JP2006513976A - 9-oxime macrolide antibacterial drugs - Google Patents

Abstract

Antibacterial compounds having formula I, and salts, prodrugs, and salts of the prodrugs, methods of making the compounds and intermediates used in the methods, compositions containing the compounds, and using the compounds Disclosed are methods for preventing or treating bacterial infections in fish or mammals.
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Description

  The present invention relates to compounds useful as antibacterial agents, methods for making the compounds and intermediates used in the methods, compositions containing the compounds, and methods for preventing or treating bacterial infections using the compounds About.

  Because the effectiveness of many drugs currently available for the prevention or treatment of bacterial infections has been compromised by the emergence of drug-resistant bacteria, new antibacterials have their therapeutic value and their potential for antibacterial technology. It will be beneficial for contribution.

  Thus, the first embodiment of the present invention is:

を有し、式中
Ｒ^１は、アルキル、−（ＣＨ_２）アルケニル、−（ＣＨ_２）アルキニル、−ＣＨ_２Ｒ^６、シクロアルキル、ハロ、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されているアルキル、シクロアルキル、ハロ、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルケニル、またはシクロアルキル、ハロ、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルキニルであり；
Ｒ^２は、水素、アルキル、−（ＣＨ_２）アルケニル、−（ＣＨ_２）アルキニル、−ＣＨ_２Ｒ^６、シクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、−ＯＲ^７、＝Ｏ、ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されているアルキル、シクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、−ＯＲ^７、＝Ｏ、ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルケニル、またはシクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、−ＯＲ^７、＝Ｏ、ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルキニルであり；
Ｒ^３は、水素またはＲ^Ｐであり、該Ｒ^Ｐはヒドロキシル保護部分であり；
Ｒ^４またはＲ^５のうち一方は水素であり、他方は、−ＯＨであり；あるいは、Ｒ^４およびＲ^５は一緒になって、＝Ｏであり；
Ｒ^６は、−Ｏ−、−ＮＨ−、−Ｎ（アルキル）−、−Ｓ−、−Ｓ（Ｏ）−および−ＳＯ_２−からなる群から独立して選択される１つまたは２つまたは３つの部分により割り込まれているアルキル、または−Ｏ−、−ＮＨ−、−Ｎ（アルキル）−、−Ｓ−、−Ｓ（Ｏ）−および−ＳＯ_２−からなる群から独立して選択される１つまたは２つまたは３つの部分により割り込まれており、かつシクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、＝Ｏ、−ＯＲ^７、−ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されているアルキルであり；
Ｒ^７は、アルキル、ヘテロアルキル、アリール、ヘテロアリール、ヘテロシクリル、またはアリール、ヘテロアリール、およびヘテロシクリルからなる群から選択される１つの置換基で置換されているアルキルであり；
Ｒ^８およびＲ^９は独立して、アルキル、シクロアルキル、ヘテロアルキル、アリール、ヘテロアリール、ヘテロシクリル、またはアリール、ヘテロアリール、およびヘテロシクリルからなる群から選択される１つの置換基で置換されているアルキルであり；
Ｒ^８およびＲ^９は一緒になって、−Ｏ−、−ＮＨ−、−Ｎ（アルキル）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−および−ＳＯ_２−からなる群から選択される１つの部分により割り込まれているＣ_３〜Ｃ_７−アルキレンまたはＣ_４〜Ｃ_７−アルキレンであり；
Ｘ^１は、水素またはフルオロである、抗菌剤として有用な化合物、または塩類、プロドラッグ、またはそのプロドラッグの塩類に関する。

Wherein R ¹ is independently from the group consisting of alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl and heterocyclyl. 1 or 2 or 3 substitutions independently selected from the group consisting of alkyl, cycloalkyl, halo, aryl, heteroaryl and heterocyclyl substituted with 1 or 2 or 3 substituents selected Substituted with — (CH ₂ ) alkenyl substituted with 1 or 2 or 3 substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl and heterocyclyl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —OR ⁷ , ═O, Alkyl, cycloalkyl, halo, aryl, heteroaryl, substituted with one, two or three substituents independently selected from the group consisting of NH ₂ , —NHR ⁸ , and —NR ⁸ R ⁹ ; _{^{heterocyclyl, -OH, -OR 7, = O}} , NH 2, substituted with one or two or three substituents independently selected from the group consisting of -NHR ^8, and ^-NR 8 ^{R 9} - (CH ₂₎ alkenyl or cycloalkyl, halo, aryl, heteroaryl, _{^{heterocyclyl, -OH, -OR 7,, =}} O, NH 2, -NHR 8 And — (CH ₂ ) alkynyl substituted with one or two or three substituents independently selected from the group consisting of —NR ⁸ R ⁹ ;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
R ⁶ is one or two independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) —, and —SO ₂ —, or An alkyl interrupted by three moieties, or independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) — and —SO ₂ —; 1 or 2 or 3 moieties, and cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, ═O, —OR ⁷ , —NH ₂ , —NHR ⁸ , and —NR ⁸ alkyl substituted with one, two or three substituents independently selected from the group consisting of R ⁹ ;
R ⁷ is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
R ⁸ and R ⁹ are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl Is;
R ⁸ and R ⁹ together comprise —O—, —NH—, —N (alkyl) —, —S—, —C (O) —, —S (O) — and —SO ₂ —. C ₃ -C ₇ -alkylene or C ₄ -C ₇ -alkylene interrupted by one moiety selected from the group;
X ¹ relates to a compound or salt, prodrug, or salt of the prodrug useful as an antibacterial agent, which is hydrogen or fluoro.

The second embodiment of the present invention is:
Formula (I) -d

を有し、式中
Ｒ^１は、アルキル、−（ＣＨ_２）アルケニル、−（ＣＨ_２）アルキニル、−ＣＨ_２Ｒ^６、シクロアルキル、ハロ、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されているアルキル、シクロアルキル、ハロ、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルケニル、またはシクロアルキル、ハロ、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルキニルであり；
Ｒ^２は、水素、アルキル、−（ＣＨ_２）アルケニル、−（ＣＨ_２）アルキニル、−ＣＨ_２Ｒ^６、シクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、−ＯＲ^７、＝Ｏ、ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されているアルキル、シクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、−ＯＲ^７、＝Ｏ、ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルケニル、またはシクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、−ＯＲ^７、＝Ｏ、ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルキニルであり；
Ｒ^４およびＲ^５は一緒になって、＝Ｏであり；
Ｒ^６は、−Ｏ−、−ＮＨ−、−Ｎ（アルキル）−、−Ｓ−、−Ｓ（Ｏ）−および−ＳＯ_２−からなる群から独立して選択される１つまたは２つまたは３つの部分により割り込まれているアルキル、または−Ｏ−、−ＮＨ−、−Ｎ（アルキル）−、−Ｓ−、−Ｓ（Ｏ）−および−ＳＯ_２−からなる群から独立して選択される１つまたは２つまたは３つの部分により割り込まれており、かつシクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、＝Ｏ、−ＯＲ^７、−ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されているアルキルであり；
Ｒ^７は、アルキル、ヘテロアルキル、アリール、ヘテロアリール、ヘテロシクリル、またはアリール、ヘテロアリール、およびヘテロシクリルからなる群から選択される１つの置換基で置換されているアルキルであり；
Ｒ^８およびＲ^９は独立して、アルキル、シクロアルキル、ヘテロアルキル、アリール、ヘテロアリール、ヘテロシクリル、またはアリール、ヘテロアリール、およびヘテロシクリルからなる群から選択される１つの置換基で置換されているアルキルであり；あるいは
Ｒ^８およびＲ^９は一緒になって、−Ｏ−、−ＮＨ−、−Ｎ（アルキル）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−および−ＳＯ_２−からなる群から選択される１つの部分により割り込まれているＣ_３〜Ｃ_７−アルキレンまたはＣ_４〜Ｃ_７−アルキレンであり；
Ｘ^１は、水素である化合物、または塩類、プロドラッグ類、またはそのプロドラッグの塩類を製造する方法であって；
（ａ）式（１）

Wherein R ¹ is independently from the group consisting of alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl and heterocyclyl. 1 or 2 or 3 substitutions independently selected from the group consisting of alkyl, cycloalkyl, halo, aryl, heteroaryl and heterocyclyl substituted with 1 or 2 or 3 substituents selected Substituted with — (CH ₂ ) alkenyl substituted with 1 or 2 or 3 substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl and heterocyclyl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —OR ⁷ , ═O, Alkyl, cycloalkyl, halo, aryl, heteroaryl, substituted with one, two or three substituents independently selected from the group consisting of NH ₂ , —NHR ⁸ , and —NR ⁸ R ⁹ ; _{^{heterocyclyl, -OH, -OR 7, = O}} , NH 2, substituted with one or two or three substituents independently selected from the group consisting of -NHR ^8, and ^-NR 8 ^{R 9} - (CH ₂₎ alkenyl or cycloalkyl, halo, aryl, heteroaryl, _{^{heterocyclyl, -OH, -OR 7,, =}} O, NH 2, -NHR 8 And — (CH ₂ ) alkynyl substituted with one or two or three substituents independently selected from the group consisting of —NR ⁸ R ⁹ ;
R ⁴ and R ⁵ together are ═O;
R ⁶ is one or two independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) —, and —SO ₂ —, or An alkyl interrupted by three moieties, or independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) — and —SO ₂ —; 1 or 2 or 3 moieties, and cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, ═O, —OR ⁷ , —NH ₂ , —NHR ⁸ , and —NR ⁸ alkyl substituted with one, two or three substituents independently selected from the group consisting of R ⁹ ;
R ⁷ is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
R ⁸ and R ⁹ are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl Or R ⁸ and R ^{9 taken} together are —O—, —NH—, —N (alkyl) —, —S—, —C (O) —, —S (O) — and —SO C ₃ -C ₇ -alkylene or C ₄ -C ₇ -alkylene interrupted by one moiety selected from the group consisting of _2- ;
A method for producing a compound, or salts, prodrugs, or salts of prodrugs thereof, wherein X ¹ is hydrogen;
(A) Formula (1)

を有し、
上記の好ましい実施態様は安息香酸（２Ｓ，３Ｒ，４Ｓ，６Ｒ）−４−（ジメチルアミノ）−２−（（（３ａＳ，４Ｒ，７Ｒ，８Ｓ，９Ｓ，１０Ｒ，１１Ｓ，１３Ｒ，１５Ｒ，１５ａＲ）−４−エチル−ｌｌ−（プロプ−２−イニルオキシ）−８−ヒドロキシ−３ａ，７，９，１１，１３，１５−ヘキサメチル−２，６，１４−トリオキソテトラデカヒドロ−２Ｈ−オキサシクロテトラデシノ［４，３−ｄ］［１，３］オキサゾール−１０−イル）オキシ）−６−メチルテトラヒドロ−２Ｈ−ピラン−３−イルである化合物と、式（２）
Ｈ_２Ｎ−ＯＲ^２
（２）、
を有する化合物またはその塩で、上記の好ましい実施態様は塩酸メトキシルアミンである化合物とを、添加物の有無において、約１．２気圧と５気圧との間の圧で反応させ、
式（Ｉ）−ａ

Have
The preferred embodiment is benzoic acid (2S, 3R, 4S, 6R) -4- (dimethylamino) -2-(((3aS, 4R, 7R, 8S, 9S, 10R, 11S, 13R, 15R, 15aR) -4-ethyl-ll- (prop-2-ynyloxy) -8-hydroxy-3a, 7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetra A compound which is decino [4,3-d] [1,3] oxazol-10-yl) oxy) -6-methyltetrahydro-2H-pyran-3-yl and a compound of formula (2)
H ^₂ N-OR ₂
(2),
Or a salt thereof, wherein the preferred embodiment described above is reacted with a compound that is methoxylamine hydrochloride, with or without additives, at a pressure between about 1.2 atmospheres and 5 atmospheres;
Formula (I) -a

を有し、
上記の好ましい実施態様は安息香酸（２Ｓ，３Ｒ，４Ｓ，６Ｒ）−４−（ジメチルアミノ）−２−（（（３ａＳ，４Ｒ，７Ｒ，８Ｓ，９Ｓ，１０Ｒ，１１Ｓ，１３Ｒ，１４Ｅ，１５Ｒ，１５ａＲ）−４−エチル−ｌｌ−（プロプ−２−イニルオキシ）−８−ヒドロキシ−１４−（メトキシイミノ）−３ａ，７，９，１１，１３，１５−ヘキサメチル−２，６−ジオキソテトラデカヒドロ−２Ｈ−オキサシクロテトラデシノ［４，３−ｄ］［１，３］オキサゾール−１０−イル）オキシ）−６−メチルテトラヒドロ−２Ｈ−ピラン−３−イルである化合物を提供するステップ、
（ｂ）ステップ（ａ）の生成物と酸化剤とを、第１の塩基の有無において反応させ、
式（Ｉ）−ｂ

Have
Preferred embodiments of the above are benzoic acid (2S, 3R, 4S, 6R) -4- (dimethylamino) -2-(((3aS, 4R, 7R, 8S, 9S, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-ll- (prop-2-ynyloxy) -8-hydroxy-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-2,6-dioxotetradeca Providing a compound that is hydro-2H-oxacyclotetradecino [4,3-d] [1,3] oxazol-10-yl) oxy) -6-methyltetrahydro-2H-pyran-3-yl;
(B) reacting the product of step (a) with an oxidant in the presence or absence of a first base;
Formula (I) -b

を有し、
上記の好ましい実施態様は安息香酸（２Ｓ，３Ｒ，４Ｓ，６Ｒ）−４−（ジメチルアミノ）−２−（（（３ａＳ，４Ｒ，７Ｒ，８Ｓ，９Ｒ，１０Ｒ，１１Ｓ，１３Ｒ，１４Ｅ，１５Ｒ，１５ａＲ）−４−エチル−ｌｌ−（プロプ−２−イニルオキシ）−１４−（メトキシイミノ）−３ａ，７，９，１１，１３，１５−ヘキサメチル−２，６，８−トリオキソテトラデカヒドロ−２Ｈ−オキサシクロテトラデシノ［４，３−ｄ］［１，３］オキサゾール−１０−イル）オキシ）−６−メチルテトラヒドロ−２Ｈ−ピラン−３−イルである化合物を提供するステップ、および
（ｃ）ステップ（ｂ）の生成物とメタノールとを反応させるステップを含む方法に関する。

Have
Preferred embodiments of the above are benzoic acid (2S, 3R, 4S, 6R) -4- (dimethylamino) -2-(((3aS, 4R, 7R, 8S, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-ll- (prop-2-ynyloxy) -14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-2,6,8-trioxotetradecahydro- Providing a compound that is 2H-oxacyclotetradecino [4,3-d] [1,3] oxazol-10-yl) oxy) -6-methyltetrahydro-2H-pyran-3-yl; c) relates to a process comprising reacting the product of step (b) with methanol.

  The third embodiment of the present invention relates to the intermediate used in the second embodiment.

The fourth embodiment of the present invention is:
Formula (I) -c

を有し、式中
Ｒ^１は、アルキル、−（ＣＨ_２）アルケニル、−（ＣＨ_２）アルキニル、−ＣＨ_２Ｒ^６、シクロアルキル、ハロ、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されているアルキル、シクロアルキル、ハロ、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルケニル、またはシクロアルキル、ハロ、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルキニルであり；
Ｒ^２は、水素、アルキル、−（ＣＨ_２）アルケニル、−（ＣＨ_２）アルキニル、−ＣＨ_２Ｒ^６、シクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、−ＯＲ^７、＝Ｏ、ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されているアルキル、シクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、−ＯＲ^７、＝Ｏ、ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルケニル、またはシクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、−ＯＲ^７、＝Ｏ、ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されている−（ＣＨ_２）アルキニルであり；
Ｒ^Ｐは、アセチルまたはベンゾイルであり；
Ｒ^６は、−Ｏ−、−ＮＨ−、−Ｎ（アルキル）−、−Ｓ−、−Ｓ（Ｏ）−および−ＳＯ_２−からなる群から独立して選択される１つまたは２つまたは３つの部分により割り込まれているアルキル、または−Ｏ−、−ＮＨ−、−Ｎ（アルキル）−、−Ｓ−、−Ｓ（Ｏ）−および−ＳＯ_２−からなる群から独立して選択される１つまたは２つまたは３つの部分により独立して割り込まれており、かつシクロアルキル、ハロ、アリール、ヘテロアリール、ヘテロシクリル、−ＯＨ、＝Ｏ、−ＯＲ^７、−ＮＨ_２、−ＮＨＲ^８、および−ＮＲ^８Ｒ^９からなる群から独立して選択される１つまたは２つまたは３つの置換基で置換されているアルキルであり；
Ｒ^７は、アルキル、ヘテロアルキル、アリール、ヘテロアリール、ヘテロシクリル、またはアリール、ヘテロアリール、およびヘテロシクリルからなる群から選択される１つの置換基で置換されているアルキルであり；
Ｒ^８およびＲ^９は独立して、アルキル、シクロアルキル、ヘテロアルキル、アリール、ヘテロアリール、ヘテロシクリル、またはアリール、ヘテロアリール、およびヘテロシクリルからなる群から独立して選択される１つの置換基で置換されているアルキルであり；あるいは
Ｒ^８およびＲ^９は一緒になって、−Ｏ−、−ＮＨ−、−Ｎ（アルキル）−、−Ｓ−、−Ｃ（Ｏ）−、−Ｓ（Ｏ）−および−ＳＯ_２−からなる群から選択される１つの部分により割り込まれているＣ_３〜Ｃ_７−アルキレンまたはＣ_４〜Ｃ_７−アルキレンである化合物、または塩類、プロドラッグ類、またはそのプロドラッグの塩類を製造する方法であって；
（ａ）式（Ｉ）−ｂ

Wherein R ¹ is independently from the group consisting of alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl and heterocyclyl. 1 or 2 or 3 substitutions independently selected from the group consisting of alkyl, cycloalkyl, halo, aryl, heteroaryl and heterocyclyl substituted with 1 or 2 or 3 substituents selected Substituted with — (CH ₂ ) alkenyl substituted with 1 or 2 or 3 substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl and heterocyclyl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —OR ⁷ , ═O, Alkyl, cycloalkyl, halo, aryl, heteroaryl, substituted with one, two or three substituents independently selected from the group consisting of NH ₂ , —NHR ⁸ , and —NR ⁸ R ⁹ ; _{^{heterocyclyl, -OH, -OR 7, = O}} , NH 2, substituted with one or two or three substituents independently selected from the group consisting of -NHR ^8, and ^-NR 8 ^{R 9} - (CH ₂₎ alkenyl or cycloalkyl, halo, aryl, heteroaryl, _{^{heterocyclyl, -OH, -OR 7,, =}} O, NH 2, -NHR 8 And — (CH ₂ ) alkynyl substituted with one or two or three substituents independently selected from the group consisting of —NR ⁸ R ⁹ ;
^RP is acetyl or benzoyl;
R ⁶ is one or two independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) —, and —SO ₂ —, or An alkyl interrupted by three moieties, or independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) — and —SO ₂ —; Independently interrupted by one or two or three moieties and are cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, ═O, —OR ⁷ , —NH ₂ , —NHR ⁸ , And alkyl substituted with 1 or 2 or 3 substituents independently selected from the group consisting of —NR ⁸ R ⁹ ;
R ⁷ is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
R ⁸ and R ⁹ are independently substituted with one substituent selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or aryl, heteroaryl, and heterocyclyl. Or R ⁸ and R ^{9 taken} together are —O—, —NH—, —N (alkyl) —, —S—, —C (O) —, —S (O) —. And a compound that is C ₃ -C ₇ -alkylene or C ₄ -C ₇ -alkylene interrupted by one moiety selected from the group consisting of and —SO ₂ —, or salts, prodrugs, or prodrugs thereof A process for producing a salt of
(A) Formula (I) -b

を有し、
上記の好ましい実施態様は安息香酸（２Ｓ，３Ｒ，４Ｓ，６Ｒ）−４−（ジメチルアミノ）−２−（（（３ａＳ，４Ｒ，７Ｒ，８Ｓ，９Ｒ，１０Ｒ，１１Ｓ，１３Ｒ，１４Ｅ，１５Ｒ，１５ａＲ）−４−エチル−ｌｌ−（プロプ−２−イニルオキシ）−１４−（メトキシイミノ）−３ａ，７，９，１１，１３，１５−ヘキサメチル−２，６，８−トリオキソテトラデカヒドロ−２Ｈ−オキサシクロテトラデシノ［４，３−ｄ］［１，３］オキサゾール−１０−イル）オキシ）−６−メチルテトラヒドロ−２Ｈ−ピラン−３−イルである化合物と、フッ化剤とを第２の塩基の有無において反応させるステップを含む方法に関する。

Have
Preferred embodiments of the above are benzoic acid (2S, 3R, 4S, 6R) -4- (dimethylamino) -2-(((3aS, 4R, 7R, 8S, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-ll- (prop-2-ynyloxy) -14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-2,6,8-trioxotetradecahydro- 2H-oxacyclotetradecino [4,3-d] [1,3] oxazol-10-yl) oxy) -6-methyltetrahydro-2H-pyran-3-yl and a fluorinating agent. It relates to a method comprising reacting in the presence or absence of a second base.

  The fifth embodiment of the present invention relates to an intermediate used in the fourth embodiment.

  A sixth embodiment of the invention relates to a composition useful for the purpose of preventing or treating bacterial infections in fish or mammals, said composition comprising the treatment of one or more compounds of the first embodiment. Contains an effective amount and excipients.

  A seventh embodiment of the invention relates to the use of a therapeutically effective amount of one or more compounds of the first embodiment for the preparation of a medicament for the prevention or treatment of bacterial infections.

  The compounds of the invention, also referred to as “compounds”, include both fixed and variable portions, the variable portions being distinguished by capital letters and accompanying numeric or alphabetic superscripts, in which the following terms: Has the meaning indicated.

  “Alkenyl” means monovalent straight and branched chain hydrocarbon moieties having from 2 to 8 carbon atoms and at least one carbon-carbon double bond.

  Examples of alkenyl moieties include but-1,3-dienyl, butenyl, but-2-enyl, ethenyl, 1-ethylhexen-2-yl, hexa-3-enyl, 1-methylbutenyl, 2-methylbutenyl, 1-methylbut- Examples include 2-enyl, 1-methylbut-1,3-dienyl, pentenyl, pent-2-enyl, and pent-3-enyl, propenyl.

  “Alkyl” means monovalent saturated straight and branched chain hydrocarbon moieties having from 1 to 6 carbon atoms.

  Examples of the alkyl moiety include butyl, 1,1-dimethylethyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, ethyl, 1-ethylpropyl, 2-ethylpropyl, hexyl, methyl, 2-methylpropyl, 3 -Methylbutyl, 1-methylpentyl, 2-methylpent-3-yl, and pentyl.

  “Alkylene” means divalent saturated straight and branched chain hydrocarbon moieties having from 1 to 8 carbon atoms.

  Examples of the alkylene moiety include butylene, 1,1-dimethylethylene, 1,1-dimethylpropylene, 1,2-dimethylpropylene, ethylene, 1-ethylpropylene, 2-ethylpropylene, hexylene, methylene, 2-methylpropylene, 3 -Methylbutylene, 1-methylpentylene, 2-methylpent-3-ylene, and pentylene.

  “Alkynyl” means monovalent straight and branched chain hydrocarbon moieties having from 2 to 6 carbon atoms and at least one carbon-carbon triple bond.

  Alkynyl moieties include ethynyl (acetylenyl), pentynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 1-methylbut-2-ynyl, 2-methylbut-3-ynyl, hexynyl, hexyl- 2-Inyl, hex-3-ynyl, hex-4-ynyl, 1-methyl-pent-2-ynyl, 1-methylenepent-3-ynyl, 1-methyl-pent-2,4-diynyl, and prop- 2-inyl (propargyl) is mentioned.

  “Aryl” is a non-condensed or bonded through a carbon atom fused to another phenyl moiety or saturated portion of a cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, naphthyl, or indanyl moiety. Means a valent unsubstituted or substituted phenyl moiety.

  The phenyl moiety fused to the saturated portion of the phenyl, naphthyl, or indanyl moiety is unsubstituted and substituted naphthyl, anthracen- (1-to-4-) yl, or fluoren- (1-to-4-) yl, respectively. .

  The phenyl moieties fused with the cycloalkyl moiety are unsubstituted and substituted indan- (1- to 4-) yl and 1,2,3,4-tetrahydronaphthy- (5- to 8-) yl.

  The phenyl moiety fused to the cycloalkenyl moiety is an unsubstituted and substituted inden- (4- to 7-) yl, 1,2-dihydronaphthy- (5- to 8-) yl and 1,2-dihydronaphthy- (5 -To 8-) yl.

  Phenyl moieties fused with a heteroaryl moiety include unsubstituted and substituted benzimidazol- (4- to 7-) yl, 1-benzofuran- (4- to 7-) yl, 1,2-benzisothiazole- (4- to 7-) yl, benzthiazol- (4- to 7-) yl, 1-benzothiophene- (4- to 7-) yl, cinnoline- (5- to 8-) yl, indole- (4 -To 7-) yl, isoquinolin- (5- to 8-) yl, phthalazine- (5- to 8-) yl, quinazoline- (5- to 8-) yl, quinolin- (5- to 8-) yl And quinoxaline- (5- to 8-) yl.

  Phenyl moieties fused with a heterocyclyl moiety include unsubstituted and substituted 1,3-benzodioxa- (4- to 7-) yl, 1,4-benzodioxa- (5- to 8-) yl, 1,3- Dihydro-2-benzofuran- (4- to 7-) yl, 2,3-dihydro-1-benzofuran- (4- to 7-) yl, 1,3-dihydro-2-benzothiophene- (4- to 7 -) Yl, 2,3-dihydro-1-benzothiophene- (4- to 7-) yl, and indoline- (4- to 7-) yl.

  “Cycloalkyl” means a monovalent unsubstituted and substituted saturated cyclic hydrocarbon moiety having from 3 to 6 carbon atoms.

  Cycloalkyl moieties include unsubstituted and substituted cyclocyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

  “Cycloalkenyl” means a monovalent unsubstituted and substituted cyclic hydrocarbon moiety having from 4 to 6 carbon atoms and at least one carbon-carbon double bond.

  Cycloalkenyl moieties include 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cyclohexenyl, cyclopentadienyl, and cyclopentenyl.

  “Halo” means fluoro (—F), chloro (—Cl), bromo (—Br), and iodo (—I) moieties.

  “Heteroaryl” means a monovalent aromatic unsubstituted and substituted 5-membered ring moiety having two double bonds, (a) one oxygen atom or one sulfur atom, (b) 1 , 2, 3 or 4 nitrogen atoms, or (c) 1 or 2 nitrogen atoms and 1 oxygen atom or 1 sulfur atom and the remaining atoms are carbon atoms, Each linked by a carbon or nitrogen atom; a monovalent 6-membered ring moiety having three double bonds and one, two, or three nitrogen atoms, the remaining atoms being carbon atoms These are linked by a carbon atom; the aforementioned heteroaryl moiety is non-fused or fused with another heteroaryl moiety or aryl moiety.

  5-membered heteroaryl moieties include unsubstituted and substituted furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, 1,3,4-thiadiazolyl, thiazolyl, thiophenyl (thienyl) 2H-tetrazolyl and 1,2,3-triazolyl.

  5-membered heteroaryl moieties fused with an aryl moiety include unsubstituted and substituted benzimidazol- (1- or 2-) yl, 1-benzofuran- (2- to 3-) yl, 1,2-benz Isothiazol-3-yl, benzthiazol-2-yl, 1-benzothiophene- (2- to 3-) yl, cinnoline- (3- or 4-) yl, indol- (1- to 3-) yl, Isoquinolin- (1-, 3- or 4-) yl, phthalazine- (1- or 4-) yl, quinazoline- (2- or 4-) yl, quinolin- (2- or 4-) yl, and quinoxaline- (2- or 3-) yl is mentioned.

  5-membered heteroaryl moieties fused to other 5-membered heteroaryl moieties include unsubstituted and substituted [1,3] thiazolo [4,5-d] [1,3] oxazolyl, [1,3 ] Thiazolo [4,5-d] [1,3] thiazolyl, thieno [3,2-d] [1,3] oxazolyl, thieno [3,2-d] [1,3] thiazolyl, and thieno [2] , 3-b] thiophenyl.

  5-membered heteroaryl moieties fused to 6-membered heteroaryl moieties include unsubstituted and substituted furo [2,3-b] pyridin- (2- or 3-) yl, 3H-imidazo [4,5 -B] pyridin- (2- or 3-) yl, [1,3] thiazolo [4,5-b] pyrazin-2-yl, [1,3] thiazolo [4,5-b] pyridin-2- And thieno [2,3-b] pyridin- (2- or 3-) yl.

  6-membered heteroaryl moieties are unsubstituted and substituted pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, and 1,3,5-triazinyl.

  6-membered heteroaryl moieties fused with an aryl moiety include unsubstituted and substituted cinnolin- (3- or 4-) yl, isoquinolin- (1-, 3- or 4-) yl, phthalazine- (1- Or 4-) yl, quinazolin- (2- or 4-) yl, quinolin- (2- or 4-) yl, and quinoxalin- (2- or 3-) yl.

  6-membered heteroaryl moieties fused to 5-membered heteroaryl moieties include unsubstituted and substituted furo [2,3-b] pyridin- (4- to 6-) yl, 3H-imidazo [4,5 -B] pyridin- (5- to 7-) yl, [1,3] thiazolo [4,5-b] pyrazin- (5- or 6-) yl, [1,3] thiazolo [4,5-b ] Pyridin- (5- to 7-) yl and thieno [2,3-b] pyridin- (4- to 6-) yl.

  6-membered heteroaryl moieties fused to other 6-membered heteroaryl moieties include unsubstituted and substituted 1,5-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, pteridinyl, pyridazino [4, 5-d] pyridazinyl, pyrido [2,3-d] pyridazinyl, and pyrido [3,4-d] pyridazinyl.

  “Heterocyclyl” refers to (a) a monovalent non-aromatic unsubstituted and substituted 4-membered ring moiety having one nitrogen, oxygen or sulfur atom with the remaining atoms being carbon atoms Monovalent non-aromatic which is bonded by a carbon atom or a nitrogen atom and has 1 or 2 nitrogen atoms, oxygen atoms or sulfur atoms, and the remaining atoms are carbon atoms. Unsubstituted and substituted 5-membered ring moieties have no double bond or have one double bond and are connected by a carbon or nitrogen atom, (c) 1, 2 or 3 nitrogens A monovalent non-aromatic unsubstituted and substituted 6-membered ring moiety having an atom, oxygen atom or sulfur atom with the remaining atoms being carbon atoms is free of one or two or two double bonds Means that it is bound by a carbon or nitrogen atom.

  4-membered heterocyclyl moieties are unsubstituted and substituted oxetanes, thietanes, and azetidines.

  5-membered heterocyclyl moieties include unsubstituted and substituted 1,4-dioxanyl, 1,3-dioxolanyl, imidazolidinyl, 2-imidazolinyl, 4,5-dihydroisoxazolyl, pyrazolidinyl, 2-pyrazolinyl, pyrrolidinyl, 2- Examples include pyrrolinyl, 3-pyrrolinyl, and 2H-pyrrolyl.

  6-membered heterocyclyl moieties include unsubstituted and substituted 1,3-dithianyl, 1,4-dithianyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, 2H-pyranyl, 4H-pyranyl, and thiomorpholinyl.

Substituted aryl and heteroaryl moieties are alkyl, alkenyl, alkynyl, cycloalkyl, _{halo, -CN, -OH, -SH, -NH} 2, -NO 2, -CF 3, -CH 2 CF 3, -CF 2 CF ₃ , —OCF ₃ , —OCH ₂ CF ₃ , —OCF ₂ CF ₃ , —OR ³⁰ , —SR ³⁰ , —S (O) (alkyl), —SO ₂ (alkyl), —C (O) H, — C (O) (alkyl), —C (O) OH, —C (O) O (alkyl), —NH (alkyl), —N (alkyl) ₂ , —C (O) NH ₂ , —C (O ) NH (alkyl), - C (O) N ( _alkyl) 2, -OC _(O) (alkyl), - OC (O) O ( _{alkyl), - OC (O) NH} 2, -OC (O) NH (Alkyl), —OC (O) N (alkyl) ₂ , —NHC (O ) H, —NHC (O) (alkyl), —NHC (O) O (alkyl), —NHC (O) NH ₂ , —NHC (O) NH (alkyl), —NHC (O) N (alkyl) ₂ 1, 2, 3, 4, or independently selected from the group consisting of:, —SO ₂ NH ₂ , —SO ₂ NH (alkyl), —SO ₂ N (alkyl) ₂ , and R ⁴⁰ A moiety substituted with 5 substituents, wherein R ³⁰ is alkyl, or alkyl substituted with 1 substituent selected from the group consisting of halo, —O (alkyl), and —S (alkyl) in ^{and, R 40} is furyl, imidazolyl, Indazorijiniru, isoquinolyl, Ishichiazoriru, isoxazolyl, morpholinyl, naphthyl, naphthyridyl, 1,2,3-oxadiazolyl, oxazolyl, phenyl Piperidinyl, piperazinyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolyl, quinolyl, quinoxalyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, 1,2,3- Triazolyl or thiomorpholinyl, each R ⁴⁰ moiety being unsubstituted or alkyl, alkenyl, alkynyl, cycloalkyl, halo, ═O, —CN, —OH, —SH, —NO ₂ , —CF ₃ , — _{CH 2 CF 3, -CF 2 CF} 3, -OCF 3, -OCH 2 CF 3, -OCF 2 CF 3, -O ( alkyl), - S (alkyl), - S (O) (alkyl), - SO ₂ (alkyl), - C (O) H , -C (O) ( alkyl), - C (O) OH , -C (O O (alkyl), _- NH 2, -NH (alkyl), - N _{(alkyl) 2, -C (O) NH} 2, -C (O) NH ( alkyl), - C (O) N ( _{alkyl) 2} , -OC (O) (alkyl), - OC (O) O _{(alkyl), - OC (O) NH} 2, -OC (O) NH ( alkyl), - OC (O) N _(alkyl) 2, - NHC (O) H, —NHC (O) (alkyl), —NHC (O) O (alkyl), —NHC (O) NH ₂ , —NHC (O) NH (alkyl), —NHC (O) N ( Substituted with one or two or three substituents independently selected from the group consisting of (alkyl) ₂ , —SO ₂ NH ₂ , —SO ₂ NH (alkyl), and —SO ₂ N (alkyl) ₂ Has been.

Substituted cycloalkyl moieties, cycloalkenyl and heterocyclyl portions are alkyl, phenyl, ^{_{halo, -CN, -OH, -NH 2,}} -CF 3, -OR 30, -SR 30, -S (O) ( alkyl), —SO ₂ (alkyl), —C (O) H, —C (O) (alkyl), —C (O) OH, —C (O) O (alkyl), —NH (alkyl), —N (alkyl) ) ₂ , —C (O) NH ₂ , —C (O) NH (alkyl), and —C (O) N (alkyl) _2, one, two, or three independently selected from the group consisting of one of a moiety substituted with a substituent, said phenyl, one of unsubstituted or halo, -CN, -OH, selected independently -NH _2, and from the group consisting of -CF _3, Substituted with 2 or 3 substituents.

  “Hydroxyl protecting moiety” means a moiety that can be selectively introduced and removed that protects the —OH moiety against unwanted side reactions. Hydroxyl protecting moieties include 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, t-butoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2 -Trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, allyloxycarbonyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoro Acetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, propionyl, 2-methoxypropionyl, benzoyl, t-butyl, 2,2,2-trichloroethyl, -Trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuryl, benzyloxymethyl, 2- Methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t -Butyldiphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.

These variable moieties can be combined to provide an eighth embodiment of the present invention, which embodiment comprises formula (I) and pharmaceutically acceptable salts, prodrugs, and prodrugs thereof. In the formula, wherein
R ¹ is substituted with one substituent selected from the group consisting of — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, cycloalkyl, halo, aryl, heteroaryl and heterocyclyl — (CH ₂ ). Alkenyl, or — (CH ₂ ) alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl and heterocyclyl;
R ² is hydrogen, alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —OR ⁷ , ═O, NH ₂ , —NHR ^8. And alkyl, cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —substituted with one, two or three substituents independently selected from the group consisting of —NR ⁸ R ⁹ — (CH ₂ ) alkenyl substituted with one, two or three substituents independently selected from the group consisting of OR ⁷ , ═O, NH ₂ , —NHR ⁸ , and —NR ⁸ R ^9. or cycloalkyl, halo, aryl, heteroaryl, _{^{heterocyclyl, -OH, -OR 7,, =}} O, NH 2, -NHR 8, and -NR Independently from the group consisting of R ⁹ is substituted with one or two or three substituents selected - (CH ₂₎ alkynyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
R ⁷ is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
R ⁸ and R ⁹ are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl Is;
X ¹ is hydrogen or fluoro;
It relates to compounds having the formula (I) and pharmaceutically acceptable salts, prodrugs and salts of these prodrugs,
R ¹ is, - (CH ₂₎ alkynyl, or cycloalkyl, halo, aryl, substituted with one substituent selected from the group consisting of heteroaryl and heterocyclyl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —OR ⁷ , ═O, NH ₂ , —NHR ^8. And alkyl, cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —substituted with one, two or three substituents independently selected from the group consisting of —NR ⁸ R ⁹ — (CH ₂ ) alkenyl substituted with one, two or three substituents independently selected from the group consisting of OR ⁷ , ═O, NH ₂ , —NHR ⁸ , and —NR ⁸ R ^9. or cycloalkyl, halo, aryl, heteroaryl, _{^{heterocyclyl, -OH, -OR 7,, =}} O, NH 2, -NHR 8, and -NR Independently from the group consisting of R ⁹ is substituted with one or two or three substituents selected - (CH ₂₎ alkynyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
R ⁷ is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
R ⁸ and R ⁹ are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl Is;
X ¹ is hydrogen or fluoro;
It relates to compounds having the formula (I) and pharmaceutically acceptable salts, prodrugs and salts of these prodrugs,
R ¹ is, - (CH ₂₎ substituted with one substituent selected from the group consisting of alkynyl, or aryl, and heteroaryl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, or alkyl substituted with one substituent selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
X ¹ is hydrogen or fluoro;
It relates to compounds having the formula (I) and pharmaceutically acceptable salts, prodrugs and salts of these prodrugs,
R ¹ is, - (CH ₂₎ substituted with one substituent selected from the group consisting of alkynyl, or aryl, and heteroaryl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, or alkyl substituted with phenyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
X ¹ is hydrogen or fluoro;
It relates to compounds having the formula (I) and pharmaceutically acceptable salts, prodrugs and salts of these prodrugs,
R ¹ is - (CH ₂₎ substituted with one substituent selected from the group consisting of alkynyl, or aryl, and heteroaryl - (CH ₂₎ alkynyl; ^{R 2} is alkyl; ^{R 3} is hydrogen or ^{R P,} the ^{R P} is a hydroxyl a protecting moiety; is hydrogen one of ^{R 4} or ^{R 5,} the other is an -OH; or, ^{R 4} and ^{R 5} together = O; X ¹ is hydrogen or fluoro;
It relates to compounds having the formula (I) and pharmaceutically acceptable salts, prodrugs and salts of these prodrugs,
R ¹ is, - (CH ₂₎ alkynyl, or quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, thienyl, isoxazolyl, thiazolyl, substituted with one substituent selected from the group consisting of pyridyl and pyrimidinyl - (CH ₂₎ alkynyl The thienyl, isoxazolyl, thiazolyl, pyridyl and pyrimidinyl are independently pyrimidinyl, pyridyl, thienyl, isoxazolyl, thiazolyl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, 1-methyl-1H- Selected from the group consisting of tetrazol-5-yl and 2-methyl-2H-tetrazol-5-yl;
R ² is alkyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
X ¹ is hydrogen or fluoro;
It relates to compounds having the formula (I) and pharmaceutically acceptable salts, prodrugs and salts of these prodrugs,
R ¹ is prop-2-ynyl, 3- (quinolin-3-yl) -prop-2-ynyl, 3- (1,5-naphthyridin-3-yl) prop-2-ynyl, 3- (quinoxaline- 6-yl) prop-2-ynyl, 3- (5- (2-methyl-2H-tetrazol-5-yl) thien-2-yl) prop-2-ynyl, 3- (5- (pyridin-2- Yl) thien-2-yl) prop-2-ynyl, 3- (2- (pyrimidin-2-yl) thien-5-yl) prop-2-ynyl, 3- (2- (2-methyl-2H-) Tetrazol-5-yl) 1,3-thiazol-5-yl) prop-2-ynyl, 3- (2- (2-methyl-2H-tetrazol-5-yl) pyridin-6-yl) prop-2- Inyl, 3- (3- (pyridin-2-yl) isoxazole-5 -Yl) prop-2-ynyl, or 3- (3- (2-methyl-2H-tetrazol-5-yl) isoxazol-5-yl) prop-2-ynyl;
R ² is alkyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
X ¹ is hydrogen or fluoro;
It relates to compounds having the formula (I) and pharmaceutically acceptable salts, prodrugs and salts of these prodrugs,
R ¹ is, - (CH ₂₎ substituted with one substituent selected from the group consisting of alkynyl, or aryl, and heteroaryl - (CH ₂₎ alkynyl;
R ² is methyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
X ¹ is hydrogen or fluoro.

Specific examples of the R ¹ moiety are 3- (quinolin-3-yl) prop-2-ynyl, 3- (1,5-naphthyridin-3-yl) prop-2-ynyl, 3- (quinoxalin-6-yl ) Prop-2-ynyl, 3- (5- (2-methyl-2H-tetrazol-5-yl) thien-2-yl) prop-2-ynyl and 3- (5- (pyridin-2-yl) thien -2-yl) prop-2-ynyl.

A specific example of the R ² moiety is methyl.

A specific example of the R ³ moiety is hydrogen.

A specific example of the R ⁴ and R ⁵ moiety is ═O when R ⁴ and R ⁵ are taken together.

Specific examples of the X ¹ moiety are hydrogen and fluoro.

  These specific portions of the compound, together with the immobilized portion thereof, may form a ninth embodiment of the present invention, which comprises compounds useful as antibacterial agents, or salts, prodrugs Or a salt of a prodrug thereof, which compound has the formula (I);

式中、Ｒ^１は、ナフチリジニル、キノリニル、キノキサリニル、およびチエニルからなる群から選択される１つの置換基で置換されている−（ＣＨ_２）アルキニルであり、前記チエニルは、ピリジルおよび２Ｈ−テトラゾリルからなる群から選択される１つの置換基で置換されており、前記２Ｈ−テトラゾリルは、アルキルで置換されており、；Ｒ^２は、アルキルであり；Ｒ^３は、水素であり；Ｒ^４およびＲ^５は一緒になって、＝Ｏであり；Ｘ^１は、水素またはフルオロであり；
本発明の第１０の実施態様を形成し、この実施態様は、式（Ｉ）を有する化合物、または塩類、プロドラッグ類、またはそのプロドラッグの塩類に関するものであり、

Wherein R ¹ is — (CH ₂ ) alkynyl substituted with one substituent selected from the group consisting of naphthyridinyl, quinolinyl, quinoxalinyl, and thienyl, wherein the thienyl is from pyridyl and 2H-tetrazolyl Substituted with one substituent selected from the group consisting of: 2H-tetrazolyl substituted with alkyl; R ² is alkyl; R ³ is hydrogen; R ⁴ and R ^{5 taken} together is ═O; X ¹ is hydrogen or fluoro;
Forming a tenth embodiment of the invention, this embodiment relates to a compound having the formula (I), or a salt, a prodrug, or a salt of the prodrug,

式中、Ｒ^１は、ナフチリジニル、キノリニル、キノキサリニル、およびチエニルからなる群から選択される１つの置換基で置換されている−（ＣＨ_２）アルキニルであり、前記チエニルは、ピリジルおよび２Ｈ−テトラゾリルからなる群から選択される１つの置換基で置換されており、前記２Ｈ−テトラゾリルは、Ｃ_１−アルキルで置換されており；Ｒ^２は、Ｃ_１−アルキルであり；Ｒ^３は、水素であり；Ｒ^４およびＲ^５は一緒になって、＝Ｏであり；Ｘ^１は、水素またはフルオロであり；
この実施態様は、式（Ｉ）を有する化合物、または塩類、プロドラッグ類、またはそのプロドラッグの塩類に関するものであり、
式中、Ｒ^１は、３−（キノリン−３−イル）プロプ−２−イニル、３−（１，５−ナフチリジン−３−イル）プロプ−２−イニル、または３−（キノキサリン−６−イル）プロプ−２−イニルであり；Ｒ^２は、メチルであり；Ｒ^３は、水素であり；Ｒ^４およびＲ^５は一緒になって、＝Ｏであり；Ｘ^１は、水素であり；
この実施態様は、式（Ｉ）を有する化合物、または塩類、プロドラッグ類、またはそのプロドラッグの塩類に関するものであり、
式中、Ｒ^１は、３−（キノリン−３−イル）プロプ−２−イニル、３−（１，５−ナフチリジン−３−イル）プロプ−２−イニル、または３−（キノキサリン−６−イル）プロプ−２−イニルであり；Ｒ^２は、メチルであり；Ｒ^３は、水素であり；Ｒ^４およびＲ^５は一緒になって、＝Ｏであり；Ｘ^１は、フルオロであり；
この実施態様は、式（Ｉ）を有する化合物、または塩類、プロドラッグ類、またはそのプロドラッグの塩類に関するものであり、
式中、Ｒ^１は、３−（５−（２−メチル−２Ｈ−テトラゾール−５−イル）チエン−２−イル）プロプ−２−イニル、または３−（５−（ピリジン−２−イル）チエン−２−イル）プロプ−２−イニルであり；Ｒ^２は、メチルであり；Ｒ^３は、水素であり；Ｒ^４およびＲ^５は一緒になって、＝Ｏであり；Ｘ^１は、水素であり；
この実施態様は、式（Ｉ）を有する化合物、または塩類、プロドラッグ類、またはそのプロドラッグの塩類に関するものであり、
式中、Ｒ^１は、３−（５−（２−メチル−２Ｈ−テトラゾール−５−イル）チエン−２−イル）プロプ−２−イニル、または３−（５−（ピリジン−２−イル）チエン−２−イル）プロプ−２−イニルであり；Ｒ^２は、メチルであり；Ｒ^３は、水素であり；Ｒ^４およびＲ^５は一緒になって、＝Ｏであり；Ｘ^１は、フルオロであり；
（３ａＳ，４Ｒ，７Ｒ，９Ｒ，１０Ｒ，１１Ｓ，１３Ｒ，１４Ｅ，１５Ｒ，１５ａＲ）−４−エチル−１４−（メトキシイミノ）−３ａ，７，９，１１，１３，１５−ヘキサメチル−２，６，８−トリオキソ−１１−（（３−キノリン−３−イルプロプ−２−イニル）オキシ）テトラデカヒドロ−２Ｈ−オキサシクロテトラデシノ（４，３−ｄ）（１，３）オキサゾール−１０−イル３，４，６−トリデオキシ３−（ジメチルアミノ）−β−Ｄ−キシロ−ヘキソピラノシド；
（３ａＳ，４Ｒ，７Ｒ，９Ｒ，１０Ｒ，１１Ｓ，１３Ｒ，１４Ｅ，１５Ｒ，１５ａＲ）−４−エチル−１４−（メトキシイミノ）−３ａ，７，９，１１，１３，１５−ヘキサメチル−１１−（（３−（１，５−ナフチリジン−３−イル）プロプ−２−イニル）オキシ）−２，６，８−トリオキソテトラデカヒドロ−２Ｈ−オキサシクロテトラデシノ（４，３−ｄ）（１，３）オキサゾール−１０−イル３，４，６−トリデオキシ−３−（ジメチルアミノ）−β−Ｄ−キシロ−ヘキソピラノシド；
（３ａＳ，４Ｒ，７Ｒ，９Ｒ，１０Ｒ，１１Ｓ，１３Ｒ，１４Ｅ，１５Ｒ，１５ａＲ）−４−エチル−１４−（メトキシイミノ）−３ａ，７，９，１１，１３，１５−ヘキサメチル−２，６，８−トリオキソ−１１−（（３−キノキサリン−６−イルプロプ−２−イニル）オキシ）テトラデカヒドロ−２Ｈ−オキサシクロテトラデシノ（４，３−ｄ）（１，３）オキサゾール−１０−イル３，４，６−トリデオキシ−３−（ジメチルアミノ）−β−Ｄ−キシロ−ヘキソピラノシド；
（３ａＳ，４Ｒ，７Ｒ，９Ｒ，１０Ｒ，１１Ｓ，１３Ｒ，１４Ｅ，１５Ｒ，１５ａＲ）−４−エチル−１４−（メトキシイミノ）−３ａ，７，９，１１，１３，１５−ヘキサメチル−１１−（（３−（５−（２−メチル−２Ｈ−テトラゾール−５−イル）チエン−２−イル）プロプ−２−イニル）オキシ）−２，６，８−トリオキソテトラデカヒドロ−２Ｈ−オキサシクロテトラデシノ（４，３−ｄ）（１，３）−オキサゾール−１０−イル３，４，６−トリデオキシ−３−（ジメチルアミノ）−β−Ｄ−キシロ−ヘキソピラノシド；
（３ａＳ，４Ｒ，７Ｒ，９Ｒ，１０Ｒ，１１Ｓ，１３Ｒ，１４Ｅ，１５Ｒ，１５ａＲ）−４−エチル−１４−（メトキシイミノ）−３ａ，７，９，１１，１３，１５−ヘキサメチル−２，６，８−トリオキソ−１１−（（３−（５−ピリジン−２−イルチエン−２−イル）プロプ−２−イニル）オキシ）テトラデカヒドロ−２Ｈ−オキサシクロテトラデシノ（４，３−ｄ）（１，３）オキサゾール−１０−イル３，４，６−トリデオキシ−３−（ジメチルアミノ）−β−Ｄ−キシロ−ヘキソピラノシド；
（３ａＳ，４Ｒ，７Ｓ，９Ｒ，１０Ｒ，１１Ｓ，１３Ｒ，１４Ｅ，１５Ｒ，１５ａＲ）−４−エチル−７−フルオロ−１４−（メトキシイミノ）−３ａ，７，９，１１，１３，１５−ヘキサメチル−２，６，８−トリオキソ−１１−（（３−キノリン−３−イルプロプ−２−イニル）オキシ）テトラデカヒドロ−２Ｈ−オキサシクロテトラデシノ（４，３−ｄ）（１，３）オキサゾール−１０−イル３，４，６−トリデオキシ−３−（ジメチルアミノ）−β−Ｄ−キシロ−ヘキソピラノシド；あるいは
（３ａＳ，４Ｒ，７Ｓ，９Ｒ，１０Ｒ，１１Ｓ，１３Ｒ，１４Ｅ，１５Ｒ，１５ａＲ）−４−エチル−７−フルオロ−１４−（メトキシイミノ）−３ａ，７，９，１１，１３，１５−ヘキサメチル−１１−（（３−（５−（２−メチル−２Ｈ−テトラゾール−５−イル）チエン−２−イル）プロプ−２−イニル）オキシ）−２，６，８−トリオキソテトラデカヒドロ−２Ｈ−オキサシクロテトラデシノ（４，３−ｄ）（１，３）オキサゾール−１０−イル３，４，６−トリデオキシ−３−（ジメチルアミノ）−β−Ｄ−キシロ−ヘキソピラノシド。
である化合物、または塩類、プロドラッグ類またはそのプロドラッグの塩類に関するものである。

Wherein R ¹ is — (CH ₂ ) alkynyl substituted with one substituent selected from the group consisting of naphthyridinyl, quinolinyl, quinoxalinyl, and thienyl, wherein the thienyl is from pyridyl and 2H-tetrazolyl Substituted with one substituent selected from the group consisting of: 2H-tetrazolyl substituted with C ₁ -alkyl; R ² is C ₁ -alkyl; R ³ is hydrogen R ⁴ and R ^{5 taken} together are ═O; X ¹ is hydrogen or fluoro;
This embodiment relates to compounds having the formula (I), or salts, prodrugs, or salts of the prodrugs thereof,
Wherein R ¹ is 3- (quinolin-3-yl) prop-2-ynyl, 3- (1,5-naphthyridin-3-yl) prop-2-ynyl, or 3- (quinoxalin-6-yl ) Prop-2-ynyl; R ² is methyl; R ³ is hydrogen; R ⁴ and R ^{5 taken} together are ═O; X ¹ is hydrogen;
This embodiment relates to compounds having the formula (I), or salts, prodrugs, or salts of the prodrugs thereof,
Wherein R ¹ is 3- (quinolin-3-yl) prop-2-ynyl, 3- (1,5-naphthyridin-3-yl) prop-2-ynyl, or 3- (quinoxalin-6-yl ) Prop-2-ynyl; R ² is methyl; R ³ is hydrogen; R ⁴ and R ^{5 taken} together are ═O; X ¹ is fluoro;
This embodiment relates to compounds having the formula (I), or salts, prodrugs, or salts of the prodrugs thereof,
In the formula, R ¹ represents 3- (5- (2-methyl-2H-tetrazol-5-yl) thien-2-yl) prop-2-ynyl, or 3- (5- (pyridin-2-yl) Thien-2-yl) prop-2-ynyl; R ² is methyl; R ³ is hydrogen; R ⁴ and R ^{5 taken} together are ═O; X ¹ is Hydrogen;
This embodiment relates to compounds having the formula (I), or salts, prodrugs, or salts of the prodrugs thereof,
In the formula, R ¹ represents 3- (5- (2-methyl-2H-tetrazol-5-yl) thien-2-yl) prop-2-ynyl, or 3- (5- (pyridin-2-yl) Thien-2-yl) prop-2-ynyl; R ² is methyl; R ³ is hydrogen; R ⁴ and R ^{5 taken} together are ═O; X ¹ is Is fluoro;
(3aS, 4R, 7R, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-2,6 , 8-Trioxo-11-((3-quinolin-3-ylprop-2-ynyl) oxy) tetradecahydro-2H-oxacyclotetradecino (4,3-d) (1,3) oxazole-10- Yl 3,4,6-trideoxy 3- (dimethylamino) -β-D-xylo-hexopyranoside;
(3aS, 4R, 7R, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-11- ( (3- (1,5-naphthyridin-3-yl) prop-2-ynyl) oxy) -2,6,8-trioxotetradecahydro-2H-oxacyclotetradecino (4,3-d) ( 1,3) Oxazol-10-yl 3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside;
(3aS, 4R, 7R, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-2,6 , 8-Trioxo-11-((3-quinoxalin-6-ylprop-2-ynyl) oxy) tetradecahydro-2H-oxacyclotetradecino (4,3-d) (1,3) oxazole-10- Yl 3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside;
(3aS, 4R, 7R, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-11- ( (3- (5- (2-Methyl-2H-tetrazol-5-yl) thien-2-yl) prop-2-ynyl) oxy) -2,6,8-trioxotetradecahydro-2H-oxacyclo Tetradecino (4,3-d) (1,3) -oxazol-10-yl3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside;
(3aS, 4R, 7R, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-2,6 , 8-Trioxo-11-((3- (5-pyridin-2-ylthien-2-yl) prop-2-ynyl) oxy) tetradecahydro-2H-oxacyclotetradecino (4,3-d) (1,3) oxazol-10-yl3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside;
(3aS, 4R, 7S, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-7-fluoro-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl -2,6,8-trioxo-11-((3-quinolin-3-ylprop-2-ynyl) oxy) tetradecahydro-2H-oxacyclotetradecino (4,3-d) (1,3) Oxazol-10-yl3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside; or (3aS, 4R, 7S, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-7-fluoro-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-11-((3- (5- (2-methyl-2H Tetrazol-5-yl) thien-2-yl) prop-2-ynyl) oxy) -2,6,8-trioxotetradecahydro-2H-oxacyclotetradecino (4,3-d) (1, 3) Oxazol-10-yl 3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside.
Or a salt, a prodrug or a salt of the prodrug.

  The compounds of the present invention contain carbon atoms that are asymmetrically substituted in the R or S configuration, and the terms “R” and “S” refer to EUPAC 1974 Recommendations of E Group, Basic Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds having carbon atoms in which the R and S configurations are asymmetrically substituted in equal amounts are racemic at these carbon atoms. The excess of atoms in one arrangement over the other is present in higher amounts, preferably about 85% to 90% excess, more preferably about 95% to 99% excess, even more preferably about 99% or more excess Belongs to the arrangement. Accordingly, the present invention is intended to include all stereoisomers of the compounds, including racemic mixtures, enantiomers, enantiomeric mixtures, diastereomers and diastereomeric mixtures of the compounds.

  Individual stereoisomers of the compounds can be prepared by any one of a number of methods within the ordinary skill of the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, enzymatic resolution, and conversion of enantiomers to diastereomers in enantiomeric mixtures, diastereomers, Chromatographic separation of mers and regeneration of individual enantiomers.

  Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions that do not cause racemization or inversion of stereochemistry at the chiral center.

  The diastereomeric mixture of compounds resulting from the synthesis reaction can be separated by chromatographic methods well known to those skilled in the art.

  Chromatographic resolution of the enantiomers can be achieved in commercially available chiral chromatography resins. In practice, the racemate is placed in solution and packed into a column containing the chiral stationary phase. The enantiomers are then separated by high performance liquid chromatography.

  Enzymes such as esterases, phosphatases and lipases may also be useful for resolution of enantiomeric derivatives in enantiomeric mixtures. For example, an ester derivative of the carboxyl group of the compound to be separated can be prepared. Certain enzymes selectively hydrolyze only one of the enantiomeric mixtures. The resulting enantiomerically pure acid can then be separated from the unhydrolyzed ester.

  Enantiomeric resolution can also be achieved by converting the enantiomeric mixture into diastereomers by reacting the former with a chiral auxiliary. The resulting diastereomers can then be separated by column chromatography. This method is particularly useful when the compound to be separated contains a carboxyl, amino or hydrosyl group that forms a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids, or organic sulfonic acids are particularly useful as chiral auxiliaries. If the diastereomers are separated by chromatography, the individual enantiomers can be regenerated. The chiral auxiliary can often be recovered and reused.

  The compounds of the present invention may also contain a carbon-carbon double bond or a carbon-nitrogen double bond in the Z or E configuration, wherein the term “Z” refers to a carbon-carbon double bond or a carbon-nitrogen double bond. Two larger substituents are represented on the same side of the heavy bond, and the term “E” represents two larger substituents on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond. The compound may also exist as an equilibrium mixture in the Z or E configuration.

Compounds of the invention that contain an —OH, —NH—, or —CO ₂ H moiety can have a prodrug-forming moiety attached to it. Prodrug-forming moieties are removed by metabolic processes to release compounds with free hydroxyl, amino, or carboxylic acid in vivo. Prodrugs are useful for adjusting the pharmacokinetic properties of a compound such as solubility and / or hydrophobicity, gastrointestinal absorption, bioavailability, tissue permeability, clearance rate.

  The compounds of the present invention may exist as acid addition salts, base addition salts, or zwitterions. Salts of the compounds are prepared during isolation or after purification. Acid addition salts of the compound are derived from the reaction of the compound with an acid. For example, compound acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate , Digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate , Lactate, maleate, mesitylene sulfonate, methane sulfonate, naphthylene sulfonate, nicotinate, oxalate, pamoate, pectate, persulfate, phosphate, picrate, propion Acid salt, succinate, tartrate, thiocyanate, trichloroacetate, trifluoroacetate, para-toluenesulfonate, undecanoate and Equivalent salts and prodrugs thereof, are considered as being encompassed by the present invention. When the compound contains a carboxylic acid, base addition salts can be prepared therefrom by reaction with bases such as hydroxides, carbonates and bicarbonates of cations such as lithium, sodium, potassium, calcium and magnesium. .

  The compounds of the invention can be administered with or without excipients. Excipients include absorption promoters, antioxidants, binders, buffers, coatings, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, fragrances, moisturizers, lubricants, fragrances. Encapsulating materials or formulation additives such as preservatives, propellants, mold release agents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof. Excipients for orally administered compounds in solid dosage forms include agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch , Corn oil, cottonseed oil, ethanol, ethyl acetate, ethyl carbonate, ethyl cellulose, ethyl laurate, ethyl oleate, gelatin, germ oil, glucose, glycerol, peanut oil, isopropanol, isotonic saline, lactose, magnesium hydroxide, Magnesium stearate, malt, olive oil, peanut oil, potassium phosphate, potato starch, propylene glycol, Ringer's solution, talc, tragacanth, water, safflower oil, sesame oil, sodium carboxymethylcellulose, la Sodium Lil sulfate, sodium phosphate, soybean oil, sucrose, tetrahydrofurfuryl alcohol, and mixtures thereof. Ophthalmic and oral excipients in liquid dosage forms include benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, ethyl acetate, ethyl carbonate, sorbitan fatty acids Examples include esters, germ oil, peanut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, tetrahydrofurfuryl alcohol, water, and mixtures thereof. Excipients for osmotic administration compounds include chlorofluorohydrocarbons, ethanol, isopropanol, water and mixtures thereof. Examples of excipients for parenteral administration include 1,3-butanediol, castor oil, corn oil, cottonseed oil, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, Soybean oil, U.S.A. S. P. Or an isotonic sodium chloride solution, water, and mixtures thereof. Excipients for rectal or vaginal administration compounds include cocoa butter, polyethylene glycols, waxes and mixtures thereof.

  The compounds of the present invention can be administered for oral, ophthalmic, osmotic, parenteral (subcutaneous, intramuscular, intrasternal, intravenous), rectal, topical, transdermal and vaginal use. Compounds for oral administration in solid dosage forms can be administered as capsules, dragees, granules, pills, powders, and tablets. Compounds for ophthalmic and oral administration in liquid dosage forms can be administered as elixirs, emulsions, microemulsions, solutions, suspensions and syrups. Osmotic and topical compounds can be administered as creams, gels, inhalants, lotions, ointments, pastes, powders, solutions, and sprays. Parenterally administered compounds can be administered as aqueous or oily liquids or aqueous and oily suspensions, which include crystalline, amorphous, and other insoluble forms of the compound. Rectal or vaginal administration compounds can be administered as creams, gels, lotions, ointments, and pastes.

  The therapeutically effective amount of a compound of the present invention depends on the therapeutic recipient, the disease being treated and its severity, the composition comprising the compound, the time of administration, the route of administration, the treatment period, the effectiveness of the compound, and the excretion rate of the compound Dependent. The daily therapeutically effective amount of a compound administered to a patient in a single dose or in divided doses ranges from about 0.1 mg to about 200 mg / kg body weight, preferably from about 0.25 mg to about 100 mg / kg body weight. Single dose compositions contain these compound amounts or a combination thereof.

  To determine the antibacterial activity of the compounds of the invention, 12 petri each containing an aqueous serial dilution of the test compound in sterile brain-cardiac exudate agar (Difco 0418-01-5) (10 mL). The dish was incubated with a 1: 100 dilution of a representative microorganism in Table 1 (or a 1:10 dilution of a slow-growing Streptococcus strain) using a Steers replicator block, and a control plate without compound. Tests that are co-incubated at 35-37 ° C. for 20-24 hours to produce no colonies, slight cloudiness, or sparsely separated colonies on the inoculation spot when compared to growth on control plates Visual inspection was performed to obtain a minimum inhibitory concentration (MIC) μg / mL, meaning the lowest concentration of the compound.

本発明の化合物は、表１に示す微生物に対して約０．００８μｇ／ｍＬから約１２８μｇ／ｍＬを超える範囲で抗菌活性を示した。この抗菌活性は、抗菌剤としての化合物の有用性を示す。

The compounds of the present invention exhibited antibacterial activity in the range of about 0.008 μg / mL to over about 128 μg / mL against the microorganisms shown in Table 1. This antibacterial activity indicates the utility of the compound as an antibacterial agent.

  It should also be understood that certain metabolites of the compounds of the present invention produced by in vitro or in vivo metabolic processes are also considered useful as antibacterial agents and are encompassed by the present invention.

  In addition, it is to be understood that certain precursor compounds that can be metabolized in vitro or in vivo to form the compounds of the invention are encompassed by the present invention.

  The compounds of the present invention can also be prepared by synthetic chemical methods, examples of which are shown below for synthetic chemical methods and intermediates used in the methods. The order of the steps in the method can be varied, and equivalent reagents, solvents and reaction conditions can be substituted for those specifically described, and susceptible parts can be protected and deprotected during the reaction process. .

  Abbreviations used herein are DME for 1,2-dimethoxyethane; DMF for N, N-dimethylformamide; and THF for tetrahydrofuran. A specific carbonate resin used in the synthesis of the compounds of the present invention is MP carbonate (Argonaut Technologies, San Carlos, Calif.).

  Compounds having formula (1) are typically prepared as described in commonly owned US Pat. No. 5,866,549, US Pat. No. 6,054,435, and US Pat. No. 6,075,133. Can do.

式（１）を有する化合物を、前者、式（２）
Ｈ_２Ｎ−ＯＲ^２
（２）、
を有する化合物またはその塩と、添加物の有無において反応させることにより式（Ｉ）−ａを有する化合物に変換し得る。添加物としては、カンファースルホン酸、フッ化セシウム、ジイソプロピルエチルアミン、トリエチルアミン、酢酸ナトリウム、三弗化硼素エーテラート、および炭酸エステル樹脂が挙げられる。前記反応は典型的に、メタノール、エタノール、イソプロパノール、ジクロロメタン、１，２−ジクロロエタン、１，４−ジオキサン、およびＤＭＥなどの溶媒中、約１気圧から５気圧の圧、約４０℃から１２０℃で約１時間から約１４日に亘り実施される。

The compound having the formula (1) is converted into the former formula (2).
H ^₂ N-OR ₂
(2),
Can be converted to a compound having the formula (I) -a by reacting with a compound having a salt or a salt thereof in the presence or absence of an additive. Additives include camphorsulfonic acid, cesium fluoride, diisopropylethylamine, triethylamine, sodium acetate, boron trifluoride etherate, and carbonate ester resins. The reaction is typically carried out in a solvent such as methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, and DME at a pressure of about 1 to 5 atmospheres and about 40 to 120 ° C. Performed for about 1 hour to about 14 days.

式（Ｉ）−ａを有する化合物は、第１の塩基の有無において前者と酸化剤とを反応させることにより式（Ｉ）−ｂを有する化合物に変換し得る。酸化剤としては、Ｎ−クロロスクシンイミド−ジメチルスルフィド、トリフルオロ酢酸ピリジニウムと共にジシクロヘキシルカルボジイミド−ジメチルスルホキシド、およびデス−マーチンペリオジナン（Ｄｅｓｓ−Ｍａｒｔｉｎ ｐｅｒｉｏｄｉｎａｎｅ）が挙げられる。第１の塩基としては、ジイソプロピルアミンおよびトリエチルアミンが挙げられる。前記反応は典型的に、ジクロロメタン、クロロホルム、および１，２−ジクロロエタンなどの溶媒中、約−２０℃から約０℃で約１時間から約２時間に亘り実施される。

A compound having formula (I) -a can be converted to a compound having formula (I) -b by reacting the former with an oxidizing agent in the presence or absence of a first base. Oxidizing agents include N-chlorosuccinimide-dimethyl sulfide, pyridinium trifluoroacetate and dicyclohexylcarbodiimide-dimethyl sulfoxide, and Dess-Martin periodinane. Examples of the first base include diisopropylamine and triethylamine. The reaction is typically carried out in a solvent such as dichloromethane, chloroform, and 1,2-dichloroethane at about −20 ° C. to about 0 ° C. for about 1 hour to about 2 hours.

式（Ｉ）−ｂを有する化合物は、前者、フッ化剤、および場合によっては第２の塩基を反応させることにより式（Ｉ）−ｃを有する化合物に変換し得る。フッ素化剤としては、テトラフルオロホウ酸３，５−ジクロロ−１−フルオロピリジニウム、Ｎ−フルオロベンゼンスルホンイミド、３，５−ジクロロ−１−フルオロピリジニウムトリフレート、Ｎ−フルオロ−Ｎ−メチル−パラ−トルエンスルホンアミド、Ｎ−フルオロピリジニウムトリフレート、およびＮ−フルオロペルフルオロピペリジンが挙げられる。第２の塩基としては、水素化ナトリウム、水素化カリウム、リチウムジイソプロピルアミド、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、リチウムビス（トリメチルシリル）アミド、ナトリウムビス（トリメチルシリル）アミド、およびカリウムビス（トリメチルシリル）アミドが挙げられる。前記反応は典型的に、ＤＭＦ、ＴＨＦ、およびジエチルエーテルなどの溶媒中、約−７８℃から約０℃で約２時間から約２４時間に亘り実施される。

Compounds having formula (I) -b can be converted to compounds having formula (I) -c by reacting the former, a fluorinating agent, and optionally a second base. As the fluorinating agent, 3,5-dichloro-1-fluoropyridinium tetrafluoroborate, N-fluorobenzenesulfonimide, 3,5-dichloro-1-fluoropyridinium triflate, N-fluoro-N-methyl-para -Toluenesulfonamide, N-fluoropyridinium triflate, and N-fluoroperfluoropiperidine. The second base includes sodium hydride, potassium hydride, lithium diisopropylamide, triethylamine, N, N-diisopropylethylamine, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide. Can be mentioned. The reaction is typically carried out in a solvent such as DMF, THF, and diethyl ether at about −78 ° C. to about 0 ° C. for about 2 hours to about 24 hours.

R ³ is R ^P, compound R ^P is acetyl or benzoyl, by reacting the former and methanol can be converted to compounds wherein R ³ is hydrogen. The reaction is typically carried out in methanol at about 25 ° C. to about 65 ° C. for about 2 hours to about 60 hours.

R ³ is R ^P, compound R ^P is trimethylsilyl, by reacting the former with a fluoride donor agent, it may be converted to compounds wherein R ³ is hydrogen. Fluoride donors include tetrabutylammonium fluoride, fluorinated polymer-bound ammonium, tetrabutylammonium fluoride, pyridine-hydrogen fluoride, and triethylamine-trihydrofluoride. The reaction is typically carried out in a solvent such as THF and 1,4-dioxane at about 0 ° C. to about 50 ° C. for about 1 hour to about 24 hours.

  The compounds and methods of this invention will be better understood in connection with the following examples.

Benzoic acid (2S, 3R, 4S, 6R) -4- (dimethylamino) -2-(((3aS, 4R, 7R, 8S, 9S, 10R, 11S, 13R, 15R, 15aR) -4-ethyl-11 -(Prop-2-ynyloxy) -8-hydroxy-3a, 7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino [4,3 -D] [1,3] oxazol-10-yl) oxy) -6-methyltetrahydro-2H-pyran-3-yl (1 g), methoxylamine hydrochloride (1.69 g) and boron trifluoride etherate (0. 34 mL) in ethanol (10 mL) was stirred in a sealed tube at 99 ° C. for 14 days, then cooled, diluted with isopropyl acetate (100 mL), 5% sodium bicarbonate (25 mL) Quenched with and aqueous (100 mL), concentrated to remove the organic solvent, and extracted with isopropyl acetate. The extract was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated; the concentrate was subjected to silica gel flash chromatography with 25% acetone / hexane.

A solution of N-chlorosuccinimide (90 mg) in dichloromethane (2.5 mL) at −10 ° C. with dimethyl sulfide (56 μL), stirred for 10 min, treated with a solution of Example 1 (350 mg) in dichloromethane (2 mL), − The mixture was stirred at 10 to 0 ° C. for 1.5 hours, treated with triethylamine (63 μL) warmed to room temperature, and washed with saturated sodium carbonate and water. The washings were combined and extracted with dichloromethane, and the organics were combined and washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated.

A solution of Example 2 (313 mg) in methanol (20 mL) was stirred at 55 ° C. for 18 hours and concentrated; the concentrate was flash chromatographed on silica gel with 1-3% 2M NH ₃ in methanol / dichloromethane.

Example 3 (38.7 mg), 3-bromoquinoline (11.8 μL), triethylamine (5 mL), dichlorobis (triphenylphosphine) palladium (II) (2 mg) and copper iodide (0.1 mg) in acetonitrile (0 0.5 mL) solution was stirred at 80 ° C. for 18 hours, then cooled and concentrated; the concentrate was subjected to silica gel flash chromatography with 2% 2M NH ₃ in methanol / dichloromethane.

  This example was prepared by substituting 3-bromo-1,5-naphthyridine for the 3-bromoquinoline of Example 4.

  This example was prepared by substituting 6-bromoquinoxaline for the 3-bromoquinoline of Example 4.

  This example was prepared by substituting 2-bromo-5- (3-methyltetrazole) thiophene for the 3-bromoquinoline of Example 4.

  This example was prepared by substituting 2-bromo-5- (2-pyridine) thiophene for the 3-bromoquinoline of Example 4.

Treat a solution of Example 1 (781 mg) in DMF (5 mL) at -10 ° C with 60% oily sodium hydride (81 mg), stir at -10 ° C for 45 min, treat with N-fluorobenzenesulfonimide (352 mg). And stirred at −10 ° C. for 3 hours, diluted with isopropyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated; 1.5% 2M NH ₃ in methanol / dichloromethane in the concentrate. On silica gel flash chromatography.

A solution of Example 9 (630 mg) in methanol (20 mL) was stirred at 55 ° C. for 18 hours and concentrated; the concentrate was subjected to silica gel flash chromatography with 4% 2M NH ₃ in methanol / dichloromethane.

Example 10 (120 mg), 3-bromoquinoline (35 μL), triethylamine (1.5 mL), dichlorobis (triphenylphosphine) palladium (II) (6.2 mg) and copper iodide (0.3 mg) in acetonitrile (1 0.5 mL) solution was stirred at 80 ° C. for 18 hours, then cooled and concentrated; the concentrate was subjected to silica gel flash chromatography with 4% 2M NH ₃ in methanol / dichloromethane.

  This example was prepared by substituting 2-bromo-5- (3-methyltetrazole) thiophene for the 3-bromoquinoline of Example 11.

  Spectral data

  Example 1

  Example 2

  Example 3

  Example 4

  Example 5

  Example 6

  Example 7

  Example 8

  Example 9

  Example 10

  Example 11

  Example 12

上記は、本発明の単なる例示であり、本発明を開示された化合物および方法に限定する意図はない。当業者に自明な変化および変更は、請求項に定義された本発明の範囲および概念内であることが意図されている。

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds and methods. Changes and modifications obvious to those skilled in the art are intended to be within the scope and concept of the invention as defined in the claims.

Claims (20)

Formula (I)

Wherein R ¹ is independently from the group consisting of alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl and heterocyclyl. 1 or 2 or 3 substitutions independently selected from the group consisting of alkyl, cycloalkyl, halo, aryl, heteroaryl and heterocyclyl substituted with 1 or 2 or 3 substituents selected Substituted with — (CH ₂ ) alkenyl substituted with 1 or 2 or 3 substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl and heterocyclyl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —OR ⁷ , ═O, Alkyl, cycloalkyl, halo, aryl, heteroaryl, substituted with one, two or three substituents independently selected from the group consisting of NH ₂ , —NHR ⁸ , and —NR ⁸ R ⁹ ; _{^{heterocyclyl, -OH, -OR 7, = O}} , NH 2, substituted with one or two or three substituents independently selected from the group consisting of -NHR ^8, and ^-NR 8 ^{R 9} - (CH ₂₎ alkenyl or cycloalkyl, halo, aryl, heteroaryl, _{^{heterocyclyl, -OH, -OR 7,, =}} O, NH 2, -NHR 8 And — (CH ₂ ) alkynyl substituted with one or two or three substituents independently selected from the group consisting of —NR ⁸ R ⁹ ;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
R ⁶ is one or two independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) —, and —SO ₂ —, or An alkyl interrupted by three moieties, or independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) — and —SO ₂ —; 1 or 2 or 3 moieties, and cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, ═O, —OR ⁷ , —NH ₂ , —NHR ⁸ , and —NR ⁸ alkyl substituted with one, two or three substituents independently selected from the group consisting of R ⁹ ;
R ⁷ is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
R ⁸ and R ⁹ are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl Is;
R ⁸ and R ⁹ together comprise —O—, —NH—, —N (alkyl) —, —S—, —C (O) —, —S (O) — and —SO ₂ —. C ₃ -C ₇ -alkylene or C ₄ -C ₇ -alkylene interrupted by one moiety selected from the group;
A compound, or salt, prodrug, or salt of a prodrug thereof, wherein X ¹ is hydrogen or fluoro. Having the formula (I)
R ¹ is substituted with one substituent selected from the group consisting of — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, cycloalkyl, halo, aryl, heteroaryl and heterocyclyl — (CH ₂ ). Alkenyl, or — (CH ₂ ) alkynyl substituted with one substituent selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl and heterocyclyl;
R ² is hydrogen, alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —OR ⁷ , ═O, NH ₂ , —NHR ^8. And alkyl, cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —substituted with one, two or three substituents independently selected from the group consisting of —NR ⁸ R ⁹ — (CH ₂ ) alkenyl substituted with one, two or three substituents independently selected from the group consisting of OR ⁷ , ═O, NH ₂ , —NHR ⁸ , and —NR ⁸ R ^9. or cycloalkyl, halo, aryl, heteroaryl, _{^{heterocyclyl, -OH, -OR 7,, =}} O, NH 2, -NHR 8, and -NR Independently from the group consisting of R ⁹ is substituted with one or two or three substituents selected - (CH ₂₎ alkynyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
R ⁷ is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
R ⁸ and R ⁹ are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl Is;
The compound according to claim 1, wherein X ¹ is hydrogen or fluoro, or a salt, prodrug, or salt of the prodrug thereof. Having the formula (I)
R ¹ is, - (CH ₂₎ alkynyl, or cycloalkyl, halo, aryl, substituted with one substituent selected from the group consisting of heteroaryl and heterocyclyl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —OR ⁷ , ═O, NH ₂ , —NHR ^8. And alkyl, cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —substituted with one, two or three substituents independently selected from the group consisting of —NR ⁸ R ⁹ — (CH ₂ ) alkenyl substituted with one, two or three substituents independently selected from the group consisting of OR ⁷ , ═O, NH ₂ , —NHR ⁸ , and —NR ⁸ R ^9. or cycloalkyl, halo, aryl, heteroaryl, _{^{heterocyclyl, -OH, -OR 7,, =}} O, NH 2, -NHR 8, and -NR Independently from the group consisting of R ⁹ is substituted with one or two or three substituents selected - (CH ₂₎ alkynyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
R ⁷ is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
R ⁸ and R ⁹ are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl Is;
The compound according to claim 2, wherein X ¹ is hydrogen or fluoro, or a salt, prodrug, or salt of the prodrug thereof. Having the formula (I)
R ¹ is, - (CH ₂₎ substituted with one substituent selected from the group consisting of alkynyl, or aryl, and heteroaryl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, or alkyl substituted with one substituent selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl, and heterocyclyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
The compound according to claim 3, wherein X ¹ is hydrogen or fluoro, or a salt, prodrug, or salt of the prodrug thereof. Having the formula (I)
R ¹ is, - (CH ₂₎ substituted with one substituent selected from the group consisting of alkynyl, or aryl, and heteroaryl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, or alkyl substituted with phenyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
The compound according to claim 4, wherein X ¹ is hydrogen or fluoro, or a salt, prodrug, or salt of the prodrug thereof. Having the formula (I)
R ¹ is, - (CH ₂₎ substituted with one substituent selected from the group consisting of alkynyl, or aryl, and heteroaryl - (CH ₂₎ alkynyl;
R ² is alkyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
X ¹ is A compound according to claim 5 is hydrogen or fluoro, or a salt, prodrug or salt of a prodrug thereof. Having the formula (I)
R ¹ is, - (CH ₂₎ alkynyl, or quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, thienyl, isoxazolyl, thiazolyl, substituted with one substituent selected from the group consisting of pyridyl and pyrimidinyl - (CH ₂₎ alkynyl The thienyl, isoxazolyl, thiazolyl, pyridyl and pyrimidinyl are independently unsubstituted, pyrimidinyl, pyridyl, thienyl, isoxazolyl, thiazolyl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, 1-methyl Selected from the group consisting of -1H-tetrazol-5-yl and 2-methyl-2H-tetrazol-5-yl;
R ² is alkyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
The compound according to claim 6, or a salt, prodrug, or salt of the prodrug thereof, wherein X ¹ is hydrogen or fluoro. Having the formula (I)
R ¹ is prop-2-ynyl, 3- (quinolin-3-yl) -prop-2-ynyl, 3- (1,5-naphthyridin-3-yl) prop-2-ynyl, 3- (quinoxaline- 6-yl) prop-2-ynyl, 3- (5- (2-methyl-2H-tetrazol-5-yl) thien-2-yl) prop-2-ynyl, 3- (5- (pyridin-2- Yl) thien-2-yl) prop-2-ynyl, 3- (2- (pyrimidin-2-yl) thien-5-yl) prop-2-ynyl, 3- (2- (2-methyl-2H-) Tetrazol-5-yl) 1,3-thiazol-5-yl) prop-2-ynyl, 3- (2- (2-methyl-2H-tetrazol-5-yl) pyridin-6-yl) prop-2- Inyl, 3- (3- (pyridin-2-yl) isoxazole-5 -Yl) prop-2-ynyl, or 3- (3- (2-methyl-2H-tetrazol-5-yl) isoxazol-5-yl) prop-2-ynyl;
R ² is alkyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
X ¹ is A compound according to claim 7 is hydrogen or fluoro, or a salt, prodrug or salt of a prodrug thereof. Having the formula (I)
R ¹ is, - (CH ₂₎ substituted with one substituent selected from the group consisting of alkynyl, or aryl, and heteroaryl - (CH ₂₎ alkynyl;
R ² is methyl;
R ³ is hydrogen or ^{R P,} the ^{R P} is a hydroxyl protecting moiety;
One of R ⁴ or R ⁵ is hydrogen and the other is —OH; or R ⁴ and R ^{5 taken} together are ═O;
The compound according to claim 6, or a salt, prodrug, or salt of the prodrug thereof, wherein X ¹ is hydrogen or fluoro. Formula (I)

Wherein R ¹ is — (CH ₂ ) alkynyl substituted with one substituent selected from the group consisting of naphthyridinyl, quinolinyl, quinoxalinyl, and thienyl, wherein the thienyl is pyridyl and Substituted with one substituent selected from the group consisting of 2H-tetrazolyl, wherein the 2H-tetrazolyl is substituted with alkyl; R ² is alkyl; R ³ is hydrogen; R ⁴ and R ^{5 taken} together are ═O; X ¹ is hydrogen or fluoro, or a compound, salt, prodrug or prodrug salt thereof according to claim 1. Formula (I)

Wherein R ¹ is — (CH ₂ ) alkynyl substituted with one substituent selected from the group consisting of naphthyridinyl, quinolinyl, quinoxalinyl, and thienyl, wherein the thienyl is Substituted with one substituent selected from the group consisting of pyridyl and 2H-tetrazolyl, wherein said 2H-tetrazolyl is substituted with C ₁ -alkyl; R ² is C ₁ -alkyl; R ³ is hydrogen; R ⁴ and R ^{5 taken} together are ═O; X ¹ is hydrogen or fluoro, or a compound, salt, prodrug, or prodrug thereof according to claim 1. Salt. R ¹ is 3- (quinolin-3-yl) prop-2-ynyl, 3- (1,5-naphthyridin-3-yl) prop-2-ynyl, or 3- (quinoxalin-6-yl) prop- be a 2-ynyl; ^{R 2} is methyl; ^{R 3} is hydrogen; ^{R 4} and ^{R 5} together = be O; ^{X 1} is claimed in claim 11 is hydrogen Or a salt, prodrug, or salt of the prodrug. R ¹ is 3- (quinolin-3-yl) prop-2-ynyl, 3- (1,5-naphthyridin-3-yl) prop-2-ynyl, or 3- (quinoxalin-6-yl) prop- be a 2-ynyl; ^{R 2} is methyl; ^{R 3} is hydrogen; ^{R 4} and ^{R 5} together = be O; ^{X 1} is claimed in claim 11 is fluoro Or a salt, prodrug, or salt of the prodrug. R ¹ is 3- (5- (2-methyl-2H-tetrazol-5-yl) thien-2-yl) prop-2-ynyl or 3- (5- (pyridin-2-yl) thien-2 - yl) be a prop-2-ynyl; ^{R 2} is methyl; ^{R 3} is hydrogen; ^{R 4} and ^{R 5} together = be O; ^{X 1} is hydrogen 12. A compound according to claim 11, or a salt, prodrug, or salt of a prodrug thereof. R ¹ is 3- (5- (2-methyl-2H-tetrazol-5-yl) thien-2-yl) prop-2-ynyl or 3- (5- (pyridin-2-yl) thien-2 - yl) be a prop-2-ynyl; ^{R 2} is methyl; ^{R 3} is hydrogen; ^{R 4} and ^{R 5} together = be O; ^{X 1} is fluoro 12. A compound according to claim 11, or a salt, prodrug, or salt of a prodrug thereof.   A composition for treating or preventing a bacterial infection in fish or mammals comprising a therapeutically effective amount of the compound of claim 1 and an excipient.   Use of a therapeutically effective amount of a compound according to claim 1 for the preparation of a medicament for preventing or treating bacterial infection. (3aS, 4R, 7R, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-2,6 , 8-Trioxo-11-((3-quinolin-3-ylprop-2-ynyl) oxy) tetradecahydro-2H-oxacyclotetradecino (4,3-d) (1,3) oxazole-10- Yl 3,4,6-trideoxy 3- (dimethylamino) -β-D-xylo-hexopyranoside;
(3aS, 4R, 7R, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-11- ( (3- (1,5-naphthyridin-3-yl) prop-2-ynyl) oxy) -2,6,8-trioxotetradecahydro-2H-oxacyclotetradecino (4,3-d) ( 1,3) Oxazol-10-yl 3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside;
(3aS, 4R, 7R, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-2,6 , 8-Trioxo-11-((3-quinoxalin-6-ylprop-2-ynyl) oxy) tetradecahydro-2H-oxacyclotetradecino (4,3-d) (1,3) oxazole-10- Yl 3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside;
(3aS, 4R, 7R, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-11- ( (3- (5- (2-Methyl-2H-tetrazol-5-yl) thien-2-yl) prop-2-ynyl) oxy) -2,6,8-trioxotetradecahydro-2H-oxacyclo Tetradecino (4,3-d) (1,3) -oxazol-10-yl3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside;
(3aS, 4R, 7R, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-2,6 , 8-Trioxo-11-((3- (5-pyridin-2-ylthien-2-yl) prop-2-ynyl) oxy) tetradecahydro-2H-oxacyclotetradecino (4,3-d) (1,3) oxazol-10-yl3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside;
(3aS, 4R, 7S, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-7-fluoro-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl -2,6,8-trioxo-11-((3-quinolin-3-ylprop-2-ynyl) oxy) tetradecahydro-2H-oxacyclotetradecino (4,3-d) (1,3) Oxazol-10-yl3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside; or (3aS, 4R, 7S, 9R, 10R, 11S, 13R, 14E, 15R, 15aR) -4-ethyl-7-fluoro-14- (methoxyimino) -3a, 7,9,11,13,15-hexamethyl-11-((3- (5- (2-methyl-2H Tetrazol-5-yl) thien-2-yl) prop-2-ynyl) oxy) -2,6,8-trioxotetradecahydro-2H-oxacyclotetradecino (4,3-d) (1, 3) Oxazol-10-yl 3,4,6-trideoxy-3- (dimethylamino) -β-D-xylo-hexopyranoside.
The compound according to claim 1, or a salt, prodrug, or salt of the prodrug thereof. Formula (I) -d

Wherein R ¹ is independently from the group consisting of alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl and heterocyclyl. 1 or 2 or 3 substitutions independently selected from the group consisting of alkyl, cycloalkyl, halo, aryl, heteroaryl and heterocyclyl substituted with 1 or 2 or 3 substituents selected Substituted with — (CH ₂ ) alkenyl substituted with 1 or 2 or 3 substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl and heterocyclyl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —OR ⁷ , ═O, Alkyl, cycloalkyl, halo, aryl, heteroaryl, substituted with one, two or three substituents independently selected from the group consisting of NH ₂ , —NHR ⁸ , and —NR ⁸ R ⁹ ; _{^{heterocyclyl, -OH, -OR 7, = O}} , NH 2, substituted with one or two or three substituents independently selected from the group consisting of -NHR ^8, and ^-NR 8 ^{R 9} - (CH ₂₎ alkenyl or cycloalkyl, halo, aryl, heteroaryl, _{^{heterocyclyl, -OH, -OR 7,, =}} O, NH 2, -NHR 8 And — (CH ₂ ) alkynyl substituted with one or two or three substituents independently selected from the group consisting of —NR ⁸ R ⁹ ;
R ⁴ and R ⁵ together are ═O;
R ⁶ is one or two independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) —, and —SO ₂ —, or An alkyl interrupted by three moieties, or independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) — and —SO ₂ —; 1 or 2 or 3 moieties, and cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, ═O, —OR ⁷ , —NH ₂ , —NHR ⁸ , and —NR ⁸ alkyl substituted with one, two or three substituents independently selected from the group consisting of R ⁹ ;
R ⁷ is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
R ⁸ and R ⁹ are independently alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl Or R ⁸ and R ^{9 taken} together are —O—, —NH—, —N (alkyl) —, —S—, —C (O) —, —S (O) — and —SO C ₃ -C ₇ -alkylene or C ₄ -C ₇ -alkylene interrupted by one moiety selected from the group consisting of _2- ;
A method for producing a compound, or salt, prodrug, or salt of a prodrug thereof, wherein X ¹ is hydrogen;
(A) Formula (1) wherein R ^P is acetyl or benzoyl

A compound having the formula (2)
H ^₂ N-OR ₂
(2),
Or a salt thereof with or without additives at a pressure between about 1.2 atmospheres and 5 atmospheres,
Formula (I) -a

Providing a compound having:
(B) reacting the product of step (a) with an oxidant in the presence or absence of a first base;
Formula (I) -b

Providing a compound having: and (c) reacting the product of step (b) with methanol. Formula (I) -c

Wherein R ¹ is independently from the group consisting of alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl and heterocyclyl. 1 or 2 or 3 substitutions independently selected from the group consisting of alkyl, cycloalkyl, halo, aryl, heteroaryl and heterocyclyl substituted with 1 or 2 or 3 substituents selected Substituted with — (CH ₂ ) alkenyl substituted with 1 or 2 or 3 substituents independently selected from the group consisting of cycloalkyl, halo, aryl, heteroaryl and heterocyclyl - (CH ₂₎ alkynyl;
R ² is hydrogen, alkyl, — (CH ₂ ) alkenyl, — (CH ₂ ) alkynyl, —CH ₂ R ⁶ , cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, —OR ⁷ , ═O, Alkyl, cycloalkyl, halo, aryl, heteroaryl, substituted with one, two or three substituents independently selected from the group consisting of NH ₂ , —NHR ⁸ , and —NR ⁸ R ⁹ ; _{^{heterocyclyl, -OH, -OR 7, = O}} , NH 2, substituted with one or two or three substituents are independently selected from the group consisting of -NHR ^8, and ^-NR 8 ^{R 9} - (CH ₂₎ alkenyl or cycloalkyl, halo, aryl, heteroaryl, _{^{heterocyclyl, -OH, -OR 7,, =}} O, NH 2, -NHR 8 And — (CH ₂ ) alkynyl substituted with one or two or three substituents independently selected from the group consisting of —NR ⁸ R ⁹ ;
^RP is acetyl or benzoyl;
R ⁶ is one or two independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) —, and —SO ₂ —, or An alkyl interrupted by three moieties, or independently selected from the group consisting of —O—, —NH—, —N (alkyl) —, —S—, —S (O) — and —SO ₂ —; Independently interrupted by one or two or three moieties and are cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, —OH, ═O, —OR ⁷ , —NH ₂ , —NHR ⁸ , And alkyl substituted with one, two or three substituents independently selected from the group consisting of —NR ⁸ R ⁹ ;
R ⁷ is alkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or alkyl substituted with one substituent selected from the group consisting of aryl, heteroaryl, and heterocyclyl;
R ⁸ and R ⁹ are independently substituted with one substituent selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, or aryl, heteroaryl, and heterocyclyl. Or R ⁸ and R ^{9 taken} together are —O—, —NH—, —N (alkyl) —, —S—, —C (O) —, —S (O) —. And a compound that is C ₃ -C ₇ -alkylene or C ₄ -C ₇ -alkylene interrupted by one moiety selected from the group consisting of and —SO ₂ —, or a salt, prodrug, or prodrug thereof A method for producing a salt;
(A) Formula (I) -b

Reacting a compound having a fluorinating agent with or without a second base.