜６アルキル、ＺＡＺ−Ｃ_１〜６アルキル−ＺＡＺ−Ｃ_１〜６アルキルまたはＺＡＺ−Ｃ_１〜６アルキル−ＺＡＺであり、それにより環を形成し、ここでＺおよびＡの各出現は、独立に共有結合以外であり；
Ｒ^８およびＲ^９は、独立に水素、金属カチオン、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、アリール、ヘテロアリール、Ｃ_１〜６アラルキルおよびＣ_１〜８ヘテロアラルキルより選択され、好ましくは水素、金属カチオンおよびＣ_１〜６アルキルより選択されるか、またはＲ^８およびＲ^９は一緒になってＣ_１〜６アルキルであり、それにより環を形成し；
各Ｒ^１０は、独立に水素およびＣ_１〜６アルキルより選択され、好ましくはＣ_１〜６アルキルであり；
各Ｒ^１１は、独立に水素、ＯＲ^１０、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６アラルキル、およびＣ_１〜６ヘテロアラルキルより選択され；
Ｒ^１４は、水素、（Ｒ^１５Ｏ）（Ｒ^１６Ｏ）Ｐ（＝Ｏ）Ｗ−、Ｒ^１５ＧＢ−、ヘテロシクリル−、（Ｒ^１７）_２Ｎ−、（Ｒ^１７）_３Ｎ^＋−、Ｒ^１７ＳＯ_２ＧＢＧ−およびＲ^１５ＧＢＣ_１〜８アルキル−より選択され、ここでこのＣ_１〜８アルキル部分は必要に応じてＯＨ、Ｃ_１〜８アルキルＷ（必要に応じてハロゲン、好ましくはフッ素で置換されている）、アリール、ヘテロアリール、カルボシクリル、ヘテロシクリルおよびＣ_１〜６アラルキルで置換されており、好ましくはＲ^１４の出現の少なくとも１つは、水素以外であり；
Ｒ^１５およびＲ^１６は、独立に、水素、金属カチオン、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、アリール、ヘテロアリール、Ｃ_１〜６アラルキル、およびＣ_１〜６ヘテロアラルキルより選択され、好ましくは素、金属カチオン、およびＣ_１〜６アルキルより選択されるか、またはＲ^１５およびＲ^１６は一緒になってＣ_１〜６アルキルであり、それにより環を形成し；そして
各Ｒ^１７は、独立に水素、ＯＲ^１０、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６アラルキルおよびＣ_１〜６ヘテロアラルキルより選択されるが；
ただしＲ^６がＨであり、ＬがＣ＝Ｏであり、そしてＱが存在しない場合、Ｒ^７は、水素でも、Ｃ_１〜６アルキルでも、置換または非置換のアリールもしくはヘテロアリールでもなく；そして
Ｄ、Ｇ、Ｖ、ＫおよびＷは、Ｏ−Ｏ、Ｎ−Ｏ、Ｓ−ＮまたはＳ−Ｏ結合が存在しないように選択されるが；しかし
ただし、式（ＩＶ）の化合物は、以下：
各Ａが独立にＣ＝Ｏ、Ｃ＝Ｓ、およびＳＯ_２より選択され、好ましくはＣ＝Ｏであり；
各Ｂが独立にＣ＝Ｏ、Ｃ＝Ｓ、およびＳＯ^２より選択され、好ましくはＣ＝Ｏであり；
Ｄが存在しないかまたはＣ_１〜８アルキルであり；
ＧがＯ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され；
Ｋが存在しないかまたはＣ＝Ｏ、Ｃ＝Ｓ、およびＳＯ_２より選択され、好ましくはＫが存在しないかまたはＣ＝Ｏであり；
Ｌが存在しないかまたはＣ＝Ｏ、Ｃ＝Ｓ、およびＳＯ_２より選択され、好ましくはＬが存在しないかまたはＣ＝Ｏであり；
Ｍが存在しないかまたはＣ_１〜８アルキルであり；
Ｑが存在しないかまたはＯ、ＮＨ、およびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＱが存在しないか、ＯまたはＮＨであり、最も好ましくはＱが存在せず；
ＸがＯ、Ｓ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＯであり；
各Ｖが独立に、存在しないかまたはＯ、Ｓ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＶが存在しないかまたはＯであり；
Ｗが存在しないかまたは独立にＯ、Ｓ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＯであり；
Ｙが存在しないかまたはＯ、ＮＨ、Ｎ−Ｃ_１〜６アルキル、Ｓ、ＳＯ、ＳＯ_２、ＣＨＯＲ^１０、およびＣＨＣＯ_２Ｒ^１０より選択され；
各Ｚが独立に、Ｏ、Ｓ、ＮＨおよびＮ−Ｃ_１〜６アルキルより選択され、好ましくはＯであり；
Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４が、各々独立に、Ｃ_１〜６アルキル、Ｃ_１〜６ヒドロキシアルキル、Ｃ_１〜６アルコキシアルキル、アリール、Ｃ_１〜６アラルキル、およびＲ^１４ＤＶＫＯＣ_１〜３アルキル−より選択され、ここでＲ^１およびＲ^３のうちの少なくとも１つは、Ｒ^１４ＤＶＫＯＣ_１〜３アルキル−であり；
Ｒ^５がＮ（Ｒ^６）ＬＱＲ^７であり；
Ｒ^６が、水素、ＯＨ、およびＣ_１〜６アルキルより選択され、好ましくはＣ_１〜６アルキルであり；
Ｒ^７が、アミノ酸のさらなる鎖、水素、保護基、アリールまたはヘテロアリールであり、これらの基のいずれも、必要に応じてハロゲン、カルボニル、ニトロ、ヒドロキシ、アリール、Ｃ_１〜５アルキル置換されるか；またはＲ^７は、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、Ｃ_１〜６アラルキル、Ｃ_１〜６ヘテロアラルキル、Ｒ^８ＺＡ−Ｃ_１〜８アルキル−、Ｒ^１１Ｚ−Ｃ_１〜８アルキル−、（Ｒ^８Ｏ）（Ｒ^９Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−ＺＡＺ−Ｃ_１〜８アルキル−、（Ｒ^８Ｏ）（Ｒ^９Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−Ｚ−Ｃ_１〜８アルキル−、Ｒ^８ＺＡ−Ｃ_１〜８アルキル−ＺＡＺ−Ｃ_１〜８アルキル−、ヘテロシクリルＭＺＡＺ−Ｃ_１〜８アルキル−、（Ｒ^８Ｏ）（Ｒ^９Ｏ）Ｐ（＝Ｏ）Ｏ−Ｃ_１〜８アルキル−、（Ｒ^１０）_２Ｎ−Ｃ_１〜８アルキル−、（Ｒ^１０）_３Ｎ^＋−Ｃ_１〜８アルキル−、ヘテロシクリルＭ−、カルボシクリルＭ−、Ｒ^１１ＳＯ_２Ｃ_１〜８アルキル−、およびＲ^１１ＳＯ_２ＮＨより選択されるか；または
Ｒ^６およびＲ^７が、一緒になってＣ_１〜６アルキル−Ｙ−Ｃ_１〜６アルキル、Ｃ_１〜６アルキル−ＺＡ−Ｃ_１〜６アルキル、Ａ−Ｃ_１〜６アルキル−ＺＡ−Ｃ_１〜６アルキル、Ａ−Ｃ_１〜６アルキル−ＡまたはＣ_１〜６アルキル−Ａであり、好ましくはＣ_１〜２アルキル−Ｙ−Ｃ_１〜２アルキル、Ｃ_１〜２アルキル−ＺＡ−Ｃ_１〜２アルキル、Ａ−Ｃ_１〜２アルキル−ＺＡ−Ｃ_１〜２アルキル、Ａ−Ｃ_１〜３アルキル−ＡまたはＣ_１〜４アルキル−Ａであり、それにより環を形成し、好ましくはＲ^６は水素であり、Ｒ^７はＣ_１〜６アルキルであり；
Ｒ^８およびＲ^９が、独立に、水素、金属カチオン、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、アリール、ヘテロアリール、Ｃ_１〜６アラルキルおよびＣ_１〜６ヘテロアラルキルより選択され、好ましくは水素、金属カチオンおよびＣ_１〜６アルキルより選択されるか、またはＲ^８およびＲ^９は一緒になってＣ_１〜６アルキルであり、それにより環を形成し；
各Ｒ^１０が、独立に、水素およびＣ_１〜６アルキルより選択され、好ましくはＣ_１〜６アルキルであり；
各Ｒ^１１が、独立に、水素、ＯＲ^１０、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６アラルキル、およびＣ_１〜６ヘテロアラルキルより選択され；
Ｒ^１４が、水素、（Ｒ^１５Ｏ）（Ｒ^１６Ｏ）Ｐ（＝Ｏ）Ｗ−、Ｒ^１５ＧＢ−、ヘテロシクリル−、（Ｒ^１７）_２Ｎ−、（Ｒ^１７）_３Ｎ^＋−、Ｒ^１７ＳＯ_２ＧＢＧ−およびＲ^１５ＧＢＣ_１〜８アルキル−より選択され、ここでこのＣ_１〜８アルキル部分は、必要に応じてＯＨ、Ｃ_１〜８アルキルＷ（必要に応じてハロゲン、好ましくはフッ素で置換されている）、アリール、ヘテロアリール、カルボシクリル、ヘテロシクリルおよびＣ_１〜６アラルキルで置換され、好ましくはＲ^１４の出現の少なくとも１つは、水素以外であり；
Ｒ^１５およびＲ^１６が、独立に、水素、金属カチオン、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、アリール、ヘテロアリール、Ｃ_１〜８アラルキルおよびＣ_１〜６ヘテロアラルキルより選択され、好ましくは水素、金属カチオンおよびＣ_１〜６アルキルより選択されるか、またはＲ^１５およびＲ^１６が一緒になってＣ_１〜６アルキルであり、それにより環を形成し；そして
各Ｒ^１７が、独立に、水素、ＯＲ^１０、Ｃ_１〜６アルキル、Ｃ_１〜６アルケニル、Ｃ_１〜６アルキニル、カルボシクリル、ヘテロシクリル、アリール、ヘテロアリール、Ｃ_１〜６アラルキルおよびＣ_１〜６ヘテロアラルキルより選択される、
化合物ではない。

Wherein each A is independently selected from C═O, C═S and SO ₂ , preferably C═O;
A is optionally a covalent bond when adjacent to the occurrence of Z;
Each B is independently selected from C═O, C═S and SO ₂ , preferably C═O;
D is absent or is C _1-8 alkyl;
G is selected from O, NH and N—C _1-6 alkyl;
K is absent or selected from C═O, C═S, and SO ₂ , preferably K is absent or C═O;
L is absent or selected from C═O, C═S and SO ₂ , preferably L is absent or C═O;
M is absent or C _1-8 alkyl;
Q is absent or selected from O, NH and N—C _1-6 alkyl, preferably Q is absent or O, NH, most preferably Q is absent;
X is selected from O, S, NH and N—C _1-6 alkyl, preferably O;
Each V is independently absent or selected from O, S, NH and N—C _1-6 alkyl, preferably V is absent or O;
W is absent or independently selected from O, S, NH, and N—C _1-6 alkyl, preferably O;
Y is absent or selected from O, NH, N—C _1-6 alkyl, S, SO, SO ₂ , CHOR ¹⁰ and CHCO ₂ R ¹⁰ ;
Each Z is independently selected from O, S, NH and N—C _1-6 alkyl, preferably O; or, if Z is adjacent to the occurrence of A, optionally shared A bond;
R ¹ , R ² , R ³ and R ⁴ are each independently C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxyalkyl, aryl, C _1-6 aralkyl, and R ¹⁴ DVKOC _{1 ~ 3} alkyl-, wherein at least one of R ¹ and R ³ is R ¹⁴ DVKOC _1-3 alkyl-;
R ⁵ is N (R ⁶ ) LQR ⁷ ;
R ⁶ is selected from hydrogen, OH and C _1-6 alkyl, preferably C _1-6 alkyl;
R ⁷ is an additional chain of amino acids, hydrogen, protecting group, aryl or heteroaryl, any of these groups optionally substituted with halogen, carbonyl, nitro, hydroxy, aryl, C _1-5 alkyl Or R ⁷ is C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 aralkyl, C _1-6 heteroaralkyl, R ⁸ ZAZ-C _1-8 alkyl-, R ¹¹ Z—C _1-8 alkyl-, (R ⁸ O) (R ⁹ O) P (═O) O—C _1-8 alkyl-ZAZ-C _1-8 alkyl-, R ⁸ ZAZ-C _{1- 8} alkyl-ZAZ-C _1-8 alkyl-, heterocyclyl MZAZ-C _1-8 alkyl-, (R ⁸ O) (R ⁹ O) P (═O) O—C _1-8 alkyl-, (R ¹⁰ ) _{2 N-C 1 to 8} Alkyl ^{_{-, (R 10) 3 N}} + -C 1~8 alkyl -, heterocyclyl M-, carbocyclyl _^M-, R ₁₁ SO _{2 C} ^1~8 alkyl - is selected from and ^R 11 _SO 2 NH, wherein Z and Each occurrence of A is independently other than a covalent bond; or R ⁶ and R ^{7 taken} together are C _1-6 alkyl-YC _1-6 alkyl, ZAZ-C _1-6. Alkyl-ZAZ-C _1-6 alkyl or ZAZ-C _1-6 alkyl-ZAZ, thereby forming a ring, wherein each occurrence of Z and A is independently other than a covalent bond;
R ⁸ and R ⁹ are independently hydrogen, metal cation, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, aryl, heteroaryl, C _1-6 aralkyl and C _1-8 heteroaralkyl. Selected, preferably selected from hydrogen, metal cation and C _1-6 alkyl, or R ⁸ and R ⁹ together are C _1-6 alkyl, thereby forming a ring;
Each R ¹⁰ is independently selected from hydrogen and C _1-6 alkyl, preferably C _1-6 alkyl;
Each R ¹¹ is independently hydrogen, OR ¹⁰ , C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C _1-6 aralkyl, and C _1-6. Selected from heteroaralkyl;
R ¹⁴ is ^{hydrogen, (R 15 O) (R} 16 O) P (= O) W-, R 15 GB-, heterocyclyl ^{_{-, (R 17) 2 N}} -, (R 17) 3 N + -, R ¹⁷ SO ₂ GBG- and R ¹⁵ GBC _1-8 alkyl-, wherein the C _1-8 alkyl moiety is optionally OH, C _1-8 alkyl W (optionally halogen, preferably fluorine Substituted with aryl, heteroaryl, carbocyclyl, heterocyclyl and C _1-6 aralkyl, preferably at least one of the occurrences of R ¹⁴ is other than hydrogen;
R ¹⁵ and R ¹⁶ are independently hydrogen, metal cation, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, aryl, heteroaryl, C _1-6 aralkyl, and C _1-6 hetero Selected from aralkyl, preferably selected from elementary, metal cations, and C _1-6 alkyl, or R ¹⁵ and R ¹⁶ together are C _1-6 alkyl, thereby forming a ring; And each R ¹⁷ is independently hydrogen, OR ¹⁰ , C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C _1-6 aralkyl and C _1-6. Selected from heteroaralkyl;
Provided that when R ⁶ is H, L is C═O and Q is absent, R ⁷ is not hydrogen, C _1-6 alkyl, substituted or unsubstituted aryl or heteroaryl; and D, G, V, K and W are selected such that no O—O, N—O, S—N or S—O bond is present; however, the compound of formula (IV) is:
Each A is independently selected from C═O, C═S, and SO ₂ , preferably C═O;
Each B is independently selected from C═O, C═S, and SO ² , preferably C═O;
D is absent or C _1-8 alkyl;
G is selected from O, NH and N—C _1-6 alkyl;
K is absent or selected from C═O, C═S, and SO ₂ , preferably K is absent or C═O;
L is absent or selected from C═O, C═S, and SO ₂ , preferably L is absent or C═O;
M is absent or C _1-8 alkyl;
Q is absent or selected from O, NH and N—C _1-6 alkyl, preferably Q is absent, O or NH, most preferably Q is absent;
X is selected from O, S, NH and N—C _1-6 alkyl, preferably O;
Each V is independently absent or selected from O, S, NH and N—C _1-6 alkyl, preferably V is absent or O;
W is absent or independently selected from O, S, NH and N—C _1-6 alkyl, preferably O;
Y is absent or selected from O, NH, N—C _1-6 alkyl, S, SO, SO ₂ , CHOR ¹⁰ , and CHCO ₂ R ¹⁰ ;
Each Z is independently selected from O, S, NH and N—C _1-6 alkyl, preferably O;
R ¹ , R ² , R ³ and R ⁴ are each independently C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxyalkyl, aryl, C _1-6 aralkyl, and R ¹⁴ DVKOC _{1 ~ 3} alkyl-, wherein at least one of R ¹ and R ³ is R ¹⁴ DVKOC _1-3 alkyl-;
R ⁵ is N (R ⁶ ) LQR ⁷ ;
R ⁶ is selected from hydrogen, OH, and C _1-6 alkyl, preferably C _1-6 alkyl;
R ⁷ is an additional chain of amino acids, hydrogen, protecting group, aryl or heteroaryl, any of these groups optionally halogen, carbonyl, nitro, hydroxy, aryl, C _1-5 alkyl substituted Or R ⁷ is C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 aralkyl, C _1-6 heteroaralkyl, R ⁸ ZA-C _1-8 alkyl-, R ¹¹ Z-C _1-8 alkyl-, (R ⁸ O) (R ⁹ O) P (═O) O—C _1-8 alkyl-ZAZ-C _1-8 alkyl-, (R ⁸ O) (R ⁹ O) P (═O) O—C _1-8 alkyl-Z—C _1-8 alkyl-, R ⁸ ZA-C _1-8 alkyl-ZAZ-C _1-8 alkyl-, heterocyclyl MZAZ-C _1-8 Alkyl-, (R ⁸ O) (R ⁹ O) P (═O) O—C _1-8 alkyl-, (R ¹⁰ ) ₂ N—C _1-8 alkyl-, (R ¹⁰ ) ₃ N ⁺ —C _1-8 alkyl-, heterocyclyl M-, Selected from carbocyclyl M-, R ¹¹ SO ₂ C _1-8 alkyl-, and R ¹¹ SO ₂ NH; or R ⁶ and R ^{7 taken} together are C _1-6 alkyl-YC _{1- 6 alkyl, C 1 to 6} alkyl _{-ZA-C 1 to 6} alkyl, _{A-C 1 to 6} alkyl _{-ZA-C 1 to 6} alkyl, _{A-C 1 to 6} alkyl -A or _{C 1 to 6} alkyl -A Preferably, C _1-2 alkyl-Y-C _1-2 alkyl, C _1-2 alkyl-ZA-C _1-2 alkyl, AC _1-2 alkyl-ZA-C _1-2 alkyl, A in -C _{1 to 3} alkyl -A or _{C 1 to 4} alkyl -A Ri, thereby forming a ring, preferably ^{R 6} is hydrogen, ^{R 7} is an _{C 1 to 6} alkyl;
R ⁸ and R ⁹ are independently hydrogen, metal cation, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, aryl, heteroaryl, C _1-6 aralkyl and C _1-6 heteroaralkyl. More preferably selected from hydrogen, metal cations and C _1-6 alkyl, or R ⁸ and R ^{9 taken} together are C _1-6 alkyl, thereby forming a ring;
Each R ¹⁰ is independently selected from hydrogen and C _1-6 alkyl, preferably C _1-6 alkyl;
Each R ¹¹ is independently hydrogen, OR ¹⁰ , C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C _1-6 aralkyl, and C _{1-6 .} Selected from ₆ heteroaralkyls;
R ¹⁴ is ^{hydrogen, (R 15 O) (R} 16 O) P (= O) W-, R 15 GB-, heterocyclyl ^{_{-, (R 17) 2 N}} -, (R 17) 3 N + -, R ¹⁷ SO ₂ GBG- and R ¹⁵ GBC _1-8 alkyl-, wherein the C _1-8 alkyl moiety is optionally OH, C _1-8 alkyl W (optionally halogen, preferably Substituted with fluorine), substituted with aryl, heteroaryl, carbocyclyl, heterocyclyl and C _1-6 aralkyl, preferably at least one occurrence of R ¹⁴ is other than hydrogen;
R ¹⁵ and R ¹⁶ are independently hydrogen, metal cation, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, aryl, heteroaryl, C _1-8 aralkyl and C _1-6 heteroaralkyl. More preferably selected from hydrogen, metal cations and C _1-6 alkyl, or R ¹⁵ and R ^{16 taken} together are C _1-6 alkyl, thereby forming a ring; and each R ¹⁷ is independently hydrogen, OR ¹⁰ , C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C _1-6 aralkyl and C _1-6 hetero Selected from aralkyl,
It is not a compound.

  In certain embodiments, the chain of amino acids has the structure of formula (V) or (VI):

を有するか、またはその薬学的に受容可能な塩であり、ここで
各Ａｒは、独立に、必要に応じて１〜４個の置換基で置換された芳香族基または複素芳香族基であり；
Ｌは、存在しないか、またはＣ＝Ｏ、Ｃ＝Ｓ、およびＳＯ_２より選択され、好ましくはＳＯ_２またはＣ＝Ｏであり；
Ｘは、ＣＯＯＨもしくはその活性化形態であり、好ましくはＸはＣＯＯＨ、ＣＯＣｌ、またはＣＯＮ（Ｍｅ）（ＯＭｅ）であり、最も好ましくはＸはＣＯＯＨはＣＯＣｌであり；
Ｙは存在しないかまたはＣ＝ＯおよびＳＯ_２より選択され；
Ｚは存在しないかまたはＣ_１〜６アルキルであり；そして
Ｒ^５およびＲ^６は、各々独立に、Ｃ_１〜６アルキル、Ｃ_１〜６ヒドロキシアルキル、Ｃ_１〜６アルコキシアルキル、アリール、およびＣ_１〜６アラルキルより選択され、これらの基のいずれも、必要に応じて、１つ以上のアミド、アミン、カルボン酸（もしくはその塩）、エステル（Ｃ_１〜６アルキルエステル、Ｃ_１〜５アルキルエステル、およびアリールエステルを含む）、チオールまたはチオエステル置換基で置換されており；
Ｒ^９はＮ（Ｒ^１０）Ｌ−Ｚ−Ｒ^１１であり；
Ｒ^１０は、水素、ＯＨ、Ｃ_１〜６アラルキル−Ｙ−、およびＣ_１〜６アルキル−Ｙ−より選択され、好ましくは水素であり；
Ｒ^１１は、水素、ＯＲ^１２、Ｃ_１〜６アルケニル、Ａｒ−Ｙ−、カルボシクリルおよびヘテロシクリルより選択され；そして
Ｒ^１２は、水素、Ｃ_１〜６アルキル、およびＣ_１〜６アラルキルより選択され、好ましくは水素である。

Or a pharmaceutically acceptable salt thereof, wherein each Ar is independently an aromatic or heteroaromatic group optionally substituted with 1 to 4 substituents ;
L is absent or selected from C═O, C═S, and SO ₂ , preferably SO ₂ or C═O;
X is COOH or an activated form thereof, preferably X is COOH, COCl, or CON (Me) (OMe), most preferably X is COOH COCO;
Y is absent or selected from C═O and SO ₂ ;
Z is absent or is C _1-6 alkyl; and R ⁵ and R ⁶ are each independently C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxyalkyl, aryl, and C Selected from _1-6 aralkyls, any of these groups may optionally include one or more amides, amines, carboxylic acids (or salts thereof), esters (C _1-6 alkyl esters, C _1-5 alkyls). Esters, and aryl esters), substituted with thiol or thioester substituents;
R ⁹ is N (R ¹⁰ ) LZR ¹¹ ;
R ¹⁰ is selected from hydrogen, OH, C _1-6 aralkyl-Y—, and C _1-6 alkyl-Y—, preferably hydrogen;
R ¹¹ is selected from hydrogen, OR ¹² , C _1-6 alkenyl, Ar—Y—, carbocyclyl and heterocyclyl; and R ¹² is selected from hydrogen, C _1-6 alkyl, and C _1-6 aralkyl; Preferably it is hydrogen.

In certain embodiments, L is selected from C═O, C═S, and SO ₂ , preferably SO ₂ or C═O.

In certain embodiments, R ¹⁰ is selected from hydrogen, OH, C _1-6 aralkyl, and C _1-6 alkyl, preferably hydrogen.

In certain embodiments, R ¹¹ is selected from hydrogen, C _1-6 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl.

In certain embodiments, R ⁵ and R ⁶ are each independently selected from C _1-6 alkyl, C _1-6 hydroxyalkyl, and C _1-6 aralkyl. In preferred such embodiments, R ⁵ is C _1-6 alkyl and R ⁶ is C _1-6 aralkyl. In more preferred such embodiments, R ⁵ is isobutyl and R ⁶ is phenylmethyl.

In certain embodiments, R ¹⁰ is hydrogen, L is C═O or SO ₂ , R ¹¹ is Ar—Y—, and each Ar is independently phenyl, indolyl, benzofuranyl, naphthyl, Selected from quinolinyl, quinolonyl, thienyl, pyridyl, pyrazyl and the like. In certain such embodiments, Ar may be substituted with Ar—Q—, wherein Q is selected from a direct bond, —O—, and C _1-6 alkyl. In certain other such embodiments where Z is C _1-6 alkyl, Z is preferably substituted with Ar (eg, phenyl).

In certain embodiments, R ¹⁰ is hydrogen, Z is absent, L is C═O or SO ₂ , and R ¹¹ is selected from Ar—Y and heterocyclyl. In certain preferred such embodiments, the heterocyclyl is selected from chromonyl, chromanyl, morpholino and piperazinyl. In certain other preferred such embodiments, Ar is selected from phenyl, indolyl, benzofuranyl, naphthyl, quinolinyl, quinolonyl, thienyl, pyridyl, pyrazyl, and the like.

In certain embodiments, R ¹⁰ is hydrogen, L is C═O or SO ₂ , Z is absent, and R ¹¹ is C _1-6 alkenyl, where C _1-6 alkenyl is , A substituted vinyl group, and the substituent is preferably an aryl group or a heteroaryl group, more preferably a phenyl group substituted with 1 to 4 substituents as necessary.

In certain embodiments, R ¹² is selected from hydrogen and C _1-6 alkyl. In certain preferred such embodiments, R ¹² is selected from hydrogen and methyl. In more preferred such embodiments, R ¹² is hydrogen.

  In certain preferred embodiments, the chain of amino acids has the structure of formula (VII):

を有し、Ｘは、ＣＯＯＨまたはその活性化形態であり、好ましくはＸはＣＯＯＨ、ＣＯＣｌまたはＣＯＮ（Ｍｅ）（ＯＭｅ）であり、最も好ましくはＸはＣＯＯＨまたはＣＯＣｌであり；
Ｒ^５、Ｒ^６およびＲ^７は、独立にＣ_１〜６アルキル、Ｃ_１〜６ヒドロキシアルキル、Ｃ_１〜６アルコキシアルキル、アリールおよびＣ_１〜６アラルキルより選択され、これらの基のいずれも、必要に応じてアミド、アミン、カルボン酸またはその薬学的に受容可能な塩、カルボン酸エステル、チオールおよびチオエステルより選択される基で置換され、好ましくはＲ^６はＣ_１〜６アルキルであり、Ｒ^５およびＲ^７はＣ_１〜６アラルキルであり、最も好ましくは、Ｒ^６はイソブチルであり、Ｒ^５は２−フェニルエチルであり、Ｒ^７はフェニルメチルであり；
Ｒ^９は、アミノ酸のさらなる鎖、水素、Ｃ_１〜６アシル、保護基、アリールまたはヘテロアリールであり、ここで置換基としてはハロゲン、カルボニル、ニトロ、ヒドロキシ、アリール、およびＣ_１〜５アルキルが挙げられ、好ましくはＲ^９はＣ_１〜６アシルであり、最も好ましくはＲ^９はセチルである。

And X is COOH or an activated form thereof, preferably X is COOH, COCl or CON (Me) (OMe), most preferably X is COOH or COCl;
R ⁵ , R ⁶ and R ⁷ are independently selected from C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxyalkyl, aryl and C _1-6 aralkyl, any of these groups being Optionally substituted with a group selected from amides, amines, carboxylic acids or pharmaceutically acceptable salts, carboxylic esters, thiols and thioesters, preferably R ⁶ is C _1-6 alkyl, R ⁵ and R ⁷ are C _1-6 aralkyl, most preferably R ⁶ is isobutyl, R ⁵ is 2-phenylethyl, and R ⁷ is phenylmethyl;
R ⁹ is a further chain of amino acids, hydrogen, C _1-6 acyl, protecting group, aryl or heteroaryl, where the substituents are halogen, carbonyl, nitro, hydroxy, aryl, and C _1-5 alkyl Preferably, R ⁹ is C _1-6 acyl, most preferably R ⁹ is cetyl.

  The terms “amine” and “amino” are art-recognized and both unsubstituted and substituted amines and salts thereof, such as the general formula:

により示され得る部分をいい、ここでＲ^９、Ｒ^１０およびＲ^１０’は各々独立に、水素、アルキル、アルケニル、−（ＣＨ_２）_ｍ−Ｒ^８を表すか、またはＲ^９およびＲ^１０は、それらが結合しているＮ原子と一緒になって、その環構造に４〜８個の原子を有する複素環を完成し；Ｒ^８はアリール、シクロアルキル、シクロアルケニル、ヘテロシクリルまたはポリシクリルを表し；そしてｍは０または１〜８の整数である。好ましい実施形態では、Ｒ^９またはＲ^１０のうちの１つのみがカルボニルであり得、例えば、Ｒ^９、Ｒ^１０および上記窒素は一緒になってイミドを形成することはない。さらにより好ましい実施形態では、Ｒ^９およびＲ^１０（および必要に応じて^Ｒ１０’）は、各々独立に、水素、アルキル、アルケニル、−（ＣＨ_２）_ｍ−Ｒ^８を表す。特定の実施形態では、このアミノ基は塩基性であり、それはその共役酸がｐＫａ≧７．００を有することを意味する。

Wherein R ⁹ , R ¹⁰ and R ^{10 ′} each independently represent hydrogen, alkyl, alkenyl, — (CH ₂ ) _m —R ⁸ , or R ⁹ and R ¹⁰ are Together with the N atom to which they are attached completes a heterocyclic ring having 4 to 8 atoms in its ring structure; R ⁸ represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl or polycyclyl; And m is 0 or an integer of 1-8. In a preferred embodiment, only one of R ⁹ or R ¹⁰ can be carbonyl, for example R ⁹ , R ¹⁰ and the nitrogen do not combine to form an imide. In an even more preferred embodiment, R ⁹ and R ¹⁰ (and optionally ^{R 10 ′} ) each independently represent hydrogen, alkyl, alkenyl, — (CH ₂ ) _m —R ⁸ . In certain embodiments, the amino group is basic, which means that the conjugate acid has a pKa ≧ 7.00.

  The terms “amide” and “amide” are art-recognized and refer to an amino-substituted carbonyl and have the general formula:

で表され得る部分を含み、ここで、Ｒ^９およびＲ^１０は、「アミン」または「アミノ」について上で定義されたとおりである。アミドの好ましい実施形態は、不安定であり得るイミドは含まない。

Wherein R ⁹ and R ¹⁰ are as defined above for “amine” or “amino”. Preferred embodiments of the amide do not include imides that can be unstable.

  The term “aryl”, as used herein, includes 5, 6 and 7 membered substituted or unsubstituted monocyclic aromatic groups where each atom of the ring is carbon. The term “aryl” also has two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is aromatic, eg, other rings It includes polycyclic ring systems in which the formula ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Examples of the aryl group include benzene, naphthalene, phenanthrene, phenol, aniline and the like.

  The terms “carbocycle” and “carbocyclyl” as used herein refer to a non-aromatic substituted or unsubstituted ring in which each carbon atom of the ring is carbon. The terms “carbocycle” and “carbocyclyl” also have two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is carbocyclic For example, including polycyclic ring systems where other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl.

  The term “carbonyl” is art-recognized and has the general formula:

で表され得るような部分を含み、ここでＸは結合であるか、または酸素または硫黄を表し、そしてＲ^１１は水素、アルキル、アルケニル、−（ＣＨ_２）_ｍ−Ｒ^８または薬学的に受容可能な塩を表し、Ｒ^１１’は水素、アルキル、アルケニルまたは−（ＣＨ_２）_ｍ−Ｒ^８を表し、ここでｍおよびＲ^８は上で定義されたとおりである。Ｘが酸素であり、Ｒ^１１またはＲ^１１’が水素でない場合、上式は「エステル」を表す。Ｘが酸素であり、Ｒ^１１が水素である場合、上式「カルボン酸」を表す。

Wherein X is a bond or represents oxygen or sulfur, and R ¹¹ is hydrogen, alkyl, alkenyl, — (CH ₂ ) _m —R ⁸ or pharmaceutically acceptable Represents a possible salt, R ^{11 ′} represents hydrogen, alkyl, alkenyl or — (CH ₂ ) _m —R ⁸ , where m and R ⁸ are as defined above. Where X is oxygen and R ¹¹ or R ^{11 ′} is not hydrogen, the above formula represents an “ester”. When X is oxygen and R ¹¹ is hydrogen, the above formula “carboxylic acid” is represented.

  As used herein, an “enzyme” can be any partially proteinaceous molecule or a whole proteinaceous molecule that performs a chemical reaction in a catalytic manner. Such enzymes include natural enzymes, fusion enzymes, proenzymes, apoenzymes, denaturing enzymes, farnesylated enzymes, ubiquitinated enzymes, fatty acylated enzymes, gellanylated acylated enzymes. Enzymes, GPI-linked enzymes, lipid-linked enzymes, prenylated enzymes, naturally occurring or artificially produced mutant enzymes, enzymes with side chain or backbone modifications, enzymes with leader sequences, and non- It can be an enzyme complexed with a proteinaceous substance (eg, proteoglycan, proteoliposome). Enzymes can be made by any means including natural expression, facilitated expression, cloning, various solution-based and solid-phase based peptide synthesis and similar methods known to those skilled in the art.

The term “C _1-6 heteroaralkyl” as used herein refers to a C _1-6 alkyl group substituted with a heteroaryl group.

  The term “heteroaryl” includes substituted or unsubstituted 5 to 7 membered aromatic ring structures, more preferably 5 to 6 membered aromatic ring structures, wherein the ring structure contains 1 to 4 heteroatoms. . The term “heteroaryl” also has two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is heteroaromatic, eg, other The cyclic rings of include polycyclic ring systems that can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Examples of heteroaryl include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

  The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, phosphorus and sulfur.

  The term “heterocyclyl” or “heterocyclic group” refers to a substituted or unsubstituted, non-aromatic 3-10 membered ring structure, more preferably 3-7, wherein the ring structure contains 1-4 heteroatoms. A member ring. The term “heterocyclyl” or “heterocyclic group” also has two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is heterocyclic. Including, for example, polycyclic ring systems in which the other cyclic ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Examples of the heterocyclyl group include piperidine, piperazine, pyrrolidine, morpholine, lactone, and lactam.

The term “C _1-6 hydroxyalkyl” refers to a C _1-6 alkyl group substituted with a hydroxy group.

  As used herein, the term “inhibitor” blocks or reduces the activity of an enzyme (eg, a standard fluorogenic peptide substrate (eg, Suc-LLVY-AMC, Box-LLR-AMC And inhibition of proteolytic cleavage of Z-LLE-AMC), inhibition of various catalytic activities of the 20S proteasome) are intended to be described. Inhibitors can act with competitive inhibition, uncompetitive inhibition, or noncompetitive inhibition. Inhibitors can bind reversibly or irreversibly and thus the term includes compounds that are suicide substrates of the enzyme. Inhibitors can modify one or more sites in the vicinity of the active site of the enzyme, or it can cause conformational changes elsewhere in the enzyme.

  As used herein, the term “peptide” refers to commonly used peptide mimetics as detailed below, as well as standard amide linkages with standard α substituents. (Peptidomimetics), other modified linkages, non-natural side chains, and side chain modifications.

  The term “polycyclyl” or “polycyclic” refers to two or more rings in which two or more carbons are common to adjacent rings (eg, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or Heterocycle), for example, the ring is a “fused ring”. Each ring of the polycycle can be substituted or unsubstituted.

  The term “preventing” is art-recognized, eg, local recurrence (eg, pain), disease (eg, cancer), syndrome complex (eg, heart failure), or any other medical When used in connection with a condition, such as a condition, is well understood in the art and reduces the frequency of symptoms of a medical condition in a subject compared to a subject who does not receive the composition, Or administration of a composition that delays the onset of the symptoms. Thus, prevention of cancer is, for example, statistically and / or clinically significant in the number of detectable cancerous growths in a population of patients receiving prophylactic treatment relative to an untreated control population. Reducing the amount and / or delaying the appearance of detectable cancer growth in the treated population by a statistically and / or clinically significant amount relative to an untreated control population. . Prevention of infection, for example, reduces the number of diagnoses of infection in the treated population relative to the untreated control population, and / or in the treated population relative to the untreated control population. Including delaying the onset of symptoms of infection. Prevention of pain includes, for example, reducing the perceived intensity of pain experienced by a subject in the treated population or delaying the perception of pain relative to an untreated control population.

  The term “prophylactic or therapeutic” treatment is art-recognized and includes administration of one or more subject compositions to a host. If it is administered prior to clinical onset of an undesired condition (eg, host animal disease or other undesired state), the treatment is prophylactic (ie, it is desirable Protects the host animal from the onset of a condition), whereas if it is administered after the clinical onset of the undesirable condition, the treatment is therapeutic (ie, The treatment is intended to reduce, ameliorate, or stabilize an existing undesirable condition or its side effects.

  The term “stereoselective” is art-recognized and is more than one that a diastereomer (or one enantiomeric pair of diastereomers) would have been formed or destroyed. A reaction that is formed or destroyed fairly preferentially.

  The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. “Substituted” or “substituted with” means that such substituents are in accordance with the permissible valences of the substituent atoms and substituents and are spontaneously undergoing transformations, eg, by rearrangement, cyclization, elimination, etc. It is understood to include an implied proviso that results in a stable organic compound that does not. As used herein, “substituted” is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. It is done. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For the purposes of the present invention, a heteroatom such as nitrogen represents a hydrogen substituent and / or any acceptable substituent of the organic compounds described herein that satisfies the valence of the heteroatom. Can have. Substituents include, for example, halogen, hydroxyl, carbonyl (eg, carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (eg, thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino Amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, aromatic or heteroaromatic moieties. It will be appreciated by those skilled in the art that the moiety substituted on the hydrocarbon itself can be substituted if appropriate.

  A “therapeutically effective amount” of a compound with respect to the subject method of treatment is clinical for the disorder or condition to be treated when administered (as a mammal, preferably a human) as part of the desired dosage regimen. According to acceptable standards or according to cosmetic purposes, for example, at a reasonable benefit / risk ratio applicable to any medical procedure, to alleviate symptoms, improve their condition, or develop a disease state Refers to the amount of compound in the preparation that slows down.

  As used herein, the term “treat” or “treatment” reverses the symptoms, clinical signs, and potential medical conditions of the condition in a manner that improves or stabilizes the condition of the subject. Including reducing or preventing.

  The phrase “pharmaceutically acceptable” is within reasonable medical judgment, balanced with a reasonable benefit / risk ratio, without excessive toxicity, irritation, allergic response, other problems or complications. Is employed herein to refer to ligands, substances, compositions and / or dosage forms suitable for use in contact with human or animal tissue.

  The term “pharmaceutically acceptable salts” refers to the relatively non-toxic inorganic and organic acid addition salts of the inhibitors. These salts can be prepared in situ during the final isolation and purification of the inhibitor, or by reacting the purified inhibitor in free base form separately with a suitable organic or inorganic acid, and so on. It can be prepared by isolating the salt formed. Typical salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, lauric acid Salt, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptanoate, lactobionate, Lauryl sulfate and amino acid salts and the like (see, for example, Berge et al., (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19).

  In other cases, inhibitors useful in the methods of the invention may have one or more acidic substituents and thus form a pharmaceutically acceptable salt with a pharmaceutically acceptable base. The term “pharmaceutically acceptable salts” in these examples refers to the relatively non-toxic inorganic acid base addition salts and organic base addition salts of inhibitors. These salts can also be prepared in situ during the final isolation and purification of the inhibitor, or the purified inhibitor in free acid form can be converted to a suitable base (eg, a pharmaceutically acceptable metal cation). Hydroxide, carbonate, ammonia, or pharmaceutically acceptable organic primary amine, secondary amine or tertiary amine). Typical alkali metal salts or alkaline earth metal salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, and the like. Representative organic amines suitable for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, eg, Berge et al., Supra).

  (Scheme 1: Synthesis of Examples 1 and 2)

（（Ｂ）および（Ｃ）の合成）
４００ｍＬのＭｅＯＨ中の（Ａ）（１０．５７ｇ、３６．５２ｍｍｏｌ）（Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．１９９９，９，２２８３−８８に記載されるように調製した）の０℃の溶液に、ＣｅＣｌ_３・７Ｈ_２Ｏ（１６．３３ｇ、４３．８２ｍｍｏｌ）を添加した。この溶液を、ＣｅＣｌ_３・７Ｈ_２Ｏが完全に溶解するまで、アルゴン雰囲気下で攪拌した。この溶液に、ＮａＢＨ_４（１．６５ｇ、４３．８２ｍｍｏｌ）を、２分間かけて、１０回に分けて添加した。この反応物を、アルゴン雰囲気下、０℃で６時間攪拌し、この時点でこの混合物は、乳白色になった。この反応物を、０℃で、約５ｍＬの氷酢酸でクエンチし、０℃でさらに３０分間攪拌した後、この混合物は、透明になった。揮発分を減圧下で除去し、残った油状物をＥｔＯＡｃ（３００ｍＬ）中に取り込んだ。この有機層を水（２×２００ｍＬ）、ブライン（２×２００ｍＬ）で洗浄し、そしてＭｇＳＯ_４で乾燥した。このＭｇＳＯ_４を濾過により除き、そして揮発分を減圧下で除去した。フラッシュクロマトグラフィーによる精製により、（Ｂ）および（Ｃ）を９：１混合物（１０．５ｇ）として得た。Ｒ_ｆ＝０．２１（５：１ ヘキサン／ＥｔＯＡｃ）；^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：（Ｂ）δ ７．３８−７．２５（ｍ，５Ｈ），５．１８−４．８２（ｍ，５Ｈ），４．１７（ｂｒ ｓ，１Ｈ），３．９１（ｍ，１Ｈ），１．９９（ｂｒ ｓ，１Ｈ），１．７８（ｓ，３Ｈ），１．６４（ｍ，１Ｈ），１．２６（ｍ，２Ｈ），０．９１（ｍ，６Ｈ）。

(Synthesis of (B) and (C))
To a 0 ° C solution of (A) (10.57 g, 36.52 mmol) (prepared as described in Bioorg. Med. Chem. Lett. 1999, 9, 2283-88) in 400 mL of MeOH was added CeCl. _{3 · 7H 2 O (16.33g,} 43.82mmol) was added. The solution was stirred under an argon atmosphere until the CeCl ₃ · 7H ₂ O was completely dissolved. To this solution, NaBH ₄ (1.65 g, 43.82 mmol) was added in 10 portions over 2 minutes. The reaction was stirred at 0 ° C. for 6 hours under an argon atmosphere, at which point the mixture became milky white. The reaction was quenched at 0 ° C. with about 5 mL of glacial acetic acid and stirred at 0 ° C. for an additional 30 minutes, after which the mixture became clear. Volatiles were removed under reduced pressure and the remaining oil was taken up in EtOAc (300 mL). The organic layer was washed with water (2 × 200 mL), brine (2 × 200 mL) and dried over MgSO ₄ . Except for this MgSO ₄ by filtration, and the volatiles removed under reduced pressure. Purification by flash chromatography gave (B) and (C) as a 9: 1 mixture (10.5 g). R _f = 0.21 (5: 1 hexane / EtOAc); ¹ H NMR (300 MHz, CDCl ₃ ): (B) δ 7.38-7.25 (m, 5H), 5.18-4.82 ( m, 5H), 4.17 (brs, 1H), 3.91 (m, 1H), 1.99 (brs, 1H), 1.78 (s, 3H), 1.64 (m, 1H) ), 1.26 (m, 2H), 0.91 (m, 6H).

  As shown in Table (1), several reaction conditions were examined for the conversion from (A) to (B) and (C). In all cases, the starting enone was completely consumed.

（（Ｄ）および（Ｅ）の合成）
０℃の３６０ｍＬの乾燥ジクロロメタン中の（Ｂ）および（Ｃ）の９／１混合物（１０．５６ｇ、３６．２４ｍｍｏｌ）の溶液に、アルゴン雰囲気下でＶＯ（ａｃａｃ）_２（０．２８９ｇ、１．０９ｍｍｏｌ）を添加した。この溶液に、ｔ−ＢｕＯＯＨ（５．５Ｍ デカン溶液、１３．２ｍＬ、７２．５ｍｍｏｌを添加した。ｔ−ＢｕＯＯＨの添加の際に、反応物の色は明緑色から深赤色に変化した。この反応物を、氷水浴から取り出し、６時間攪拌しながら、室温まで温めた。このとき、反応物の色は、明黄色になり、ＴＬＣにより反応が完了したと見なした。この反応混合物を、セライトの栓を通して濾過し、分液漏斗に移し、１／２飽和ＮａＨＣＯ_３（２×２００ｍＬ）で洗浄し、水層をジクロロメタン（２×１００ｍＬ）で抽出した。この有機層を合わせ、水（２×２００ｍＬ）およびブライン（２×２００ｍＬ）で洗浄し、ＭｇＳＯ_４で乾燥した。このＭｇＳＯ_４を濾過により除き、揮発分を減圧下で除去して、（Ｄ）および（Ｅ）の９／１混合物（１０．０ｇ）を得た。Ｒ_ｆ＝０．１８（３：１ ヘキサン／ＥｔＯＡｃ）；^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：（Ｄ）δ ７．３８−７．３１（ｍ，５Ｈ），５．１５−４．９８（ｍ，３Ｈ），３．９９（ｍ，１Ｈ），３．８７（ｂｒ ｓ，１Ｈ），２．９７（ｄ，Ｊ＝４．６９Ｈｚ，１Ｈ），２．６４（ｄ，Ｊ＝４．６９Ｈｚ，１Ｈ），２．１５（ｂｒ ｓ，１Ｈ），１．６５（ｍ，１Ｈ），１．４７（ｍ，１Ｈ），１．３７（ｓ，３Ｈ），１．０９（ｍ，１Ｈ），０．９２（ｍ，６Ｈ）。

(Synthesis of (D) and (E))
To a solution of 9/1 mixture (10.56 g, 36.24 mmol) of (B) and (C) in 360 mL of dry dichloromethane at 0 ° C. was added VO (acac) ₂ (0.289 g, 1.. 09 mmol) was added. To this solution was added t-BuOOH (5.5 M decane solution, 13.2 mL, 72.5 mmol. Upon addition of t-BuOOH, the color of the reaction changed from light green to deep red. The product was removed from the ice-water bath and allowed to warm to room temperature with stirring for 6 hours, at which time the reaction color became light yellow and the reaction was deemed complete by TLC. Filtered through a plug, transferred to a separatory funnel, washed with 1/2 saturated NaHCO ₃ (2 × 200 mL), and the aqueous layer was extracted with dichloromethane (2 × 100 mL) The organic layers were combined and water (2 × 200 mL) and brine (2 × 200 mL) and dried over MgSO _4. The MgSO ₄ was removed by filtration, the volatiles were removed under reduced pressure, and a 9/1 mixture of (D) and (E) ( 10 R _g = 0.18 (3: 1 hexane / EtOAc); ¹ H NMR (300 MHz, CDCl ₃ ): (D) δ 7.38-7.31 (m, 5H), 5 15-4.98 (m, 3H), 3.99 (m, 1H), 3.87 (brs, 1H), 2.97 (d, J = 4.69 Hz, 1H), 2.64 ( d, J = 4.69 Hz, 1H), 2.15 (brs, 1H), 1.65 (m, 1H), 1.47 (m, 1H), 1.37 (s, 3H), 1. 09 (m, 1H), 0.92 (m, 6H).

（（Ｄ）および（Ｅ）の代替の合成）
ＤＣＭ（５ｍＬ）中の（Ｂ）および（Ｃ）の９／１混合物（０．３４ｍｍｏｌ、０．１０ｇ）の溶液にｍＣＰＢＡ（０．５２ｍｍｏｌ、０．０８９ｇ）を添加し、この混合物を５時間攪拌した。この混合物を飽和ＮａＨＣＯ_３（５ｍＬ）で希釈し、層を分離させた。水層をＤＣＭ（２×５ｍＬ）で抽出し、それらの層を合わせ、飽和ＮａＨＣＯ_３（３×１５ｍＬ）、水（１×１０ｍＬ）、ブライン（１×１５ｍＬ）で洗浄し、ＭｇＳＯ_４で乾燥した。このＭｇＳＯ_４を濾過により除き、揮発分を減圧下で除去し、（Ｄ）および（Ｅ）の９／１混合物（０．０９７ｇ）を得た。

(Alternative synthesis of (D) and (E))
To a solution of a 9/1 mixture (0.34 mmol, 0.10 g) of (B) and (C) in DCM (5 mL) was added mCPBA (0.52 mmol, 0.089 g) and the mixture was stirred for 5 hours. did. The mixture was diluted with saturated NaHCO ₃ (5 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 × 5 mL) and the layers were combined, washed with saturated NaHCO ₃ (3 × 15 mL), water (1 × 10 mL), brine (1 × 15 mL) and dried over MgSO ₄ . . The MgSO ₄ was removed by filtration and the volatiles were removed under reduced pressure to give a 9/1 mixture (0.097 g) of (D) and (E).

(Synthesis of Compounds 1 and 2)
To 225 mL of dry dichloromethane was added oxalyl chloride (22.85 g, 15.7 mL, 180 mmol) and the mixture was cooled to −78 ° C. under an argon atmosphere. To this cooled solution, DMSO (16.88 g, 15.33 mL, 216 mmol) freshly distilled from CaH ₂ and dissolved in 60 mL of dry dichloromethane was added dropwise. During the addition of DMSO, the temperature of the reaction was monitored and the addition rate was adjusted to maintain a temperature of -65 ° C. The dropping took about 45 minutes. Ten minutes after the addition of DMSO, a 9/1 mixture (10.0 g, 32.5 mmol) of (D) and (E) dissolved in 75 mL of dry dichloromethane was added dropwise. The reaction was stirred at −78 ° C. for 30 minutes, triethylamine (36.4 g, 50.6 mL, 360 mmol) was added dropwise and the reaction mixture was placed in a 0 ° C. ice bath. The reaction was maintained at 0 ° C. for 30 minutes, at which time the reaction, deemed complete by TLC, was quenched with 20 mL H ₂ O mixed with 80 mL dichloromethane. The cloudy brown mixture became clear after about 10 minutes of stirring. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 × 50 mL). The organic layers were combined, washed with brine (2 × 100 mL) and dried over MgSO ₄ . The MgSO ₄ was removed by filtration and the volatiles were removed under reduced pressure. Purification by flash chromatography gave compound 1 (3.18 g). R _f = 0.26 (5: 1 hexane / EtOAc); ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.39-7.22 (m, 5H), 5.11 (d, J = 9.4 Hz) , 1H), 5.07 (d, J = 15.5 Hz, 1H), 5.03 (d, J = 15.2 Hz, 1H), 4.40 (ddd, J = 10.3, 8.8, 2.9 Hz, 1H), 3.27 (d, J = 5.0, 1H), 2.90 (d, J = 5.0 Hz, 1H), 1.71 (m, 1H), 1.47 ( s, 3H), 1.21 (m, 2H), 0.97 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 201.9, 156.2, 136.1, 128.5, 128.1, 128.0, 66.9, 52.2, 51.8, 4 0.5, 25.0, 23.4, 21.2, 16.7. Compound 2: R _f = 0.15 (5: 1 hexane / EtOAc); ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.39-7.25 (m, 5H), 5.09 (m, 3H) 4.66 (ddd, J = 7.3, 7.0, 7.0 Hz, 1H), 3.03 (d, J = 4.7 Hz, 1H), 2.86 (d, J = 5.0 Hz) , 1H), 1.70 (m, 1H), 1.55 (s, 3H), 1.37 (m, 2H), 0.97 (d, J = 6.5 Hz, 3H), 0.91 ( d, J = 6.7 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 207.4, 155.7, 136.1, 128.4, 128.1, 128.0, 66.9, 58.6, 53.0, 52.7, 41.0, 24.7, 23.2, 21.4, 17.4.

（１および２の代替（Ａ）の合成）
ＤＣＭ（１０ｍＬ）中の（Ｄ）および（Ｅ）の９／１混合物（０．２９ｇ、０．９５ｍｍｏｌ）の溶液にＮＭＯ（０．１７ｇ、１．４３ｍｍｏｌ）、砕いた４Åモレキュラーシーブ（０．７６ｇ）を添加し、この反応を１５分間攪拌した。ＴＰＡＰ（０．０２ｇ、０．０５ｍｍｏｌ）をこの混合物に添加し、この反応物を３６時間攪拌した。この反応物を、ヘキサン（１５ｍＬ）で希釈し、シリカゲルの栓を通して濾過し、洗浄した（５：１ ヘキサン／ＥｔＯＡｃ、５０ｍＬ）。揮発分を減圧下で除去し、粗物質をフラッシュクロマトグラフィーにより精製し１（０．１３８ｇ）を得た。

(Synthesis of alternatives 1 and 2 (A))
A solution of 9/1 mixture (0.29 g, 0.95 mmol) of (D) and (E) in DCM (10 mL) was added to NMO (0.17 g, 1.43 mmol), crushed 4Å molecular sieves (0.76 g). ) And the reaction was stirred for 15 minutes. TPAP (0.02 g, 0.05 mmol) was added to the mixture and the reaction was stirred for 36 hours. The reaction was diluted with hexane (15 mL), filtered through a plug of silica gel and washed (5: 1 hexane / EtOAc, 50 mL). Volatiles were removed under reduced pressure and the crude material was purified by flash chromatography to give 1 (0.138 g).

（１および２の代替（Ｂ）の合成）
５℃の８０ｍＬのＤＭＳＯ中のＤｅｓｓ−Ｍａｒｔｉｎペルヨージナン（６．９５ｇ、１６．４ｍｍｏｌ）の溶液に、（Ｄ）および（Ｅ）の４／１ 混合物（２．５２ｇ、８．２０ｍｍｏｌ）をＤＭＳＯ溶液（１５ｍＬ）として添加した。この混合物をアルゴン雰囲気下に置き、一晩攪拌しながら、室温まで温めた。完了したとき、白色沈殿が生成し、この反応物を氷浴で冷却し、１００ｍＬの飽和ＮａＨＣＯ_３で希釈した。この混合物をさらに４００ｍＬのＥｔＯＡｃで希釈し、固体をセライトの栓を通して濾過することにより除いた。この混合物を分液漏斗に移し、層を分離させた。水層をＥｔＯＡｃ（２×２００ｍＬ）で抽出し、これらの有機層を合わせ、Ｈ_２Ｏ（３×１００ｍＬ）、ブライン（１×４００ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥した。このＮａ_２ＳＯ_４を濾過によって除き、揮発分を減圧下で除去して淡黄色の油状物を得た。フラッシュクロマトグラフィーによる精製によって、１（１．０ｇ）および２（０．２０ｇ）を得た。

(Synthesis of 1 and 2 alternative (B))
To a solution of Dess-Martin periodinane (6.95 g, 16.4 mmol) in 80 mL DMSO at 5 ° C., a 4/1 mixture of (D) and (E) (2.52 g, 8.20 mmol) was added to the DMSO solution ( 15 mL). The mixture was placed under an argon atmosphere and allowed to warm to room temperature with stirring overnight. When complete, a white precipitate formed and the reaction was cooled in an ice bath and diluted with 100 mL of saturated NaHCO ₃ . The mixture was further diluted with 400 mL of EtOAc and the solid was removed by filtration through a plug of celite. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 200 mL) and the organic layers were combined, washed with H ₂ O (3 × 100 mL), brine (1 × 400 mL) and dried over Na ₂ SO ₄ . The Na ₂ SO ₄ was removed by filtration and the volatiles were removed under reduced pressure to give a pale yellow oil. Purification by flash chromatography gave 1 (1.0 g) and 2 (0.20 g).

（（Ｇ）および（Ｈ）の合成）
化合物（Ｇ）および（Ｈ）を、（Ａ）を（Ｆ）に置き換えた以外は、（Ａ）から（Ｂ）および（Ｃ）への変換と同じ手順に従って、得た。

(Synthesis of (G) and (H))
Compounds (G) and (H) were obtained following the same procedure as the conversion from (A) to (B) and (C) except that (A) was replaced by (F).

(Synthesis of (I) and (J))
Compounds (I) and (J) were replaced from (B) and (C) to (D) and (E), respectively, except that (B) was replaced with (G) and (C) was replaced with (H). According to the same procedure as the conversion to

(Synthesis of Compounds 3 and 4)
Compounds 3 and 4 were the same procedure as conversion from (D) and (E) to compounds 1 and 2, respectively, except that (D) was replaced with (I) and (E) was replaced with (J). According to the obtained. The ¹ H NMR spectrum and ¹³ C NMR spectrum of compounds 3 and 4 were identical to compounds 1 and 2, respectively.

(Equivalent)
Those skilled in the art will recognize, or at best be able to ascertain using no more than routine experimentation, many equivalents to the compounds of the invention and methods of use described herein. Such equivalents are considered to be within the scope of this invention and are covered by the appended claims.

  All of the references and publications cited above are hereby incorporated by reference.

Claims (22)

A method of synthesizing an amino acid keto epoxide comprising a reaction sequence according to Scheme (I);

here,
R ¹ is selected from a protecting group or an additional chain of amino acids, which further group of protecting groups or amino acids may themselves be optionally substituted;
R ² is selected from hydrogen and C _1-6 alkyl; or R ¹ and R ² together are C (O) -aryl-C (O) or C (O) C _1-6 alkenyl. C (O) thereby forming a ring;
R ³ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxyalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 heteroaralkyl, and C _1-6 aralkyl;
A is a stereoselective reduction under reducing conditions;
B is stereoselective epoxidation under epoxidation conditions; and C is oxidation under oxidation conditions. The method of claim 1, wherein R ¹ is a protecting group. The method of claim 2, wherein R ¹ is an electron withdrawing protecting group. 4. The method of claim 3, wherein R ¹ is t-butoxycarbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), and benzyloxycarbonyl. A method selected from (Cbz). The method of claim 4, wherein R ¹ is Cbz. The method according to claim 4, R ² is hydrogen, method. 7. The method according to any one of claims 1 to 6, wherein A is selected from sodium borohydride with cerium trichloride, lithium tri-tert-butoxyaluminum hydride, or L-Selectride. Method. 8. The method of claim 7, wherein A is sodium borohydride with cerium trichloride. 9. The method according to any one of claims 1 to 8, wherein B is selected from m-chloroperbenzoic acid or VO (acac) ₂ with t-BuOOH. 10. The method of claim 9, wherein B is VO (acac) ₂ with t-BuOOH. 11. The method according to any one of claims 1 to 10, wherein C is Swern oxidation, or the ruthenium with 4-methylmorpholine-N-oxide (NMO), or the oxidizing agent is Dess-Martin periodinane. A process selected from oxidation which is tetrapropyl acid (TPAP). 12. The method of claim 11, wherein C is Swern oxidation. 12. The method of claim 11, wherein C is oxidation with Dess-Martin periodinane. 14. The method according to any one of claims 1 to 13, wherein the compound in the scheme (I) has the following stereochemistry:

Having a method. 15. The method according to any one of claims 1 to 14, further comprising the step of removing the protecting group and combining with a chain of amino acids, if necessary. 16. The method of claim 15, wherein the amino acid chain comprises 3 amino acids. 17. The method of claim 16, wherein the chain of amino acids is of formula (VII):

Wherein X is COOH or an activated form thereof;
R ^{5, R 6,} and ^{R 7,} _{independently, C 1 to 6 alkyl, C 1 to 6 hydroxyalkyl, C 1 to 6} alkoxyalkyl is selected from aryl and _{C 1 to 6} aralkyl, the _{C 1 to 6} Each of alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxyalkyl, aryl and C _1-6 aralkyl is an amide, amine, carboxylic acid or pharmaceutically acceptable salt thereof, carboxylic acid ester, thiol and thioester Optionally substituted with a group selected from;
R ⁹ is a further chain of amino acids, hydrogen, C _1-6 acyl, protecting group, aryl or heteroaryl, where the substituents are halogen, carbonyl, nitro, hydroxy, aryl and C _1-5 alkyl Can be mentioned. The method according to claim 17, X is COOH or COCl, ^{R 5} and ^{R 7} are _{C 1 to 6} aralkyl, ^{R 6} is a _{C 1 to 6} alkyl, and ^{R 9} is _{C 1 The} method, which is _{~ 6} acyl. The method according to claim 18, X is COOH, are ^{R 5} is 2-phenyl ethyl, ^{R 6} is isobutyl, ^{R 7} is phenylmethyl, and ^{R 9} is acetyl, Method. A method for synthesizing allyl alcohol according to scheme (II),

Wherein R ¹ is selected from a protecting group or an additional chain of amino acids, which further chain of protecting groups or amino acids may itself be optionally substituted;
R ² is selected from hydrogen and C _1-6 alkyl; or R ¹ and R ² together are C (O) -aryl-C (O) or C (O) C _1-6 alkenyl. C (O) thereby forming a ring;
R ³ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxyalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 heteroaralkyl and C _1-6 aralkyl; and A is under reducing conditions A synthesis method that is a stereoselective reduction of A method of synthesizing an epoxide according to scheme (III),

Wherein R ¹ is selected from a protecting group or an additional chain of amino acids, which further chain of protecting groups or amino acids may themselves be optionally substituted;
R ² is selected from hydrogen and C _1-6 alkyl; or R ¹ and R ^{2 taken} together are C (O) -aryl-C (O) or C (O) C _1-6 alkenyl. C (O), thereby forming a ring;
R ³ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxyalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 heteroaralkyl, and C _1-6 aralkyl; and B is an epoxidation condition Synthetic method, stereoselective epoxidation below. A method of synthesizing an amino acid ketoepoxide according to scheme (IV), comprising:

here,
R ¹ is selected from a protecting group or an additional chain of amino acids, which further group of protecting groups or amino acids may themselves be optionally substituted;
R ² is selected from hydrogen and C _1-6 alkyl; or R ¹ and R ^{2 taken} together are C (O) -aryl-C (O) or C (0) C _1-6 alkenyl. C (O), thereby forming a ring;
R ³ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxyalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 heteroaralkyl, and C _1-6 aralkyl; and C under oxidizing conditions Is a method of synthesis.