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HK1113931A - Macrolides - Google Patents

Macrolides Download PDF

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Publication number
HK1113931A
HK1113931A HK08103176.2A HK08103176A HK1113931A HK 1113931 A HK1113931 A HK 1113931A HK 08103176 A HK08103176 A HK 08103176A HK 1113931 A HK1113931 A HK 1113931A
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HK
Hong Kong
Prior art keywords
methyl
alkyl
oxo
substituted
group
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HK08103176.2A
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Chinese (zh)
Inventor
L.S.丘帕克
M.E.弗拉纳根
卓史 金子
T．V．马吉
M．C．诺伊
U．赖利
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辉瑞产品公司
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Description

Macrolides
Technical Field
The present invention relates to macrolide compounds and their use, for example, as antibacterial and antiprotozoal agents in animals, including humans. The invention also relates to processes for the preparation of these compounds, intermediates useful in the preparation of these compounds, and pharmaceutical compositions containing these compounds. The invention further includes methods of treating and/or preventing diseases, such as bacterial and/or protozoal infections (or other indications, such as cancer, inflammation, atherosclerosis, or decreased gastric motility) by administering a compound or composition to a subject in need of such treatment.
Background
Erythromycin and clarithromycin are well known macrolides. Other erythromycin-based macrocyclic lactone compounds have been made, for example, by introducing modifications at various positions of erythromycin or clarithromycin, such as in: US4,331,803; US4,474,768; US4,517,359; US 5,523,399; US 5,527,780; US 5,635,485; US 5,804,565; US 6,020,521; US 6,025,350; US 6,075,133; US 6,162,794; US 6,191,118; US 6,248,719; US 6,291,656; US 6,437,151; US 6,472,371; US 6,555,524; US 2002/0052328; US 2002/0061856; US 2002/0061857; US 2002/0077302; US 2002/0151507; US 2002/0156027; US 2003/0100518; US 2003/0100742; US 2003/0199458; US 2004/0077557; WO 99/11651; WO 99/21866; WO 99/21869; WO 99/35157; EP 1114826; and j.med.chem., 46, 2706 (2003). Other relevant publications are cited below. These and all documents cited herein are incorporated by reference in their entirety for all purposes, including statements, improvements and methods relating to the variation of the position of objects on the macrolide ring in various combinations. Thus, derivatives may include modifications such as at the C-2, C-3, C-6, C-9, C-10, C-H, C spit 2 and C-13 erythromycin positions, and the corresponding azalide derivatives.
There is a need for novel macrolides that respond to increasingly emerging drug-resistant organisms, improve safety, and improve the spectrum of activity, among other reasons.
Disclosure of Invention
The present invention relates to certain macrolide compounds per se, to their preparation and useful intermediates, to pharmaceutical compositions thereof, and to methods of treatment and prevention of, for example, infections therewith. In many embodiments, these compounds are active and effective against organisms that are resistant to other antibiotics, including other macrolides.
The invention includes compounds of the general formula:
wherein C11 and C12 represent the numbering of the conventional macrolide at the erythromycin-based macrolide ringCThe carbons at positions C-11 and C-12, and the other variables shown are as defined herein. Ring (C)CThere is no limitation in the structure of (1). Radical (I)2-R2To be connected to a ringAThe "helmet group" of (1).
In certain aspects, more specifically, the invention relates to compounds of formula I:
wherein the double radical1May be absent (absent means a ring)ADirectly connected to ring B) by a covalent single bond, > CH2、＞C(CH3) H or other alkyl or substituted alkyl diradical (">" symbol) represents a connecting ringAAndBa single bond of (a); -CH2Having e.g. > CH2The same meaning of the same).
Double base2Can be-C (O) (CH)2)m-、-S(O)2(CH2)m-、-SO2N(R6)-、-C(O)O(CHR20)m-、-(C(R6)(R7))m-or-C (O) N (R)6) -, where m is an integer of 0 to 3.
Double base3Carbon C-3, representing the macrolide ring, is directly bound to C-2 and C-4 and may be substituted, e.g. diyl3Can be > C (O), > CH (OC (O) R14) The ">" symbol represents a single bond connecting C-2 and C-4, meaning that C-3 is substituted by-OC (O) R14Substitution), > CH (OC (O) N (R)14)R15)、＞CH(OC(O)OR14)、＞CH(OC(O)CH(N(R14)R15)(CRaRb)n Ar)、＞CH(OC(O)CH(N((R14)R15)R14)、＞CH(OC(O)C(＝NOR14)(CRaRb)n-Ar)、＞CH(OC(O)C(＝NOR14)R14)、＞CH(OC(O)(CRaRb)n Ar)、＞CH(OC(O)(CRaRb)nN(R14)(CRaRb)n Ar) Or, alternatively:
wherein n is an integer from 0 to 5.
Double base4Can be > O or > N (R)10) Preferably, when the diradical is3Not > C (O), is diradical4Is > O.
Double base5Which are bound to C-8 and C-10 of the macrolide ring and which may be substituted, may be > C (O), -C (O) NH-, -N (H) C (O) -, > CH (N (R)8)R9)、＞C(＝NC(O)R19) Or > C (═ NOR)19). As an addition in this group, a diradical5May also be > C (═ NR)17)。
Double base6Can be- (C (R)c)(Rd))x-, where x is an integer from 0 to 5; double base7Can be- (C (R)c)(Re))y-, wherein y is an integer of 0 to 5; preferably provided that6And7wherein the sum of x + y is 1 to 5.
Radical R1Can be H, OH, halogen or (C)1-C6) Alkyl, with the preferred proviso that when1In the absence of R1Is H.
Radical R2Can be H orAr. In some embodiments, R2Or2-R2Is a protecting group such as H, Bn, Bzh, CBZ, benzyloxymethyl or BOC, or any other suitable group.
Radical R3Can be (C)1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl, any of which may be substituted, e.g. byArAnd (4) substitution.
Radical R4May be H or F, with the proviso that, preferably, when a diradical is present3When not > C (O), R4Is H.
Radical R5And R20Can independently be (C)1-C6) Alkyl, substituted for example with 1 to 3 substituents of group S.
Each R6And R7Can be independently H or (C)1-C12) Alkyl, (C)2-C12) Alkenyl or 4-6 membered heterocycle; any of which, other than H, may be substituted, for example, with 1 to 3 substituents of group S; and independently wherein (C)1-C12) Alkyl and (C)2-C12) Alkenyl groups may have 1 to2 carbons, independently replaced by, for example, a T group diradical; and independently at most one R6/R7And, together with the carbon to which they are attached, may form a 3-to 8-membered (preferably carbocyclic) ring; preferably with the proviso that not more than a total of two R6And R7The radical is not H.
Each R8And R9Can be independently H or (C)1-C6) Alkyl, -C (O) (C)1-C6) Alkyl, -S (O)2)(C1-C6) Alkyl groups, any of which, other than H, may be substituted, for example, with 1 to 3 substituents of group S. Preferably and especially when R8is-C (O) (C)1-C6) Alkyl or-S (O)2)(C1-C6) When alkyl, R9Is H or (C)1-C6) Alkyl, in addition to H, may be substituted with, for example, 1 to 3S group substituents.
Radical R10Can be H or (C)1-C6) Alkyl, which may be substituted, for example, with 1 to 3 substituents of group S.
Each R11And R12Independently are (a) H, (C)1-C12) Alkyl, (C)2-C12) Alkenyl, (C)2-C12) Alkynyl, any of which, except H, may have a carbon, is substituted by, for example, -NH-, -N (CH)3) -, -N (4-to 10-membered heterocycle), -N (4-to 10-membered carbocycle), -O-, -S-, -S (O) -or-S (O)2-substitution wherein the aforementioned R11And R12And together with the atoms to which they are attached, may form a 3-to 8-membered ring, or (b) a 9-to 10-membered heterocyclic ring, a 9-to 10-membered carbocyclic ring, a 4-to 6-membered heterocyclic ring, or a 4-to 6-membered carbocyclic ring, wherein any of (a) or (b), other than H, may be substituted, for example, with 1 to 3 of the following groups: F. cl, OH, (C)1-C3) Alkoxy group, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkyl, halogen substituted (C)1-C3) Alkyl or (C)1-C3) Alkoxy radical- (C1-C3) An alkyl group.
Radical R13And R16May be independently H, -C (O) (C) which may be substituted1-C6Alkyl), -C (O)Ar-Si (phenyl) (C1-C6Alkyl radical)2、-Si(C1-C6Alkyl radical)3Or other protecting groups.
Each R14And R15Can be independently H or (C)1-C10) An alkyl group; the alkyl group may be substituted, for example, with 1 to 3 substituents of group S; and independently, wherein 1 to2 carbons of the alkyl group may be replaced, for example, by a T-group diradical; and independently, wherein each R14/R15Pairs may form a 3 to 8 membered ring together with the atoms to which they are attached.
Radical R17Can be OR19、-C(O)(C1-C6Alkyl) or-c (o) (4-10 membered carbocyclic or heterocyclic), any of which may be substituted, for example, with 1 to 3 substituents of group S.
Radical R19Can be H, (C)1-C6) Alkyl, - (C)1-C6Alkyl) - (4-10 membered carbocyclic or heterocyclic ring) or (4-10 membered carbocyclic or heterocyclic ring); wherein any of the radicals, other than H, may be substituted, for example, by 1 to 3 substituents of the S group(or by F, Cl, OH, (C)1-C3) Alkoxy group, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkyl, halogen substituted (C)1-C3) Alkyl or (C)1-C3) Alkoxy radical- (C1-C3) Alkyl groups); in which up to 1 carbon of the radical may be replaced, for example, by a diradical of group T (or by-NH-, -N (CH)3) -, -N (4-to 10-membered carbocyclic or heterocyclic), -O-, -S-, -S (O) -or-S (O)2-)。
Each RaAnd RbCan be independently H or (C)1-C6) Alkyl, which may be substituted, for example, with 1 to 3 substituents of group S; and wherein 1 to2 carbons of the alkyl group may be replaced, for example, by a T group diradical; and each Ra/RbPairs may form 3 to 10 membered rings together with the carbon to which they are attached.
Each RcThe groups can be independently H, F, Cl, (C)1-C3) Alkyl, hydroxy, (C)1-C3) Alkoxy or CN, with the proviso that, preferably, when both radicals are present6When x is 2 to 5, only one R is presentcMay not be H.
Each RdAnd ReThe radical being H but not more than one RdRadical with an ReTogether, the radicals may form a bridging carbon-carbon single bond, or a bridge (C)1-C3) Alkyl diradicals to make the ringAIs bicyclic.
Each one ofArCan be independently (a) a 9-to 10-membered heterocycle, (b) a 9-to 10-membered carbocycle, (c) a 4-to 6-membered heterocycle, or (d) a 4-to 6-membered carbocycle, wherein (c) or (d) can be substituted with a 4-to 6-membered heterocycle or a 4-to 6-membered carbocycle.ArThe ring system may be substituted with 1 to 3 substituents of group S. However, it is possible to use a single-layer,Arand R2Are not limited to the ring sizes indicated above, and may include, for example, larger ring systems, and may be substituted with or fused to other ring systems.
Substituents of group S include: nitro, halogen, hydroxy, CF3、OCF3、OCHF2、CHF2、CN、CHO、(C1-C10) Alkoxy (optionally substituted with CN), (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy group, (C)1-C3) Alkoxy radical- (C1-C3) Alkyl, oxo, (C)1-C10) Alkanoyl, (C)1-C10) Alkyl, (C)2-C10) Alkenyl, (C)2-C10) Alkynyl, 4-to 10-membered heterocyclic or carbocyclic ring, including 9-10 and 5-6-membered, hydroxy-substituted (C)1-C6) Alkyl, -C (O) R11C (O) (4-10 membered heterocycle), C (O) (4-10 membered carbocycle), -C (O)2(4-10 membered heterocycle), -C (O)2(4-10 membered carbocycle), -O (4-10 membered heterocycle), -C (O) OR11、-OC(O)R11、-C(O)NR11R12、-OC(O)NR11R12、-NR11R12、-SO2NR11R12and-S (O)pR11Where p is 0 to2 and where a substituent of the group S is substituted for a nonaromatic carbon, the group S may also be ═ N-NR11R12N- (4-to 10-membered heterocycle), ═ N- (4-to 10-membered carbocycle), ═ N-nhc (o) R11、＝N-NHC(O)NR11R12、-N(R11)SO2R12Or ═ N-R17(ii) a Wherein any heterocyclic and carbocyclic group may be substituted by Cl, F, (C)1-C10) Alkyl, (C)1-C10) Alkoxy, keto, or CN.
The T group of diradicals comprises: -O-, -S (O)2-、-N((C1-C6) Alkyl) -, -NH-, -C (O) -, -OC (O) -, -C (O) O-, N (Ar), and-OC (O) O-.
Each variable definition of formula I includes any subset of the definition, and the definition of formula I includes any combination of subsets of variable definitions.
In other aspects of the invention, methods for preparing the compounds and intermediates of the invention are provided.
In other aspects of the invention, pharmaceutical compositions containing the compounds of the invention are provided.
In yet other aspects of the invention, there are provided methods of treating a subject in need thereof with compounds and compositions according to the invention, including the treatment of bacterial and/or protozoal infections, and prophylaxis.
Detailed Description
The following detailed description provides other non-limiting details of the invention, including general preparations and examples of the invention. Compound (I)
As discussed above, the present invention includes erythromycin-based macrocyclic lactones containing a C-11/C-12 ring or a carbamate (ring D) linked (directly or indirectly) to a cyclic amine (ring-to-ring), which in turn may be linked to a helmet group (group ethyl R)2). In certain aspects, the invention includes compounds of formula I. Furthermore, the invention includes subgenera and disclosed species (embodiments), including preferred embodiments, encompassed by formula I, including in particular the following:
in certain aspects of the invention, the diradicals1May be absent or methylene; or in some preferred embodiments, the diradicals are specifically absent.
The diradical can be- (C (R) in some aspects6)(R7))m- (especially > CH (R)6))、-C(O)O-、-C(O)N(R6)-、＝C(O)(CH2)m-or core (O)2 (CH)2)mWherein m is 0 to 2); or the diradicals may each more specifically be > C (O), > S (O)2Or > CH (R)6). In some embodiments, R6May be H or (C1-C5) alkyl, which may be substituted, for example, by OH or by (C) in addition to H1-C3) Alkoxy substitution; or more specifically, R6May be H or unsubstituted (C)1-C3) Alkyl, in particular H or methyl.
Double base3In certain aspects can be > C (O). In other embodiments, the diradical can be cladinosyl.In other embodiments, the diradical is3Can be > CH (OC (O) R14)、＞CH(OC(O)N(R14)R15)、＞CH(OC(O)OR14)、＞CH(OC(O)CH(N(R14)R15)(CRaRb)n Ar)、＞CH(OC(O)CH(N((R14)R15)R14)、＞CH(OC(O)C(＝NOR14)(CRaRb)n-Ar)、＞CH(OC(O)C(＝NOR14)R14)、＞CH(OC(O)(CRaRb)n Ar)、＞CH(OC(O)(CRaRb)nN(R14)(CRaRb)n Ar) Or, alternatively:
in certain aspects, each R14And R15Can be independently H or (C)1-C6) Alkyl, in which 1 to 3 methylene units may be replaced by, O-, -S (O) -, (S) (O)2-stretch (O) -or-dry metathesis; and each R14/R15The pair, together with the atoms to which they are attached, may form a 3-to 8-membered ring; and the 3-8 membered ring may be substituted, for example, by A ㄈ or by 1 to2 substituents of group S.
Diradicals ± can in some aspects be explicitly > O.
The double prime may be > C (o) or > C (═ NOR) in certain aspects19) Or specifically > C (O). In some embodiments, R19Can be H or (C)1-C6) Alkyl, which may be interrupted by 1 to 3 oxygen atoms and/or substituted by 4-to 10-membered carbon or heterocyclic rings.
The diradical may be- (CH) in some aspects2)xAnd the double-radical may be ≡ (CH)2) y, wherein x and y are independently integers from 0 to 4, and wherein the sum of x + y is from 2 to 4; or more specifically, x and y can be integers from 0 to 3 (or 1 to 2) providing a sum of 2 to 3(ii) a Or more specifically, both the bistatic and the royal jelly may be methylene groups.
In certain aspects, R1May be H, OH or methyl; or R1Can be specifically Ho }
In certain aspects, R3Can be (C)1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl, any of which may be substituted, for example, with a ㄈ; or more specifically, R3May be unsubstituted methyl.
In certain aspects, R5May be an unsubstituted ethyl group. In some embodiments, R13And R16When present, may all be H.
In certain aspects, is straight or R2The rings are as described above and may be substituted, for example, with 1 to2 of the following groups: nitro, Br, Cl, F, hydroxy, (C)1-C6) Alkyl, CF3、OCF3、OCHF2、CHF2CN, CHO, (Cl means 6) alkoxy (optionally substituted by CN), (C)1-C3) Alkoxy- (CI-C3) alkoxy, (Cl ═ C3) alkoxyyellow C1-C3) Alkyl, oxo, (C)1-C6) Alkanoyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, hydroxy-substituted (C)1-C6) Alkyl, -C (O) R11、-OC(O)R11、＝C(O)OR11、-C(O)NR11R12、-OC(O)NR11R12＝、-NHC(O)R11、-NR11R12、-NR11SO2R12、-SO2NR11R12 and-S (O) nR11Wherein n is 0 to 2. In some embodiments, each R is11And R12Can be independently H or (C)1-C6) Alkyl, (C3-C6) alkenyl, or (C3) alkynyl, any of which, except H, may be substituted with one or more substituents independently selected from Cl, F, OH, (C) and (C) aryl, and1-C3) Alkoxy group, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkyl, halogen substituted (C)1-C3) Alkyl or (C)1-C3) Alkoxy radical- (C1-C3) An alkyl group.
In some embodiments, R2Can be (a) a 9-to 10-membered heterocycle, (b) a 9-to 10-membered carbocycle, (c) a 4-to 6-membered heterocycle, or (d) a 4-to 6-membered carbocycle, wherein (c) or (d) can be substituted with a 4-to 6-membered heterocycle or a 4-to 6-membered carbocycle; and the above-mentioned R2The ring may be substituted, for example, with 1 to2 of the following groups: SO (SO)2R11Hydroxy-substituted (C)1-C3) Alkyl, (C)1-C3) Alkyl, CN, CHO, F, Cl, Br, hydroxy, (C)1-C3) Alkoxy ≡ (C)1-C3) Alkoxy, oxo, (C)1-C3) Alkanoyl, (C)2-C6) Alkenyl, x (C)2-C6) Alkynyl or (C)1-C3) Alkoxy (optionally substituted with CN). In addition, may be substituted by nitro, CF3、OCF3、OCHF2Or CHF2And (4) substitution. The aforementioned rings specifically include both aryl and heteroaryl groups, as defined and discussed herein.
In some embodiments, R2Can be (a) a 9-to 10-membered heterocycle, or (b) a 5-to 6-membered heterocycle or a 5-to 6-membered carbocycle, wherein (b) is substituted with a 5-to 6-membered heterocycle or with a 5-to 6-membered carbocycle, wherein R2May be substituted, for example, with 1 to2 of the following groups: SO (SO)2R11Hydroxy-substituted (C)1-C3) Alkyl, (C)1-C3) Alkyl, CN, nitro, CF3、OCF3、OCHF2、CHF2、CHO、Br、Cl、F、CF3Hydroxy, (C)1-C3) Alkoxy (optionally substituted with CN), (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkanoyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl. In some preferred embodiments, the aforementioned heterocycles are heteroaryl. In some embodiments, R2Can be obtained by menstruationSubstituted or unsubstituted 9-10 membered heteroaryl, including 1 to 3 nitrogen atoms, or other 9-10 membered heterocyclic ring.
In some embodiments, R2May be a 5-6 membered aryl or heteroaryl group, which is directly substituted with a 5-6 membered aryl or heteroaryl group, or has an intervening heteroatom. In some specific embodiments, R2May be selected from any of the heterocyclic groups listed in the non-limiting general definitions set forth in the present patent specification, claims, examples or elsewhere in the patent specification.
In some embodiments, R2Can be phenyl, pyridyl, naphthyl, quinolyl, isoquinolyl, 4H-quinolizinyl, quinazolinyl, quinoxalinyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinyl, 1, 7-naphthyridinyl, 1, 8-naphthyridinyl, cinnolinyl, phthalazinyl, pyrido [2, 3-b ] yl]Pyrazinyl, pyrido [3, 4-b ]]Pyrazinyl, pyrido [3, 2-b ]]Pyrazinyl, pyrido [2, 3-d ]]Pyrimidinyl, pyrido [2, 3-c ]]Pyridazinyl, pyrido [3, 2-b1 pyridazine, benzimidazolyl, | -yl, humming | oxazolyl, 1H-benzotriazolyl, 1H-pyrrolo [3, 2-b ]]Pyridyl, pyrrolo [3, 2-c]Pyridyl, 1H-pyrrolo [2, 3-c]Pyridyl, 1H-pyrrolo [2, 3-bI pyridyl, 1H-imidazo [4, 5-b]Pyridyl group, 1H-imidazo [4, 5-c ] pyridyl group, 1H ═ I1, 2, 31 triazolo [4, 5-bjpyridyl group, 1H-I1, 2, monthly triazolo [4, 5-c1 helicyl group, pyrazolo [1, 5-a ] pyridyl group]Pyridyl, imidazo [2, 1-b1 oxazolyl, 3H-imidazo [4, 5 ═ b 1-pyridyl, imidazo [1, 5-a]Pyridyl, imidazo [1, 2, a ] pyridyl, pyrrolo [1, 2-a ]]Pyridyl, pyrrolo [1, 2-a ]]Pyrandinyl, pyrrolo [1, 2-c ] pyrimidinyl, pyrrolo [1, 2-b1 pyridazinyl, pyrrolo [1, 5-a ] pyrimidinyl, imidazo [1, 5-a ] pyrimidinyl]Pyrimidinyl, imidazo [1, 2 σ -pyrimidylbenzo [ d1 oxazolyl, benzo [ cI [1, 2, 5I oxadiazolyl, benzo [ d ] isoxazolyl, benzo [ d ] I1.3 ] dioxolyl, benzo [ d1 oxazolyl, benzo [ d ] isoxazolyl, 5-phenyl oxazolyl, ethylphenyl-1, 3, 4 ═ oxadiazolyl, 4-phenyl oxazolyl, 4-phenyl-1, 2, 3- oxadiazolyl, 5-phenyl oxazolyl, phenyl, 1,3, 4-oxadiazolyl, 5-phenyl-1, 2, 4-oxadiazolyl, fouphenyl-1, 2, 4-oxadiazolyl, 1-phenyl-1H-pyrazolyl, 4-phenyl-4H-vomit, 2, 4-triazolyl, 1-phenyl-1H-1, 2, 4-oxazolyl, 2- (1H-vomit, 2, 4-triazolin-yl) pyridyl, 2- (1H-pyrazol-L-yl) pyridyl, 1, 3-hydrobenzo-2, 2-keto-IcI -phene, benzo [ d ] [1, 3] dioxolene, 1H-oxo-2 (3H) -biacetone, phenoxyphenyl, 4-ketotetrahydro-oxazol-3-yl) phenyl, 2, 1, 3-benzo -oxadiazolyl-2, 2-oxide or 2- (4H-1, 2, 4-oxazol-4-yl) pyridyl. Such R2The groups may be substituted as discussed herein. For example, the substitution may be by 1 to2 (C)1-C3) Alkyl, CN, CHO, Cl, F, CF3Nitro, hydroxy, oxo, (C)1-C3) Alkanoyl, (C)2-C3) Alkenyl, (C)2-C3) Alkynyl or (C)1-C3) An alkoxy group. Other heterocycles may also be used. See, for example, US 5,747,467 (columns 2-4) or US 2004/0157787 (group Ar2 therein), which are fully incorporated herein by reference. R2Relative to the diradical2Any orientation of (i.e., to the ring atoms of the diradical mutual) may be used, even if not explicitly stated above or elsewhere herein. For example, 1, 8-pyrazinyl is a preferred group, which in some embodiments is attached at the 4-position, and which may be substituted, for example, at the 3-position (attached to an ortho position to the macrolide position).
Thus, the first subgenus (1) is a subgroup of formula I in which the diradical is1Is absent or > CH2(ii) a Mutual double radicals > CH (R)6) -C (O) O-, -c (O) N (R claim, -C (O) (CH)2Heart or-S (O)2(CH2)m-, where m is 0 to 2; diradical III is > C (O); shuangji king is > O; bis-depletion is > C (O) or > C (═ NOR)19) (ii) a Bis-basic is- (CH)2) x-, wherein x is an integer from 0 to 4; shuangji is bailodo H2) y-, wherein y is an integer of 0 to 4; and wherein the sum of x + y is 2 to 4; r1H, OH or methyl; each R11And R12Are independently H, (C)1-C6) Alkyl, (c3-c6) alkenyl or (c 3)-c6) alkynyl, any of which, with the exception of H, may be substituted by 1 to2 of the following groups: c1, F, OH, (C twenty-C3) alkoxy, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkyl, halogen-substituted (C1 ═ C3) alkyl, or (C)1-C3) Alkoxy 1-C3) alkyl; r13Is H; r19Is H or (C)1-C6) An alkyl group which may be interrupted by 1 to 3 oxygen atoms and which may be substituted by a 4-to 10-membered carbocyclic or heterocyclic ring; each direct stop is independently (a) a 9-9 0 membered heterocyclic ring, (b) a 9-10 membered carbocyclic ring, (c) a 4-6 membered heterocyclic ring, or (d) a4 ═ 6 membered carbocyclic ring, wherein (c) or (d) may be substituted with a 4-6 membered heterocyclic ring or a4 ═ 6 membered carbocyclic ring; and wherein the aforementioned a ㄈ ring system (i.e., monocyclic, fused ring, or unfused bicyclic system) may be substituted with 1 to2 (or 3) of the following groups: nitro, Br, Cl, F, hydroxy, (C)1-C6) Alkyl, CF3、oCF3、oCHF2、CHF2、cN、CHO、(C1-C6) Alkoxy (optionally substituted with CN), (C)1-C3) Alkoxy- (C twenty-C3) alkoxy, (C)1-C3) Alkoxy ≡ (C)1-C3) Alkyl, oxo, (C)1-C6) Alkanoyl, (C)2-C6) Alkenyl, (C2 pen 6) alkynyl, hydroxy-substituted (C)1-C6) Alkyl, -C (O) R11、-OC(O)R11、-C(O)OR11、-C(O)NR11R12、105743ㄩ&≡OC(O)NR11R12-、-NHc(o)R11、-NR11R12、-NR11SO2R12、＝SO2NR11R12 or-S (O) pR11Wherein p is 0 to 2. Or, R13May be a benzene (O) (C) as hereinbefore described1-C6Alkyl groups). Independently, a diradical3Alternatively > CHOC (O) R14、＞CHOC(O)NR14R15、＞CHOC(O)oR15And 14R of Choc (O) CH rogue15)((CRaRb)n±)、＞CHOC(O)CH(NR14R15)R14、＞CHOC(O)c(＝NoR14)((CRaRb) n denier), > CHOC (O) c(＝NoR14)R14、＞CHOC(O)(CRaRb) n denier), or:
the second subgenus (2) of formula I (meaning formula I, in its broadest sense herein) is a subgroup of formula I or subgenus 1 wherein diradical is > C (O); r3Is methyl; r5Is ethyl; and R is6Is H or (C1 ═ C5) alkyl, which may be substituted by oH or (C)1-C3) Alkoxy substitution. In some preferred aspects thereof, the diradicals in this subgenus can be > CH (R)6) (subgenus 2a), or may be > SO2(subgenus 2 b).
The third subgenus (3) of formula I is any of the subgenus 1 to2 of formula I or subgenus' wherein the diradicals1Is absent or methylene; r1Is H; and R is6(when present) is H or (C)1-C3) Alkyl groups, such as methyl.
The fourth subgenus (4) of formula I is any of the subgenus 1 to 3 of formula I or subgenus wherein diradical is- (CH)2) x-' wherein x is an integer from 0 to 3; bistatic radical is- (CH)2) y-, wherein y is an integer of 0 to 3; and wherein the sum of x + y is 2 to 3. The present invention also includes subgenera incorporating all of the limitations of both (3) and (4).
The fifth subgenus (5) of formula I is any of the subgenus 1 to 4 of formula I or subgenus, wherein diradical1Is absent; r2Is (a) a 9-to 10-membered heterocycle or carbocycle, or (b) a 4-to 6-membered heterocycle or carbocycle, wherein (b) may be substituted with a 4-to 6-membered heterocycle or carbocycle; r2May be substituted with 1 to2 of the following groups: SO (SO)2R11Hydroxy-substituted (C)1-C3) Alkyl, CN, nitro, CF3、OCF3、OCHF2、CHF2CHO, F, Cl, Br, hydroxy, alkoxy (optionally substituted with CN), alkoxy-alkoxy, oxo, (C1 ═ C3)Alkanoyl, (C)2-C6) Alkenyl or (C)2-C6) An alkynyl group; and R is6(when present) is Ho in some preferred embodiments thereof, R2Is a substituted or unsubstituted 9-10 membered heteroaryl group containing 1 to 3 nitrogen atoms. The present invention also includes subgenera incorporating all of the limitations of (3), (4), and (5).
The sixth subgenus (6) of formula I is any of the subgenus of formula I or subgenus 1 to 5, wherein both the biradical and the royal are methylene groups.
The seventh subgenus (7) of formula I is any of the subgenus 1 to 6 of formula I or subgenus, wherein R2Is (a) a 9-to 10-membered heterocycle, or (b) a 5-to 6-membered heterocycle or carbocycle, wherein (b) is substituted with an ancient type of spoon 6-membered heterocycle or carbocycle, and wherein R2May be substituted with 1 to2 of the following groups: -SO2R11Hydroxy-substituted alkyl, CN, CHO, Br, Cl, F, CF3、OCF3、CHF2、OCHF2Nitro, hydroxy, alkoxy (optionally substituted with CN), (C twenty-C3) alkoxy-alkoxy, oxo, alkanoyl, (C2 w 6) alkenyl or (C2 w 6)2-C6) Alkynyl. The present invention also includes subgenera that combine all of the limitations of both (6) and (7).
The eighth subgenus (8) of formula I is any of the subgenus 1 to 7 of formula I or subgenus, wherein R2Is a 9-10 membered heterocyclic ring, particularly heteroaryl, containing 1 to 3 heteroatoms independently selected from N, S or O. Or, R2May be a 5-6 membered aryl or heteroaryl group, which is substituted with a 5-6 membered aryl or heteroaryl group. R2May be substituted, for example, by 1 to2 of the following groups: SO (SO)2R11Hydroxy-substituted alkyl, CN, 105743CHO, Cl, F, CF3Nitro, hydroxy, (C twenty-C3) alkoxy- (C1, C3) alkoxy, oxo, alkanoyl, (C2, C6) alkenyl, (C1, C6) alkoxy2-C6) Alkynyl oR alkoxy, optionally substituted with CN2But can also be any helmet group specifically disclosed herein.
In some more specific embodiments, the diradical is1Is absent, is > CH2、＞CH(CH3) Or > SO2Mainly > C (O), +/-O, work > C (O), and both Li and Wang > CH2，R1Is H, R3Is methyl, R4Is H or F, R5Is ethyl, and R13Is H. In these and other embodiments, R2Any R which may be selected from the examples herein or otherwise2Groups such as those described and listed above.
The ninth subgenus (9) is of formula I or a subgroup of subgenus I, wherein the diradicals are > C (O), -C (O) N (R)6) -or-c (O) O ═ O; bistatic > C (O); r3Is methyl; r5Is ethyl; and R is6Is H or (C1-C5) alkyl. More specifically, in the above, the diradicals1May be absent or methyl; the bis-alkyl radical may be- (CH)2) x, wherein x is 0 to 3; the diradical z can be- (CH)2) y-, wherein y is 0 to 3; and wherein the sum of x + y is 2 to 3; and R is6May be H or methyl. R in the above2May also be (a) a 9-9 0 membered heterocyclic or carbocyclic ring, or (b) a 4-6 membered heterocyclic or carbocyclic ring, wherein (b) may be substituted with a 6-membered heterocyclic or carbocyclic ring; and R is2May be substituted with 1 to2 of the following groups: SO (SO)2Hydroxy-substituted alkyl, CN, CHO, Br, Cl, F, CF3、OCF3、OCHF2、CHF2Nitro, hydroxy, alkoxy (optionally substituted with CN), alkoxy-alkoxy, oxo, alkanoyl, (C2 pr 6) alkenyl or (C2 pr 6) aryl2-C6) Alkynyl.
The invention also includes compounds described by any subgroup of the variables defined in formula I and any subgenera thereof.
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl) - (1- ((quinolin-5-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.06)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((1H-benzoimidazol-7-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.11)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((quinolin-8-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.12)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((quinolin-8-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.16)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((1, 8-naphthyridin-4-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.20)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1S- (1, 8-naphthyridin-4-yl) -ethyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.23
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((pyrido [2, 3-b ] pyridin-8-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.24)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- (1R- (1, 8-naphthyridin-4-yl)) -ethyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.25)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- ((1, 5-naphthyridin-4-yl)) -methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.26)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((1, 6-naphthyridin-4-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.27)
3-Decladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- ((quinolin-6-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin A (example 1.28)
3-Decladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- ((indazol-3-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin A (example 1.29)
3-Decladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- ((isoquinolin-4-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin A (example 1.30)
3-descladinosyl-11, 12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1R- (1, 8-naphthyridin-4-yl) -ethyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.32)
3-descladinosyl-11, 12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((1, 8-naphthyridin-4-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.33)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((thiazolo [4, 5-b ] pyridin-7-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.35)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1R- (1, 5-naphthyridin-4-yl) -ethyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.37)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1S- (1, 5-naphthyridin-4-yl) -ethyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.38)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- (quinolin-4-yl) -propyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.61
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- (quinolin-4-yl) -ethyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.62)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- (quinolin-4-yl) -ethyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.63
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- (quinolin-4-yl) -butyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.64)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- (quinolin-4-yl) -propyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.65
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (phenyl- (pyridin-4-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.69)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8-methoxyquinolin-5-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.70)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-methoxyquinolin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.71
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-methoxy-1, 8-naphthyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.72)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (quinoline-3-carbonitrile-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.73)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (7-bromopyrido [3, 2-b ] pyridin-8-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.74)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-bromo-1, 8-naphthyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.75)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-chloro-1, 8-naphthyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.76)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-bromopyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.77
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-fluoropyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.78)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-chloropyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.79)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((S) -1, 8-naphthyridin-4- (2-methoxyethyl-1-yl)) -azetidin-3-yl) -imino) -erythromycin a. (example 1.80)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((R) -1, 8-naphthyridin-4- (2-methoxyethyl-1-yl)) -azetidin-3-yl) -imino) -erythromycin a. (example 1.81)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4H-quinoiin-4-one-1-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.82)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (H-pyrazolo [1, 5-a ] pyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.83)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8-methoxyquinolin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.84)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1-fluoro-3-methoxybenz-2-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.85)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2-methoxynaphthalene-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.86
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1, 3-difluorophenyl-2-methyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.87
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2- (trifluoromethoxy) benzene-1-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.88)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2-cyclopropyl-3H-imidazo [4, 5-b ] pyridin-7-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.89)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (6-methoxyquinolin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.90)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (naphthalene-1-methyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.91
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2-methylnaphthalene-1-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.92)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-methyl-3H-imidazo [4, 5-b ] pyridin-7-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.93)
3-Decladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1J-indene-2 (3H) -sulfone-5-methyl-azetidin-3-yl) -imino) -erythromycin A. (example 1.94)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (quinoline-8-carbonitrile-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.95
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (quinoline-8-carbonitrile-5-methyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.96
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2-ethoxynaphthalene-1-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.97)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-methylquinolin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.98)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-methyl-1, 8-naphthyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.99)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (6-chloro-3H-imidazo [4, 5-b ] pyridin-7-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.100)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-methoxy-1, 5-naphthyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.101
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (6-methoxyquinolin-5-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.102)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2, 4-dichlorobenzene-1-methyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.103
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (benzo [ d ] [1, 3] dioxol-5-methyl) -azetidin-3-yl) -imino) -erythromycin A. (example 1.104)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (5-methoxyquinoxaline-8-methyl) -azetidin-3-yl) -imino) -erythromycin A. Example 1.105
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-bromo-1, 5-naphthyl-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.106)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-chloroquinolin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. Example 1.107
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-ethoxy-1, 8-naphthyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a. (example 1.108)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (pyridine-3-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.01)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (naphthalene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.02)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (quinoline-8-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.03)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (isoquinoline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.04)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (benzo [1, 2, 5] thiadiazole-4-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.06)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-cyanobenzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.10)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4-cyanobenzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.11)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (xazol-5-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.13)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (H-imidazo [1, 2-a ] pyridine-3-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.15)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (6- (1H-pyridin-1-yl) pyridine-3-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.16)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (imidazo [1, 2-a ] pyrimidine-3-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.17)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (-1 (2-cyanobenzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.18)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (H-imidazo [1, 5-a ] pyridine-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.19)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (2, 3, 4, 5-tetrahydro-3, 5-diketo-1, 2, 4-tria-lin-6-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.20)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2, 3-dihydro-2-ketobenzo [ d ] oxazole-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.22)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3, 5-dimethyl-1H-pyrazole-4-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.29)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (2, 4-dimethoxybenzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.31)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (5- (isoxazol-3-yl) thiophene-2-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.33)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (xazol-5-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.35)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (1H-pyrazol-3-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.36)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (1H-pyrazol-5-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.39)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (3-methylisoxazol-5-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.40)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (1, 2, 4-oxadiazol-3-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.41)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2-ketoindolin-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.41)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2-ketoindolin-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.41)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2, 3-dihydro-2-ketobenzo [ d ] oxazole-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.43)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (1H-pyrazol-1-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.44)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (1, 2, 3-thiadiazol-4-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.45)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (5-cyanonaphthalene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.49)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-cyano-4- (1H-pyrazol-1-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.50)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (2-methyl-2H-tetrazol-5-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.51)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (1H-1, 2, 4-triazol-1-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.52)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (6-methylbenzo [ d ] thiazol-2-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.54)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (2H-1, 2, 3-triazol-2-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.55)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (1, 3, 4-oxadiazol-2-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.56)
3-Decaclinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (3H-benzo [ d ] [1, 2, 3] triazole-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin A (example 3.57)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (1H-pyrazol-1-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.58)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (5-methyl-1, 3, 4-oxadiazol-2-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.60)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (5-methyl-1, 3, 4-oxadiazol-2-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.61)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (1, 3, 4-oxadiazol-2-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.62)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (1, 2, 3-thiadiazol-4-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.63)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (xazol-2-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.65)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (pyridzin-3-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.72)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (1, 3, 4-thiadiazol-2-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.76)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-fluoro-4-fluorosulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.77)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (benzo [ d ] thiazole-6-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.79)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (5- (1H-pyrazol-1-yl) pyridine-3-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.80)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-fluoro-4- (1H-imidazol-1-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.81)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (1H-imidazol-1-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.82)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1H-imidazole-6-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.85)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-fluoro-4- (1H-pyrazol-1-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.86)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1H-indazole-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.87)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4-fluoro-3- (oxazol-5-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.88)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (quinoline-6-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.89)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2-methylbenzo [ d ] thiazole-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.90)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (naphthalene-2-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.91)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (theelin-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.92)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (quinoxaline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin A. (example 3.93)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1-methyl-1H-indazole-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.94)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1, 3-dihydrobenzo-2, 2-diketo [ c ] thiophene-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.95)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (2-methyl-2H-indazole-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.96)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (6-chloroimidazo [2, 1-b ] thiazole-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.97)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (quinoxaline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin A. (example 3.98)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-cyano-4-ethoxybenzene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.99)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (quinoline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.100)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8-methoxyquinoline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.101)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8-ethoxyquinoline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.102)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-cyano-4-ethoxybenzene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. Example 3.103
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (benzo [ d ] isothiazol-6-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.104)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4-ethoxy-3-methoxybenzene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.105)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (5-chloro-2-methoxybenzene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.106)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-chlorobenzene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.107)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4-acetamidobenzene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. Example 3.108
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (cyanomethoxy) -4-methoxybenzene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.109)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (4-fluorophenoxy) benzene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.110)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8-methylquinoline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. Example 3.111
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8-methoxyquinoxaline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin A. Example 3.112
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8- (difluoromethoxy) quinoline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. Example 3.113
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8-methylquinoxaline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin A. Example 3.114
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (2-ketotetrahydro-oxazol-3-yl) benzene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. (example 3.115)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1, 3-dimethyl-2, 1, 3-benzothiadiazole-2, 2-dioxide 0-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. Example 3.116
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-ethyl-1-methyl-1H-indazole-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a. Example 3.117
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (benzhydryl) - (azetidin-3-yl) -methyl) -imino) -erythromycin a. (example 4.01)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((quinolin-6-yl) -methyl) - (azetidin-3-yl) -methyl) -imino) -erythromycin a. (example 4.14)
3-Decladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((1H-pyrrolo [2, 3-b ] pyridin-3-yl-methyl) - (azetidin-3-yl) -methyl) -imino) -erythromycin A. (example 4.18)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((6-methyl-1H-benzo [ d ] imidazol-7-yl) -methyl) - (azetidin-3-yl) -methyl) -imino) -erythromycin a. (example 4.44)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-12, 11- (oxycarbonyl- (1- ((1H-pyrrolo [2, 3-b ] pyridin-3-yl) -methyl) - (azetidin-3-yl) -methyl) -imino) -3- ((2-methyltetrahydropyrrole) -1-carbonyl) -erythromycin a. (example 5.03)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-12, 11- (oxycarbonyl- (1- ((quinolin-8-yl) -methyl) - (azetidin-3-yl) -methyl) -imino) -3- ((2-methyltetrahydropyrrole) -1-carbonyl) -erythromycin a. (example 5.04)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-12, 11- (oxycarbonyl- (1- ((1H-pyrrolo [2, 3-b ] pyridin-3-yl) -methyl) - (azetidin-3-yl) -methyl) -imino) -3- ((2- (3-fluorophenyl) tetrahydropyrrole) -1-carbonyl) -erythromycin a. (example 5.05)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-12, 11- (oxycarbonyl- (1- ((1H-pyrrolo [2, 3-b ] pyridin-3-yl) -methyl) - (azetidin-3-yl) -methyl) -imino) -3- ((2- (3-fluorophenyl) tetrahydropyrrole) -1-carbonyl) -erythromycin a. (example 5.06)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-12, 11- (oxycarbonyl- (1- ((1H-pyrrolo [2, 3-b ] pyridin-3-yl) -methyl) - (azetidin-3-yl) -methyl) -imino) -3- (tetrahydropyrrole-1-carbonyl) -erythromycin a. (example 5.10)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((quinolin-5-yl) -methyl) - (R) -tetrahydropyrol-3-yl) -imino) -3- ((2- (3-fluorophenyl) tetrahydropyrrole) -1-carbonyl) -erythromycin a. (example 9.02)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((1H-pyrrolo [2, 3-b ] pyridin-3-yl) -methyl) - (R) -tetrahydropyrol-3-yl) -imino) -erythromycin a. (example 9.03)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((1, 8-naphthyridin-4-yl) -methyl) - (R) -tetrahydropyrrol-3-yl) -imino) -erythromycin a. (example 9.05)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((1H-benzo [ d ] imidazol-4-yl) -methyl) - (R) -tetrahydropyrrole-3-yl) -imino) -erythromycin a. (example 9.06)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((isoquinolin-5-yl) -methyl) - (R) -tetrahydropyrrole-3-yl) -imino) -erythromycin A. (example 9.07)
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((1H-indazol-3-yl) -methyl) - (R) -tetrahydropyrrol-3-yl) -imino) -erythromycin a. (example 9.09)
3-descladinosyl-11, 12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1H-benzo [ d ] imidazole-2-carboxy) - ((R) -tetrahydropyrrole-2-yl) -methyl) -imino) -erythromycin a. (example 10.27)
3-descladinosyl-11, 12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((quinolin-8-yl) -methyl) - ((S) -tetrahydropyrrole-3-yl) -methyl) -iminine) -erythromycin a. (example 11.02)
3-descladinosyl-11, 12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((1H-pyrrolo [2, 3-b ] pyridin-3-yl) -methyl) - ((S) -tetrahydropyrrole-3-yl) -methyl) -iminine) -erythromycin a. (example 11.05)
3-descladinosyl-11, 12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((quinolin-4-yl) -methyl) - ((S) -tetrahydropyrrole-3-yl) -methyl) -iminine) -erythromycin a. (example 11.11)
Other embodiments include the examples herein, and compounds within the scope of this document. Of note are compounds having an in vitro MIC against streptococcus pyogenes (s.pyo.) which is resistant to clarithromycin (clarithomycin) by, for example, em1B mechanism (e.g., streptococcus pyogenes 1079), and/or compounds having an in vitro MIC against streptococcus pneumoniae (s.pneumo.) which is resistant to clarithromycin by, for example, efflux mechanism, of about 0.5 μ g/ml or less. Embodiments are provided.
The present invention is not limited to the erythromycin modifications referred to above. For example, US2003/0100518 (e.g., page 1) may be used; US 6,472,371 (e.g. column 1); US 6J40,479 (e.g. column 2); US 6,043,226 (e.g. column 4); and c-3 modifications as referred to in US2002/0H5621 (e.g. page 1); the C-5 modification referred to in US2003/0100518 (e.g., page 4) can be used; US 2003/0100742 (e.g. page 3) may be used; US2003/0100518 (e.g. page 4); US 105743 brick entr 6,075,133 (e.g. day 4 cun); and C-6 modifications as referred to in US2002/0H5621 (e.g. page 2); the C8 modifier referred to in US2003/0100518 (e.g., page 1) may be used; US4,474,768; US4,517,359; and C-9 modifications as referred to in US2003/0100518 (e.g. page 1); US 2003/0013665 (e.g. pages 12-14) may be used; modified C 2 as described in WO 03/004509; US2003/0100518 (e.g. page 5) may be used; and C-13 modifications as referred to in US 2003/0013665 (e.g. page 2). The aforementioned documents also refer to methods for preparing the analogs. These partners are fully incorporated herein by reference.
The present invention includes intermediates. For example, the invention includes those wherein B R2Compounds which are H or a protecting group (e.g. water B), for example 3-decladinosyl-H, 12-dideoxy ≡ 6-O angina-3-oxo-12, 11- (oxycarbonyl- (azetidin-3-yl) ≡ imino) -erythromycin a or 3-decladinosyl-H, 12-dideoxy-6-O ═ methyl O ═ keto-12, 11 ═ oxycarbonyl- ((1 ═ benzyl) azetidin-3-yl) -imino) -erythromycin Ao the invention also includes ethyl R2Precursors thereof, such as 1- [1, 8 ] base Tomethanol or ㄩ 1, 81 naphthyridinyl-4-methyl ethyl ketone. General preparation method
The compounds of the present invention can be prepared according to the description, drawings and embodiments herein, which are non-limiting and are within the knowledge of the skilled artisan.
Erythromycin and clarithromycin compounds, many of which are known in the art and are commercially available, may be suitable starting materials for preparing the compounds of the present invention. See, for example, US2,653,899; 2,823,203, respectively; and 4,331,803. These documents are fully incorporated herein by reference.
Known fermentation methods can be used to introduce various C-13 modifiers (formula I, R)5). For example, US2003/0100518 describes the preparation of such compounds, at page 105743-2 b 27, and references such as US 6,437,151 and WO 99 stop 5157. See also US 6,472,371 at columns 25-32. All of the above documents are fully incorporated herein by reference.
Known methods can be used to locate (formula I, R) at C63) Variants were introduced. For example, US 6,075,133, columns 55-58, describes alkylation on C ═ 6. The above documents are fully incorporated herein by reference. For some transformations, proper functional group protection and deprotection may be required.
and 4' (formula I, RI3 and R) can be protected by known methods16)。R13And R16The groups may be incorporated by reacting a compound of the formula n (scheme I), wherein R13And R16Is hydrogen, with a radical containing R13The anhydride or chloride of the group is reacted in a solvent such as DCM, THF or toluene in the presence of a base such as TEA and in the presence of an activator or catalyst such as DMAP at about room temperature for about 2 to 24 hours. If 2 equivalents of anhydride or acyl chloride are used, R13Will be installed at R13(c-lacquer and R)16(c-4 n). If 1 equivalent is used, only the radicals R are present13Will be installed. The group R can then be installed (at c-4n) in a subsequent step16Thus making a difference between R13And R16. Can makeWith various protecting groups (R)13And R16) Such as those described in Greene et al, infra, including known acyl, carbamoyl, and silyl protecting groups, and the like, which can be introduced by known methods. In some preferred embodiments, the protecting agent is acetic anhydride. Other embodiments of hydroxy protecting groups include methylthiomethyl, TMS, TBDMS, TBDP, ethers such as methoxymethyl, and esters including Ac, Bz, and the like. Examples of aprotic solvents include DCM, chloroform, DMF, THF, NMP, DMSO, Diethylidene, N ═ dimethylacetamide, hexamethylphosphoric triamide, with or without any mixture of the following solvents: ether, THF, 1, 2-dimethoxyethane, 105743 ● 44 ● MeCN, EtOAc, acetone, or the like. Other modifications are known in the literature and are known to the ordinarily skilled artisan.
The compounds may be further modified, for example, as depicted in figures 1 to 3, to obtain I anal VH, XVI and XVII compounds, i.e. compounds wherein diradicals ± are > c (O), ± ∞ O ═ and 5 is-c (O) -.
Scheme 1
Scheme 1 illustrates the preparation of compounds of formula nLVn. Formula IH can be prepared as in step 1a via formula II (wherein R is13And R16Is not hydrogen, and R13And R16The group does not contain unprotected primary alcohols or primary or secondary amines) with about 3 to 5 equivalents of CDI. See, e.g., j. org. chem., 53, 2340(1988), which is incorporated herein by reference in its entirety. The reaction may be carried out in an aprotic solvent, such as MeCN, THF, IPE, DMF or mixtures thereofAbout 2 to 5 equivalents of base, such as DBU, in the presence of about 25 to 40. C, for about 2 to 12 hours.
The compound of formula IV can be prepared from its corresponding compound of formula III according to step 1b by reaction with the primary amine of the desired N-H side chain in a solvent, such as MeCN or DMF, in the presence of a base, such as TEA or DBU, at about 40 to 80 ℃ for about 12 to 72 hours. The group P in formula IV represents a suitable protecting group, or may represent a helmet group, or2As defined herein for formula I.
The cladinose moiety of formula IV may then be removed as in step 1c by reacting with an acid, such as HCl, for example in a binary solvent mixture comprising water and an alcohol (such as EtOH) at about room temperature to 45 deg.C, preferably about room temperature to 40 deg.C, for about 6 to 24 hours, thereby obtaining representative acids of formula Vo including dilute HCl, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid or trifluoroacetic acid. Suitable solvents for the reaction include MeOH, EtOH, IPA, butanol, or the like, and mixtures thereof.
Step 1d illustrates oxidation of the C-3 hydroxyl group to the keto group to obtain formula VIo, which can be achieved using, for example, a modified Swem oxidation. For example, a compound of formula VI can be reacted with EDC and pyriproxyfen trifluoroacetate in a solvent, such as DCM, at about room temperature to 50 ℃ for about 6 to 24 hours.
When P is a protecting group, deprotection of formula VI and introduction of the desired substituent can be achieved by hydrogenation. For compounds of formula VI, wherein P represents a protecting group, such as bwe, Bn or CBZ, this group can be removed by reaction with hydrogen at about 1 to 4 atmospheres in the presence of a catalyst, such as palladium on carbon or palladium hydroxide on carbon, in a solvent, such as MeOH, EtOH, EtOAc or THF, at about 25 to 60 ℃ for about 4 to 24 hours. In the case where the group P is a protecting group, such as BOC, this group may be removed by reaction with TFA in a solvent, such as DCM, at about 0 to 25 ℃ for about 0.5 hour, or may be removed by reaction with an acid, such as HCl, in a solvent mixture, e.g., containing water and MeOH, EtOH or THF, at about 25 to 50 ℃ for about 1 to 6 hours.
R of structure once the protecting group is removed2The novel groups can be incorporated into compounds of formula VI, for example in one of the following ways: 1) in a diradical mutual being-C (O) (CH)2) In the case of n-, contains a group (CH)2)nR2The carboxylic acid may be reacted in the presence of a carbodiimide, such as EDC, in the presence of an activator, such as HOBT and/or DMAP, in a solvent, such as DCM, Dmm, THF or MeCN, at about 25 to 40 ℃ for about 2 to 20 hours. Or, contain the radical R2The acid chloride can be coupled in 105743 ● 4 kernel solvent such as DCM, THF or MeCN in the presence of a base such as TEA, DIEA, NaHCO3 or potassium carbonate at about 0 to 40 ℃ for about 1 to 8 hours; 2) in the double radicals each other as-SO2(CH2) w or-SO2N (in the case of R plateau, contains a group (CH)2)mR2Or N (R)6)R2The chlorinated sulfonyl or chlorinated amidosulfonyl group can be reacted in the presence of a base, such as TEA, DIEA, NaHCO3, or potassium carbonate, in a solvent, such as DCM, DMF, THF, or MeCN, at about 25 to 40 ℃ for about 30 minutes to 4 hours; 3) in the diradical is- (C (R)6)(R7) N-contains the group R2The aldehyde or containing R6-C(O)-(C(R6)(R7) N-ketones can be reacted in an analogous manner in the presence of a base in a solvent, such as MeOH, EtOH, DCM or THF, in some cases with the addition of 4A molecular sieves, at about 25 to 60 ℃ for about 2 to 18 hours to form their corresponding imines, which can then be further reacted with a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, at about 25 to 40. Reacting for about 4 to 24 hours under C; 4) in the diradical is- (C (R)6)(R7) N-in the case of n-, contains a group- (C (R)6)(R7))n-R2The halide or sulfonate ester of (a) can be reacted in the presence of a base at about 25 to 150 ℃ in a solvent such as DCM, THF or MeCN for about 0.1 to 12 hours; 5) on a diradical basis is C (O) N (R)6) In the case of containing a group R2Of the isocyanate or the structure ClC (O) N (R)2)(R6) The carbamyl chloride may be in the presence of a base, such as TEA, DIEA, NaHCO3 or potassium carbonate, in a solventSuch as DCM, DMF, THF or MeCN, at about 25 to 60 deg.C for about 2 to 8 hours; and 6) in the diradical are each other C (O) O (CH)2) n is a group (CH)2) The chloroformate of RauP 2 can be reacted in the presence of a base, such as TEA, DIEA, NaHCO3, or potassium carbonate, in a solvent, such as DCM, THF, or MeCN, at about 25 to 40 ℃ for about 30 minutes to 4 hours, thereby completing the group, EtR2Are transformed into each other. (R for introduction)2Preparation of reagents to macrolides is discussed at 105743 8-below).
Formula VII may be prepared according to step 1e by first generating the anion/enolate on c-2 carbon by reacting VI with a base such as sodium hydride, lithium diisopropylamine or lithium hexamethyldisilazide in a solvent such as DMF at about-50 to-30 deg.C for about 10 to 30 minutes. The anion can then be reacted with a variety of electrophiles, including electropositive fluorinating agents, such as Selectnuor @ (sold by air products and chemicals). Radical R4Incorporated in this way, R of the radicals which can be mentioned in step 1d2Before or after the interconversion, but, in some cases, may be limited by the group YR2For R just mentioned4Compatibility of mounting conditions. For this chemistry, the group R13And cannot be hydrogen. In the last step, with respect to the non-hydrogen R, whether VI or VII13The group can be removed (replaced with hydrogen) as is known in the art by reaction in a solvent, such as MeOH, at about 25 to 60 ℃ for about 6 to 24 hours to remove the acyl, or p-silyl, group, which is the TBAF o group R in THF13Or R16Can be removed in a similar manner from any of the last compounds of the invention.
Scheme 2
Alternatively, compounds of formula VI, wherein > C (O), Wang is, O-, and 5 is-C (O) -, can be prepared as outlined in scheme 2. In step 2a, formula II can be converted to the cyclic carbonate VIH by treatment with a phosgene equivalent, such as CDI, disuccinyl carbonate or ethylene carbonate, in a solvent, such as DCM, MeCN, benzene, toluene or mixtures thereof, in the presence of a base, such as TEA, DIEA, NaHCO3 or potassium carbonate, under anhydrous conditions at about 25 to 50 ℃ for about 2 to 20 hours.
The cladinose moiety may be removed as in step 2b, whether by mild aqueous acid hydrolysis, or by enzymatic hydrolysis, as described in step 1c, to give formula IX.
Step 2c illustrates oxidation of formula IX to X using a modified Swem oxidation procedure, as discussed above with respect to scheme 1. Alternatively, the reaction may be carried out by reacting IX and the complex formed between N-chlorosuccinamide and sulfurized dimethane in a solvent, such as DCM, at about-20 to 0. C for about 1 hour, followed by at least about 2 equivalents of a base, such as TEA, in about-20 to 0. Reaction at C for about 1 hour, followed by about 25. A further reaction time of about 1 hour at C.
Formula xI can be prepared according to step 2d by treatment under anhydrous conditions by reaction with CDI in the presence of a base, such as DBU, in a solvent, such as DCM or DMF, at about 25 to 40 ℃ for about 24 to 48 hours. The conversion can also be carried out stepwise by first reacting a compound of formula X with about 1 to 3 equivalents of a base, such as DBU, in a solvent, such as benzene or toluene, in about 40 to 80. And C, treating for about 4 to 24 hours. The allyl alcohol formed may then be treated with a base, such as sodium hydride, in a solvent, such as THF or DMF, at about-40 to 0 deg.C for about 10 to 30 minutes. The anion produced can then be reacted with CDI to produce its corresponding compound of formula XI.
Formula VI can be obtained as step 2e by treatment with the desired primary amine, in the general manner shown in scheme 1. When P is a protecting group, it may be substituted with the desired substituent, as depicted in scheme 1. Again, formula VI may be halogenated, etc., as discussed above with respect to scheme 1.
FIG. 3 is a drawing
The compounds of the invention, wherein the diradicals3Is that the ratio of > C (O),4is a group N-R10And 5 is-C (O) -, can be prepared according to scheme 3, starting from formula xI. Similar methods are cited in US 2003/0013665 (pages 7-14) and US 2002/0052328 (page 5), which are fully incorporated herein by reference.
Ketene acetal XH can be prepared in step 3a by treating XI with a base, such as DBU, 1, 5-diazabicyclo [4.3.01 non-5-ene, DIEA, TEA, lithium hexamethyldisilazide or potassium hexamethyldisilazide, preferably DBU, in the presence of a polar aprotic solvent, such as MeCN, DMF or THF, preferably MeCN. The reaction may be stirred at about 20 to 100 deg.C, preferably about 60 to 80 deg.C, for about 30 minutes to 3 hours.
The azide XIII can be prepared according to step 3b using about 3 equivalents of an azide reagent, such as trimethylsilane azide, sodium azide or tributyltin azide, preferably trimethylsilane azide, in the presence of a lewis acid, such as tin tetrachloride, titanium (IV) chloride, boron trifluoride etherate or aluminum trichloride, preferably tin tetrachloride, and an aprotic solvent. Suitable solvents include DCM, dichloroethane, chloroform or carbon tetrachloride, preferably DCM. The reaction may be at about-80 deg.f. c and warmed to about 25 ℃ and then reacted for about 4 to 24 hours.
The reduction of formula XIII to obtain formula xIv according to step 3c may be achieved by treating a reduced metal, such as zinc, in an acid, such as acetic acid, at about room temperature for about 30 minutes to2 hours. The amines XIV can be converted into their corresponding isocyanates by treatment with phosgene or triphosgene in the presence of a base such as TEA or pyridine and an aprotic solvent such as THF or dioxane. The reaction may be between about 0 and 50. C, preferably at about 0 deg.C for about 0.5 to 12 hours, preferably about 30 minutes.
The isocyanate may be converted to ring xv in step 3d by reacting with the desired primary amine in the presence of an aprotic solvent such as THF, hexamethylenedioxyne or DMF to form the linear gonad. The reaction may be carried out at about 0 to 100 deg.C, preferably about 25 deg.C, for about 0.5 to 12 hours, preferably about 6 hours. The resulting product may then be dissolved in a solvent, such as toluene, in the presence of a base, such as potassium hydroxide, in a range of about 60 to 80 deg.f. Heating at C for about 10 to 30 minutes to form the corresponding ring pulse Xv. The reaction may be carried out at about 25 to 100 deg.C, preferably about 80 deg.C 105743-53 ●, for about 0.5 to 12 hours, preferably about 3 hours.
At R10In the case where the compound is other than H, the compound may be treated with a strong base, such as KHMDS, at about-10 to 25 deg.C, in a solvent, such as THF, for about 1 to 4 hours, in the presence of, for example, an alkyl or allyl halide, e.g., about at least 1 equivalent of R10L, where L is a suitable leaving group, such as halogen, or alternatively, methane sulfonate or toluene sulfonate, under the time and temperature conditions indicated above.
R of the compound of formula XV in which the group P is a protecting group2The interconversion of the groups can be achieved in the same manner as in scheme 1. Radical R4The incorporation thereof (according to step 3e) to form the compound of formula XVI can be carried out in a similar manner to that described in scheme 1.
FIG. 4 is a drawing
The compounds of the invention, wherein the diradicals3Is > C (O), + -O-or-N (R)10) -, and 5 is not-C (O) -, can be made according to scheme 4. A starting compound of formula vI or xv can be 105743
According to step 4a, the structure R is used as the free base or as the hydrochloride19-O-NH2The hydroxylamine of (a) is treated in the presence of a base, such as TEA, in a solvent, such as DCM or THF, at about room temperature for about 4 to 24 hours, thus providing formula XVII. At R19In the case of H, a compound of formula XVH wherein R19Not hydrogen, via the corresponding radical R19The compound which is hydrogen is reacted with an alkyl halide or substituted alkyl halide in a solvent such as DCM, MeCN or DMF in the presence of a base such as TEA, DIEA or NaHCO3 at about 25 to 60 ℃ for about 1 to 24 hours.
R at XVH19In the case of H, the compound of formula XVIH may then be prepared according to step 4b by reacting XVn with a reducing agent, such as TiCl3, in a solvent, such as MeOH or EtOH, at about room temperature for about 4 to 24 hours.
The compound of formula XIX can be prepared as described in step 4c, via XVIII, e.g., as described in US 2004/0171818, which is fully incorporated herein by reference, in DCM, in the presence of TEA, and using a compound containing the desired R19Acylating agent of the group.
The compound of formula Xx may be prepared according to step 4d by reacting with a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in a solvent, such as water, MeOH, EtOH or mixtures thereof, at about room temperature for about 12 to 24 hours.
Compounds of formula XXI can be prepared according to step 4e by reductive amination using compounds containing R8A radical aldehyde, such as described in j.med.chem., 33, 3086(1990), which is fully incorporated herein by reference. Alternatively, direct alkylation may be employed. At R8And R9In the case where both are non-hydrogen, successive reductive amination can be carried out on a compound of formula XX using a catalyst containing a group R8And R9The aldehydes are used as the starting materials. XXI may be fluorinated. According to the art-generic technique, C-9 is modifiedSubstances (bi-basic as in formula I at 105743 ● 5) are typical for compounds of formula I. See also EP0345627 and WO02 store 7286, which are also fully incorporated herein by reference.
FIG. 5 is a schematic representation of
Compounds of the invention wherein diradical three is > C (O), + -O-or-N (R)10) -, and 5 is-C (O) NR19-or-N (R)19) C (O) can be made as shown in FIG. 5 and is described, for example, in US 6,262,030, which is fully incorporated herein by reference.
Compounds in which the diradical is other than > C (O) can be prepared according to scheme 6. Similar transformations are known, for example, as described in Jp2001-72669, which is fully incorporated herein by reference.
The compounds of formula V or corresponding intermediate systems are modified, for example, C-9 (diradical) as disclosed herein or as known in the art, with the desired carboxylic acid in the presence of a carbodiimide, such as EDC, in the presence of an activator, such as HOBT or DMAP, in a solvent, such as DcM, at about 25 to 40. c for about 8 to 48 hours, thereby forming a compound of formula xxIv (wherein the diradical is not > c (o) or > CHOC (O)) N (R)14)R15) This transition may only be in which R is present per step 6a o13On a compound of formula V other than hydrogen. In the case where the group p is a protecting group, R of the group2The interconversion can be achieved in the same manner as described in scheme 1. At this time, the protecting group R13May then be removed in a manner similar to that described in figure 1.
A compound of formula XXV may be formed according to step 6b by reacting with about 1 to 3 equivalents of bis-succinimidyl carbonate, such as MeCN, in the presence of a base, such as TEA or DIEA, at about room temperature for about 2 to 8 hours. This transition may only be in which R13On compounds other than hydrogen。
FIG. 6 is a schematic representation of
A compound of formula XXVI can then be prepared according to step 6c by reaction with a compound of structure HNR14The amine of R15 is reacted in a solvent such as DCM, THF, DMF or MeCN in the presence of a base such as TEA or DIEA at about room temperature for about 30 minutes to 4 hours. In the case where the group P is a protecting group, R2The interconversion of the groups can be achieved in the same manner as described in scheme 1. At this time, the protecting group R13Can be removed as described in figure 1. See also US2003/0100518 (e.g. page 1); US 6,472,371 (example girl column 1); US 6,140,479 (e.g. column 2); US 6,043,226 (e.g. column 4); and US2002/0H5621 (e.g. page 1), which is fully incorporated herein by reference.
R for bridging N-H to a group of the formula I2The group (cyclo-field) of (A) can be derived from any differentially protected diamine and can be incorporated into the macrocyclic lactones as shown in FIGS. 1-6 for purposes of illustration, the preparation of some differentially protected tethered groups is described in FIG. 9, alternatively, tethered and helmet groups, ethylene R2Can be made as a single unit and incorporated into the macrolide as such, as also shown in FIGS. 1-6.
FIG. 7 is a drawing
FIG. 8 is a schematic representation of
FIG. 9 of the drawings
FIG. 7 illustrates the preparation of certain tethered groups containing azetidine moieties, wherein R1Is H or alkyl. Methanesulfonic acid 1 ═ benzyl, azetidinyl (compound 1 of scheme 7, wherein R is phenyl or naphthyl)1Is H) is known in the art and is commercially available from Oakwood products. Compound 1 can be converted to its corresponding azide in step 7a by dissolving in a suitable polar organic solvent, preferably DMF, adding sodium azide in excess and heating the resulting mixture to 60-100 ℃, preferably about 80 ℃, for about 12 to 24 hours. After aqueous treatment, the crude azide product may then be treated with an excess of triphenylphosphine and refluxed in a solvent such as THF for about 3-10 hours. This mixture can be heated to about 50 to 70 by adding NH 40H. C, hydrolysis for about 12-24 hours to yield compound 2.
Compound 3, wherein R1For H or alkyl, can be prepared as in step 7b by cyanide displacement of the methanesulfonate ester followed by lithium aluminum hydride reduction, for example using the method of Frigola J. et al, J.Med.chem, 36(7), 801(1993), which is fully incorporated herein by reference.
FIG. 8 illustrates the preparation of certain other tethered groups containing azetidine moieties, wherein R1The starting ketones 4 are known and commercially available as OH or Fo. The compound 5 can be prepared in step 8a by reacting 4 with potassium cyanide in the presence of sodium bisulfite in a solvent such as hexamethylenene, THF or EtOAc or combinations thereof, in the range of about 0 to 25. And C, reacting for about 24 to 48 hours. See also WO 04/94407, which is fully incorporated herein by reference.
The reduction of compound 5 to amine 6 can be performed as in step 8b by reacting with an excess of about 2 equivalents of lithium aluminum hydride in a solvent, such as THF, at about 0 to 25 ℃ for about 4 to 6 hours.
Compound 7 can be prepared according to step 8c by reacting compound 5 with DAST, by the method of Stelzer et al, Tetrahedron Asymmet, 4, 161(1993), which is fully incorporated herein by reference. The reduction of compound 7 to amine 8 can be carried out as described in step 8d, in a manner analogous to that described in step 8 b.
The preparation of tethered intermediates H and 14 can be carried out as outlined in FIG. 9. From compound 9, wherein n is 1 to 3, the epoxidation to form its corresponding compound 10 can be achieved by reaction with trimethylsulfonium iodide in the presence of a strong base, such as sodium hydride, in a solvent, such as DMF, DCM or DMso, preferably DMF, at about room temperature for about 8 to 18 hours.
The corresponding compound H can be prepared according to step 9b by reaction with NH40H at about 25 to 80 ℃ for about 1 to 6 hours. Compound 15 can be prepared from 9 according to step 9c ═ e in a manner analogous to scheme 8.
Helmet group reagents (i.e., R used to form formula I, formula II) to react with the cyclic amine (formula I ) nitrogen of the macrocyclic lactone template for use in embodiments 1057432Or scheme 1, reagents for group P), are commercially available, are known in the art, are within the ordinary skill of the art in view of this patent specification, or are described or enabled to be obtained by scheme 10 and preparations 9 to 26 herein.
The chlorinated sulphonyl compounds used for preparing sulphonamides can be prepared in different ways. The aromatic or heteroaromatic system may be reacted with an excess of chlorosulfonic acid in a solvent, such as chloroform, at about 50 to 80 ℃ for about 12 to 48 hours. After concentration, the intermediate sulfonic acid can be converted to its corresponding chlorinated sulfonyl group by treatment with phosphoryl chloride under reflux for about 12 to 24 hours.
Illustration 10
Alternatively, the chlorosulfonyl can be prepared from aromatic or heteroaromatic nitro-or amine-containing compounds, as shown in scheme 10. The nitro compound may be converted to its corresponding amino compound in step 10a by a variety of known methods, including indium reduction, or catalytic hydrogenation, using palladium or platinum-based catalysts. The corresponding aromatic or heteroaromatic sulfonyl chloride may then be prepared from the amine according to step 10b by reaction with sodium nitrite in a mixture of glacial acetic acid and concentrated HCl at about 0 to 5 ℃ for about 5 to 15 minutes. A saturated solution of sulfur dioxide and excess copper (II) chloride in aqueous acetic acid may then be added and stirred at about room temperature for about 12 to 36 hours, followed by treatment with an aqueous alkaline solution.
Examples of Compounds
The compounds listed in tables 1 to 16 were prepared and characterized. Specifically, a macrolide intermediate (template) is prepared, followed by nitrogen coupling of the cyclic amine (formula I, Ring A) of the template to the desired helmet group to incorporate R of the group of formula I2. The following are non-limiting macrolide template preparations, non-limiting helmet group reagent preparations, and non-limiting examples of final compounds according to the present invention. 1
1: 3 ═ take off
Radlosyl-1112-dide-6-o-yl, 3-oxo-12 n-cauylcarbonyl-azetidin-3-yl-imino-Rhodomyces, A
Step 1: DBU (10 ml, 67 mmol) was added to 1-benzhydryl-azetidin-3-ylamine (9.0 g, 37.8 mmol) dissolved in anhydrous MeCN (100 ml) at room temperature. To this solution, n-deoxy-2', 4n ═ acetyl ═ 10, H-didehydro-12-O- ((1H-imidazole -yl) ═ carbonyl) -6-O-methyl-erythromycin a (32.5 g, 35.8 mmol) was added, and the resulting mixture was heated (50 ℃ c.) for 7.5 hours, and then it was stirred at room temperature overnight. The white precipitate (21 g, 19.5 mmol) was collected by filtration. Make the filtrate liquidConcentrate to about 25 ml, then add water (20 ml), saturated aqueous NaHCO3 (30 ml), and extract the resulting mixture with DCM (50 ml). The organic layer was washed with saturated aqueous NaHCO3 solution, with Na2SO4Dried by dehydration and concentrated under vacuum to a tan foam. MS (ESI +) Wz 540(W2+ H) +.
Step 2: the product from step 1 was dissolved in EtOH (100 ml) and 2N HCl (100 ml), heated (40 ℃) for 3 hours, then cooled to 30 ℃ and stirred overnight. The resulting mixture was concentrated under vacuum to about one 105743 -half of the original volume, maintaining the bath at 28. And C, below. To the resulting concentrate was added DCM (100 ml) followed by careful addition of solid potassium carbonate to basify the aqueous layer (to pH 10). The organic layer was separated and the aqueous layer re-extracted with DCM (3 × 100 ml). The combined organic layers were washed with Na2SO4Dried by dehydration and concentrated to a white foam oMs (EsI +) z440(M/2+ H) +.
And step 3: the crude product from step 2 was redissolved in anhydrous DCM (200 ml) and to this was added anhydrous DMSO (20 ml, 282 mmol), pyriproxyfen (15 g, 77.7 mmol) and finally EDC (30 g, 156.5 mmol). The mixture was stirred at room temperature for 3 hours and then treated with saturated aqueous NaHCO3 (30 ml), water (30 ml). The reaction mixture was placed in a separatory funnel and the layers were allowed to separate over a period of hours. The aqueous layer was re-extracted with DCM (3 × 75 ml) and the combined organic layers were washed with water (50 ml). Adding Na to organic substance2SO4After drying, the solvent was removed under vacuum to give a yellow foam oMS (ESI +) M/z439(M + H) +.
And 4, step 4: the yellow foam from step 3 was redissolved in MeOH (200 ml) and heated (50 ℃) for 24 hours, then concentrated to dryness under vacuum. The solid was washed with hexane/diethyl ether (2/1), treated with MeOH (50 ml), and the resulting slurry was heated to boiling point on a steam bath and then cooled to room temperature. The white solid formed was filtered and dried under vacuum (10.5 g, 12.6 mmol, 35% yield in four steps)Flash) oMS (ESI +) cutting z418(W2+ H) +.1HNMR(CDCl3)δ7.41(m，4H)，7.21(m，4H)，7.16(m，2H)，4.88(br d，1H)，4.60(s，1H).
And 5: the white solid from step 4 was dissolved in MeOH and treated with concentrated aqueous Hcl (2.4 ml, 28 mmol). To this was added Pearlman's catalyst 105743 5- \ medium (palladium hydroxide, 20 wt% pd, about 6 grams) and the slurry was subjected to hydrogen gas (40 to 50psi) while heating (35 ℃) for up to2 hours in a parr shaker. The parr flask was cooled to room temperature, purged with nitrogen, and the solid filtered off. The filtrate was treated with TEA (6.0 mL, 43 mmol) and concentrated in vacuo to give the title compound, along with diphenylmethane (1 equivalent) and TEA hydrochloride (2.2 equivalents), as a free-flowing crude solid (total 14 g; about 59% by weight of the title compound) oMS (ESI +) M/z335(M + H) +.1HNMR(CD30D)δ4.71-4.59(m，2H)，4.48(br t，1H)，433(d，1H)，4.27(d，1H)，4.16(br t，1H).
The products of preparation 1 correspond to the macrocyclic lactone templates of tables 1 to 3. ' j rather 2 a: 2-acetyl-3-deamino
Radlosyl-H12-didenity-6-O-1211-digylcarbonyl-1-twenty-two
Yl-azetidin-cun-yl-imino) -erythromycin A
Step 1: to H-deoxy-2', 4-menthanediacetyl 0, 11-didehydro-2-O- ((1H-imidazol-1-yl) ═ carbonyl) -6-O-methyl-erythromycin a (18.8 g, 20.7 mmol) were added anhydrous MeCN (25 ml), TEA (20 ml, 144 mmol) and C- (1 ═ benzyl-azetidin-3-yl) -methylamine (5.5 g, 21.8 mmol). The mixture was heated (60 ℃ C.) for 7.5 hours, fitted with a reflux condenser, then concentrated under a stream of nitrogen and heated continuously overnight to give a solid mass oMS (ESI +) M/z1093(M + H) +.
Step 2: to the crude solid from step 1 were added EtOH (100 ml) and 2NHCl (100 ml) and the mixture was stirred at room temperature for 2.5 days. The mixture was heated (30 ℃ C.) due to incomplete reaction) After 16 hours, the temperature was allowed to increase slightly (to 40 ℃) for another 24 hours, and then cooled again to room temperature. The solvent was reduced (under vacuum) by half while maintaining 28 ℃. The resulting concentrate was extracted with EtOAc (2 × 100 ml). The combined organic material was back-washed with water (20 ml), the aqueous layers were recombined and the pH was slowly raised to 10 with saturated aqueous NaHCO3, at which time (now basic) the aqueous layer was extracted with EtOAc (4 × 100 ml). The combined organic layers were dried (Na)2SO4) Filtered and concentrated in vacuo to afford the title compound oMS (ESI +) Wz 447 (hu 2+ H) +.11 ×.2 b: 3-removing
Ladinosyl-n 12 ═ dik-6-o ═ yl-3 ═ ketoemesis 2n ═ star-carbonyl-azetidino-yl-imino-erythromycin, a
Step 1: 2 □ acetyl-3-decladinosyl-n, 12 ═ deoxy? The group 2, 11- (oxycarbonyl- ((1- (benzhydryl) -azetidin-3-yl) early group) -imino) -erythromycin a (10 g, h.2 mmol) was dissolved in DCM (75 ml). To this stirred solution was added anhydrous DMSO (10 ml, 140.8 mmol), pyriproxyfen (7.6 g, 39 mmol) and EDC (7.5 g, 39 mmol). The reaction mixture was stirred at room temperature overnight, then treated with saturated aqueous NaHCO3 (30 ml), water (30 ml), and the resulting mixture was extracted with DCM (4 × 30 ml). The combined organic layers were dried (Na)2SO4) Filtered, concentrated under vacuum, then redissolved in MeOH (70 ml) and heated (40 ℃) for 24 hours. TEA (2 ml) was added to the reaction and heating continued for an additional 24 hours to ensure complete acetylation. The methanolic solution was then concentrated under vacuum to a golden foam which was purified (SGC using DCM: MeOH: NH40H eluent at a ratio of 93: 7: 0.4) to give 6.4 g (7.55 mmol) of intermediate oMS (ESI +) M/z 425(M + H) +.
Step 2: the intermediate from step 1 (6.2 g, 7.3 mmol) was dissolved in MeOH (100 ml) and Pearlman's catalyst (palladium hydroxide 20 wt% pd, 3 g) was added thereto and the resulting slurry was shaken under hydrogen pressure (parr system, 50psi) while heating (40. C). After 5 hours, more catalyst (8 g) was added and the reaction was continued for 18 hours, but monitoring (LCMS) indicated moderate conversion to the desired product. Next, concentrated aqueous HCl (2 ml) was added and the reaction was continued in the manner described above for an additional 4 days until conversion was complete. The slurry was then filtered to remove solids and the filtrate was concentrated to the title compound as the dihydrochloride salt (5.23 g, 7.28 mmol), which was used for the analog to yield oMS (ESI +) z342(M + H) +.1HNMR (DMSO-d6) δ 4.59(br d, 1H), 4.23(d, 1H), 4.06(M, 2H).
The product of preparation 2b corresponds to the macrocyclic lactone template of Table 4. U2 c: 3-removing
labyrisyl-H12-di-cauda-6-O-mu-12H-usurping carbonyl-azetidine-mo-imino-3-tetrahydropyrrole-1-carbonyl-erythromycin, a and 3-des
Radine sugar-1112 ═ removing kappa-6 core
Certain-1211-afternoon A carbonyl-azetidine-3-aryl-imide 3-hexamethylenetetramine-1-carbonyl-Rhodomyces
Step 1: 2 □ acetyl-3-descladinosyl-n, 12-dideoxy-6-O-methyl-12, 1L (oxycarbonyl- ((L (benzhydryl) -azetidinO-yl) -methyl) dumb amine) -erythromycin A (3.0 g, 3.4 mmol) was dissolved in anhydrous MeCN (15 mL) and TEA (1.4 mL, 10 mmol). Bis-serv J-succinimidyl carbonate (1.29, 5 mmol) was added and the solution was stirred at room temperature for 24 hours at which time additional TEA (1.4 ml, 10 mmol) and bis (N-succinimidyl) carbonate (1.29, 5 mmol) were added and the reaction was stirred for an additional 24 hours. Additional MeCN (15 ml) was added and the resulting stock solution was separated into two parts (steps 2a and 2 b).
Step 2 a: the major portion (24 ml) of the stock solution from step 1 was treated with tetra 105743 ● 6 castor (1 ml, 12 mmol) and monitored by LCMS until carbamate formation was deemed complete oMS (ESI +) M/z 496(M/2+ H) +. This solution was concentrated in vacuo, redissolved in MeOH (80 mL), and heated (60 deg.C) for 20H to remove the 2 □ acetyl protecting group-MeOH, followed by purification (SGC, using DCM: MeOH: NH40H eluent at a ratio of 95: 4: 1) to give the purified intermediate (3.32 g) oMS (ESI +) m/z 475(mm2+ H) +.
And step 2 b: the minor portion (6 ml) of the stock solution from step 1 was treated with azetidine (1 ml, 18 mmol) and monitored for oMS (ESI +) M/z 489(M + H) + as per step 2a above. The 2-way acetyl protecting group was removed and the intermediate was purified as in step 2a above (yielding 0.32 g) oMS (ESI +) I cut z468(M/2+ H) +.
Step 3 a: the product from step 2a was dissolved in MeOH (100 ml) and concentrated aqueous HCl (0.331 ml, 3.85 mmol). To this was added Pearlman's catalyst (palladium hydroxide, 20 wt% Pd, 3.0 g). The slurry was subjected to hydrogen (40psi) with heating (35 ℃) while shaking (parr system) for 18 hours. After removal of solids, the filtrate was concentrated in vacuo to give 3-descladinosyl-n, 12-dideoxy-60-methylemetic 2, 1L (oxycarbonyl- ((azetidino ═ yl) -methyl) -imino) -3- (tetrahydropyrrole-1-carbonyl erythromycin a as the dihydrochloride salt (2.74 g) oMS (ESI +) M/z 385(M + H) +.
And step 3 b: subjecting the product from step 2b to hydrogenolysis according to step 3a to yield 3-descladinosyl-H, 12-dideoxy near-O-methyl ═ 12, 1L (oxycarbonyl- ((azetidinon-yl) -methyl) -imino) -3- (azetidine-1-carbonyl) -erythromycin a as dihydrochloride (0.25 g) oMS (ESI +)1 cut z 385(M + H) +.
The products of preparation 2c correspond to the templates of Table 5. 105743U2 d: 3-removing
Labyristinosyl-n 12-desmut-6-o-even 12n- -ylcarbonyl ≡ azetidino-uso-imino-ethyl-tetrahydropyrrole-erythromycin a is prepared according to preparation 2c steps 1, 2a and 3a by substituting 2 ═ methyltetrahydropyrrole for the tetrahydropyrrolidine in step 2a to yield oMS (ESI +) M/z399(M + H) +. The products of preparation 2d correspond to the templates of Table 5. 1U 2 e: 3-removing
labyrisyl-H12-des-6-O-yl-12H-ruby carbonyl-tet-3-yl-iminoalkoxy-2-3-fluoroeicosanyl kappa pyrrole) eme-carbonyl-erythromycin A was prepared by substituting ethyl (3-fluorophenyl) hydropyrrole for the tetrahydroxy in step 2a in accordance with preparation 2c steps 1, 2a and 3a, to give oMS (ESI +) M/z439(M/2+ H) +. The products of preparation 2e correspond to the templates of Table 5. 03: 3-removing
The labridinyl, H12-dide-6-O-yl-1211-baccatinyl carbonyl- ((3-methyl-azetidin-founyl) -methyl) -imino) -erythromycin a may be prepared in analogy to preparation 1, from C ═ 1 ═ benzyl-azino jai (acemetacide) aceptamine substituted 1 ═ benzyl azetidin-3-ylamine. MS (ESI +) M/z349 (M/2+ H) +. The products of preparation 3 correspond to the templates of Table 6. //1
4: 3-removing
The lamidosaccharide, n 12-dide -6-o ≡ group 211- κ group yl- ((3-hydroxy-azetidin-cun) -methyl) -imino) industrial mycin a was prepared in analogy to preparation 1 by substituting L-benzhydryl-azetidin-3-ol with 3-aminomethyl-1 ═ benzyl azetidin-3-ol to oMS (ESI +) M/z 350(M/2+ H) +. The products of preparation 4 correspond to the templates of Table 7. 1I ^ 5 a: fou-like drop
Radine glycosyl-n 12-dideoxy ═ 6-heart
Based on keto-12, H- (oxycarbonyl- ((S) -tetrahydropyrrole-3-yl) -imino) -erythromycin a: following a procedure analogous to preparation 1, steps 1 to 4, substituting 1-benzhydryl-azetidin-cun-en-ylamine with (S) -L-benzyl-tetrahydropyrrol-3-ylamine gave 3-decladinosyl 105743 tin 0 ● emetic 1, 12 ═ deoxy-6-o-methyl-3-keto 2, n- (oxycarbonyl- ((S) -1-benzyl-tetrahydropyrrolc-yl) -imino) -erythromycin AoMS (ESI +) z 387(M + H) +. This product (4 g, 5.2 mmol) was dissolved in 4.4% formic acid (360 ml) in MeOH, treated with palladium black (0.30 g), and stirred for 4 hours with heating (40 ℃). The mixture was filtered and the filtrate was neutralized with saturated aqueous NaHCO 3. The resulting mixture was concentrated under vacuum,and extracted (3 etoac). The combined organic layers were dried (Na)2SO4) Filtered and concentrated in vacuo to give the title compound (3 g, 4.4 mmol) oMS (ESI +) M/z342(M + H) +.1HNMR (CD30D) δ 1.11(dd, 3H), 0.87(t, 3H). The products of preparation 5a correspond to the templates of Table 8. Fineness 5 b: 3-deladine sugar
H12-dideoxy-6 ═ O-3-keto 211-dylcarbonyl-R hydropyrrol-3-yl ═ imino-rhodomyces, a can be prepared in analogy to preparation 5a, by substituting (R) -L-benzyl ═ tetrahydropyrrole-3-ylamine for (S) -benzyl, tetrahydropyrrole-3-ylamine.1HNMR (CD30D) δ 1.28(d, 3H), 1.17(d, 3H), 1.07(d, 3H), 0.88(t, 3H). The product of preparation 5b corresponds to the template of Table 9. Thin 6 a: 2 □ acetyl 3-deacidizing
Ladinosyl-n 12-didecumin-6-O-yl ═ 3-oxo-12 n-cauyl carbonyl-s-tetrahydropyrrole-2-yl-imino-erythro-s
Step 1. protected intermediates can be prepared in a similar manner to the preparation of steps 1 to 4 by substituting tert-butyl (S) -2-aminomethyl-tetrahydropyrrole-1-carboxylate for 1-benzhydrylazetidin-3-ylamine.
Step 2 the crude product from step 1 was prepared using excess trifluoroacetic acid in dichloroethane at room temperature for 3 hours, then concentrated under vacuum to dryness 105743 σ 1 to afford the title compound as trifluoroacetate oMS (ESI +) M/z 370(M/2+ H) +. The products of preparation 6a correspond to the templates of Table 12. Preparation 6 b: 3-decladinosyl-n, 12-dideoxy-6-o-methyl-3-ketoemesis 2H-homogenously-tampering carbonyl-R-tetrahydropyrrole-2-yl-imibenezo-rhodomyces, a was prepared in analogy to preparation 1, steps 1 to 4, by substituting (R) -2-aminomethyl-tetrahydropyrrole -carboxylic acid tert-butyl ester for 1-benzhydrylazetidin-3-ylamine followed by oMS (ESI +) M/z349 (M/2+ H) + for preparation 6a, step 2. The products of preparation 6b correspond to the templates of Table 10. U7 a: 3-removing
Laminosyl-H12-dide afternoon near-O-usu-keto 2H-exaggerate-yl-S-tetrahydropyrrole, 3-usu-yl-imino-Rhodomyces rubrum, A was prepared in a similar manner to 6b by substituting (R) -3-aminomethyl tert-butyl ester of pyrrolidine-1-carboxylic acid for (R) -2-aminomethyl-tetrahydropyrrole -carboxylic acid trihexyl ester to give oMS (ESI +) M/z349(M + H) +. The products of preparation 7a correspond to the templates of Table 11.1 s hand 7 b: 3-removing
Ladinosyl-1112 ═ didepsigar-6-O-yl-ketonic group 211-afternoon ylcarbonyl-R-tetrahydropyrrole-3 ═ pleckyl-imino-erythromycin, a can be prepared in a similar manner to that of preparation 6b, by substituting (S) -3-aminomethyl-tetrahydropyrrole-1-carboxylic acid tert-butyl ester for (R) -2-aminomethyl-tetrahydropyrrole-1-carboxylic acid tert-butyl ester. MS (ESI +) M/z349(M + H) +. The product of preparation 7b corresponds to the template of Table 13. 9
8: 2 □ acetyl-3-deoxy
ladinosyl-H12-didehydro afternoon-6-O-yl-12 n- ylcarbonyl-3 item- ; cyclo, ` 3.1.0 Hexane-6-Yl-imino-erythromycin A may be prepared in a similar manner as in preparation of 6a by substituting tert-butyl 6-aminomethyl-3-aza-bicyclo [3.1.0I hexane-3-carboxylate for tert-butyl (S) -2-aminomethyl-tetrahydropyrrole-1-105743 to give oMS (ESI +) M/z750(M + H) +. Preparation 8.1: 2 □ acetyl cun-decladinosyl-H, 1 ethanedideoxy-6-O ═ methyl 2H ═ afternoon ylcarbonyl-hexahydropyridin-4-yl-imino-rhodomyces, a was prepared in analogy to preparation of 6a by substituting tert-butyl 4-aminomethyl ═ hexahydropyridin-1 ═ carboxylic acid for tert-butyl (S) -2-aminomethyl-tetrahydropyrrole-1-carboxylic acid to O MS (ESI +) M/z 710(M + H) +. )1f 8.2: 3-removing
ladinosyl-H12-didepsigar-O-yl-12H-afternoon ylcarbonyl- ((chedroxy ≡ piperidine, 4 5) -methyl) ═ imino) -erythromycin a can be prepared in analogy to the preparation of 6a, step 1, by substituting tert-butyl(s) -2-aminomethyl-tetrahydropyrrole-L-carboxylate with tert-hexyl 4-aminomethyl-4-hydroxy ≡ piperidine-1-carboxylate to yield oMS (ESI +) M/z869(M + H) +. The product was then taken up in excess MeOH, at room temperature overnight, concentrated to dryness in vacuo, redissolved in DCM (1 ml) and treated with excess TFA (1 ml) at room temperature for 4 hours. After concentration under vacuum, the residue was used directly for derivatization. MS (ESI +) M/z 727(M + H) +. Preparation 9: chlorinated 3-cyano-441, 2, 41-triazol-1-yl-benzenesulfonyl
The conversion of anilines to chlorosulfonyl chlorides is according to the procedure shown in [ integral ] carve C plus-29, 427-433(1986), with minor modifications, which is fully incorporated herein by reference.
Step 1. A. D-aspartic acid-2-nozzle in glacial acetic acid (2.16 ml), 2, 41 triazole-1 -benzonitrile (0.40 g, 2.16 mmol) were treated with concentrated aqueous HCl (0.45 ml, 5 mmol) and the mixture was cooled to between 0-5 ℃ in an ice-water bath. Sodium nitrite (0.150 g, 2.17 mmol) was added and the slurry was stirred for about 10 minutes.
Step 2. in another flask, copper (H) chloride dihydrate (1.8 g, 105743 mmol 3-10.6 mmol) was treated with acetic acid (36 ml) and water (2.2 ml). The sulfur dioxide gas is then bubbled through to the saturation point (to constant quality) while keeping the system well aerated (the mixture formed from this step can be used for several reactions).
Step 3. add a portion (3 ml) of the mixture from step 2 to the slurry from step 1 and allow the reaction flask to warm to room temperature overnight with constant stirring (keeping the aeration). The mixture was then diluted with water and extracted repeatedly with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 solution, dried ca2 SO4, filtered and concentrated in vacuo to give the title compound (0.20 g) which was used without further purification of oIHNMR (CDCl)3) δ 9.06(s, 1H), 850(s, 1H), 8.39(d, J ═ 9Hz, 1H), 8.25(s, 1H), 8.19(d, J ═ 9Hz, 1H) · 10: ZI chloride xi Azole, '12-a' pyridine-3- acyl
Step 1 chlorosulfonic acid (0.170 ml, 2.55 mmol) was dissolved in chloroform (1 ml) and this solution was added dropwise to imidazo [1, 2-aI-pyridine (0.100 g, 0.85 mmol) in chloroform (4 ml) over 10 minutes. The reaction mixture was heated to reflux for 24 hours, then allowed to cool to room temperature and concentrated to dryness in vacuo. The crude oily product was treated with diethyl ether (10 ml) and ethanol (5 ml) to give a white precipitate. The solid was collected by filtration, washed with EtOH and dried to yield imidazo [1, ethonium-3-sulfonic acid (0.128 mg) oMS (ESL) M/z 131(M-H ^ PlP).
Step 2. the product from step 1 (0.10 g, 0.5 mmol) was treated with phosphoryl chloride (3 ml) and heated to reflux overnight. The reaction mixture was cooled to room temperature and treated with DCM (50 ml), poured into ice water (100 ml) and then extracted with DCM (4 × 100 ml). The organic layers were combined and dried (Na)2SO4) Filtered, and concentrated to dryness under vacuum to give the title compound (0.10 g) o1HNMR(DMSO-d6)δ8.87(m，1H)，8.25(s，1H)，7.98(m，2H)，7.57(m，1H).
Preparation 11: imidazo [1, 2-aF pyrimidine-2-carboxaldehyde with imidazo n, 2-aF pyrimidine ═ m
Imidazo [1, 2-a ] pyrimidine (0.30 g, 2.5 mmol) is dissolved in anhydrous DMF (10.0 ml) and added to a pre-formed solution of phosphoryl chloride (0.26 ml, 2.8 mmol) in anhydrous DMF (10.0 ml). The solution was stirred under nitrogen at room temperature for 72 hours. The solution was then poured into water (100 ml) and the residual organic material was extracted with ether (3 × 30 ml). The remaining aqueous portion was concentrated to dryness under a stream of nitrogen to yield a mixture of crude imidazo [1, 2-a1 ═ pyrimidine-3-carboxaldehyde and imidazo [1, 2-a1- σ piperidine ═ 2-carboxaldehyde (0.10 g total) which was used in the subsequent reductive amination step without further purification of oMS (ESI +) M/z148(M + H) +. After coupling to 3-decladinosyl-H, 12-dideoxy ≡ 6 ≡ O-methyl-on keto 2, n- (oxycarbonyl- ((azetidin-3-yl) quack) -imino) -erythromycin a, the isomers were isolated by RP-HPLC. Preparation 12: imidazo-1, etha 1-pyrazine, 3-carboxaldehyde
Imidazo [1, 2-prochloraz (0.30 g, 2.5 mmol) was dissolved in anhydrous DMF (10.0 ml) and added to a solution of preformed phosphoryl chloride (0.26 ml, 2.8 mmol) in anhydrous DMF (10.0 ml). The solution was stirred under nitrogen at room temperature for 72 hours. The solution was then poured into water (100 ml) and the residual organic material was extracted with ether (3 × 30 ml). The remaining aqueous portion was concentrated to dryness under a stream of nitrogen to yield the title compound (0.050 g). MS105743 ● 7 (ESI +) bloody stasis z148(M + H) +. preparation 13: pyrrolo [1, 2-aF trumpet-well-6-carboxaldehyde
Step 1 pyrrolo [1, 2-a1 core oxazine (1.92 g, 16.3 mmol) was dissolved in water (16 ml) and treated with concentrated aqueous HCl (4 ml, 46.4 mmol) and 37 wt% aqueous formaldehyde (5.6 ml, 67 mmol). The solution was heated to 60 ℃ for 4 hours, allowed to cool to room temperature, and the pH was adjusted to 10. The solution was extracted with EtOAc (3 × 50 ml) and the combined fractions were taken up with Na2SO4Dried and concentrated under vacuum to dryness. The organic residue was purified (SGC, eluent using DCM: MeOH: NH40H, 96: 3: 1). The recovered starting material was dissolved in water (20 ml) and concentrated HCl (5 ml, 0.6 mol) and formaldehyde (7 ml, 0.9 mol). The solution was heated to 60 deg.f. C, over 120 hours, which was then stirred at room temperature for 240 hours. The solution was then brought to pH 12 with sodium hydroxide solution (30% w/v aqueous solution) and extracted with EtOAc (4X 30 mL). The organic fractions are combined with Na2SO4Dried and concentrated under vacuum to dryness. The product was purified (SGC using DCM: MeOH: NH40H eluent at a ratio of 95: 4: 1) to give the title compound (0.46 g). MS (ESI +) z149(M + H) +.1HNMR(CDCl3)δ8.46(s，1H)，7.85(dd，1H)，7.19(d，1H)，6.72(d，1H)，6.63(d，1H)，4.83(s，1H)，4.78(bs，1H).
Step 2. pyrrolo [1, 2-a ] pyrrolidin-6-yl-methanol (0, 06 g, 0.41 mmol) was dissolved in EtOAc (3 mL), treated with IBX (0.34 g, 1.2 mmol) and heated to 80. And C, the time is 3 hours. The solution was allowed to cool to room temperature and filtered through a syringe filter frit. The solution was concentrated under a stream of nitrogen to give the title compound (0.06 g), which was used without further purification of o1HNMR(CDCl3) δ 9.87(s, 1H), 9.34(d, 1H), 9.02(s, 1, 7.93(d, 1H), 7.47(d, 1H), 6.82(d, 1H).105743 preparation of 14: imidazo n, 2-aF in 6-carboxaldehyde
Step 1. reacting 1H-imidazo [1, 2-a ]]Pyridine-6-carboxylic acid (2.0 g, 5.1 mmol) was dissolved in anhydrous DCM (30 ml) and cooled to 0. C. Ethyl chloroformate (130 ml, 13.6 mmol) and TEA (4.31 ml, 30.8 mmol) were added to the solution and stirred for 1 hour while the temperature was allowed to warm to ambient. Ethanethiol (2.0 ml, 27 mmol) was added and the solution was stirred overnight. The material was partially converted so TEA (2.0 ml, 14 mmol) and ethyl chloroformate (7.8 ml, 82 mmol) were added and stirred for 15 minutes followed by more ethanethiol (80 ml, 1.1 mol). The solution was stirred for 2 hours and then poured into saturated aqueous NaHCO 3. The DCM layer was removed and the aqueous portion was extracted with EtOAc (4 × 70 ml). The combined organic fractions are combined with Na2SO4Dried, filtered and concentrated under vacuum. The product was purified (SGC, using an acetone: hexane gradient elution, ratio 1: 4 to 3: 1) to yield a thioester intermediate (0.2 g).1HNMR(CDCl3)δ8.82(s，1H)，7.67-7.57(m，4H)，3.07(q，2H)，1.32(t，3H).
Step 2. the thioester from step 1 (0.H g, 0.53 mmol) was dissolved in acetone (1.0 ml) and 10% palladium on carbon (0.027 g) was added followed by triethylsilane (0.089 ml, 0.558 mmol). The mixture was stirred for 1 hour and another portion of triethylsilane (0.089 ml, 0.558 mmol) was added. After 1.5 hours, the reaction was passed through a syringe filter and purified (SGC, eluting with an acetone: hexane gradient from 3: 17 to 3: 1) to give the title compound (0.049 g). MS (ESI +) M/z 147(M + H) +.1H NMR (CDCl)3) δ 9.90(s, 1H), 8.66(s, 1H), 7.70(d, 2H), 7.66-7.60(m, 2H). 1-pyridine-ethyl-1H-pyrazole-4-carboxaldehyde
A mixture of 2-bromopyridine (3.4 mmol), 3-pyrazolecarboxaldehyde (3.2 mmol) and potassium carbonate (3.4 mmol) in anhydrous DMF (6 mL) was heated to 120 ℃ for 24 h. The reaction was cooled to rt, diluted with water, and extracted with EtOAc (3 ×). Combining the organic layers, anddehydration drying (Na)2SO4) Filtering and concentrating. After purification (SGC, using EtOAc: hexanes gradient eluent, from 0% to 100% EtOAc), the title compound was obtained. U16: 18 pyridine-4- "aldehyde
The 4 quasisyl ═ I1, 8I triazine (0.743 g, 5.15 mmol) was dissolved in piperazinone (32 ml) and water (4 ml). Selenium dioxide (1.14 g, 103 mmol) was added and the solution was heated to 80 ℃ over 1 hour. Next, more selenium dioxide (0.020 g, 1.80 mmol) was added, the solution was heated for 30 minutes and then allowed to cool to room temperature. The solution was passed through a syringe filter to remove solids and poured into a solution of water: saturated aqueous NaHCO3 (1: 1) (60 ml). The organic layer was separated and the remaining aqueous solution was extracted with DCM (2 × 100 ml) and (1 × 50 ml). The organic fractions are combined with Na2SO4Dried, filtered and concentrated under vacuum. The product was purified (SGC, using MeCN: hexane, 1: 1 ratio) to give the title compound (0.63 g) oMS (ESI +) M/z 159(M + H) +.1H NMR (CDCl)3) δ 10.39(s, 1H), 939 ≡ 937(m, 2H), 9.16(d, 1H), 7.85(d, 1H), 7.61(dd, 1H) details 17: 1 Ding 8 pyridine-4-yl-ethidium furrow
Naphthyridine -carboxaldehyde (0.300 g, 1.90 mmol) was dissolved in a mixture of anhydrous toluene (10 ml) and anhydrous THF (10 ml). The solution was cooled to 0 ℃ and methylmagnesium bromide (1.62 ml, 1.4M in THF/toluene) was added slowly and the solution was stirred for 1 hour while it was allowed to warm to room temperature. Saturated aqueous ammonium chloride 105743 solution was added until the solution reached a bright yellow color and a precipitate was evident. The solution was passed through a syringe filter and into water where it was extracted with EtOAc (3 × 30 ml). The combined organic fractions are combined with Na2SO4Dried, filtered, and concentrated under vacuum. The product was purified (SGC, first using MeCN: hexane eluent at a 1: 1 ratio, then switched to DCM: MeOH: NH40H eluent at a 89: 10: 1 ratio to complete the compound elution) to yield the title compound (0.079 g) oMS (ESI +) M/z 175(M + H) □1HNMR(CDCl3)δ8.73(m，1H)，8.64(d，1H)，8.38(m1H), 7.52(d, 1H), 7.25(dd, 1H), 6.32(bs, 1H), 5.58(dd, 1H), 1.48(s, 3H). ㄩ 1, 81 Naphthyridin-4-yl-ethanones
ㄩ 1, 81 naphthyridine -yl-ethanol (1.44 g, 8.26 mmol) was dissolved in EtOAc (250 mL), treated with IBX (7.8 g, 24.8 mmol), and heated to 80. And C, the time is 6 hours. The solution was allowed to cool to room temperature and the solids were removed by filtration. The product was purified (SGC, using MeCN eluent) to give the title compound (1.22 g) oMS (ESI +) z 173(M + H) +.1HNMR (CDCl)3) δ 9.13(d, 1H), 9.03(dd, 1H), 8.85(dd, 1H), 7.70(d, 1H), 7.46(dd, 1H), 2.64(s, 3H). 5-nitro-2 ═ n, 2, 4| triazol-1-yl Yi ζ carbonitrile
2-fluoro-5-nitro ═ benzonitrile (1.0 g, 6.0 mmol) was dissolved in anhydrous DMF (6 ml) and then treated with [1, 2, 4F triazole (0.46 g, 6.7 mmol), cesium carbonate (2.9 g, 8.9 mmol) and heated (50 ℃) overnight. After cooling to room temperature, the mixture was treated with water and the solid title compound (1.14 g) oMS (ESI +) M/z 216(M + H) +. preparation 20: 2-methyl-Gegen (4-Nitroptertomyl) -I1, 3, 41 oxadiazole 4-nitro-benzoic acid hydrazide (1.0 g, 5.6 mmol) was heated to reflux in trimethyl orthoacetate 105743-79 ● for 4 days. After cooling to room temperature, the mixture was triturated with hexane and the title compound (0.93 g) oMS (ESI +) M/z206(M + H) +. preparation 21: 5-amino-2- "1, 2, 4-triazol-1-yl-benzonitrile
5-nitro-2- [1, 2, 41-triazole-deaf-benzonitrile (1.14 g, 5.3 mmol) was dissolved in ethanol (23 ml) and saturated aqueous ammonium chloride (5.3 ml), followed by addition of indium powder (3.25 g, 28.2 mmol). The mixture was then refluxed for 3 hours, cooled to room temperature, and the solid filtered (MeOH wash). The filtrate was diluted with water, basified with 1n naoh (aq), and extracted with EtOAc. The organic layer was dried (Na)2SO4) Filtration and concentration in vacuo gave the title compound (0.88 g) oMS (ESI +) M/z 186(M + H) +. preparation 22: ethylmethyl, 5- (4-amino-phenyl) -n, 3, 41-oxadiazole
2-methyl-5- (4-nitro-phenyl) - [1, 3, 4I oxadiazole (0.930 g, 4.54 mmol) was dissolved in MeOH. To this was added 10% palladium on carbon (0.06 g) and the mixture was shaken under hydrogen pressure (35psi, parr apparatus) until the reaction was complete (LCMS monitoring). The solid was filtered off and washed with MeOH. The filtrate was concentrated to give the title compound (0.76 g) oMS (ESI +) ascaris z176(M + H) +. preparation 23: car (6-chloro-pyridazin-3-yl) -aniline
4- (4, 4,5, 5-tetramethyl-I1, 3, 21-dioxaborowurtzitane, 2-yl) -aniline (0.500 g, 2.28 mmol), 3, 6-dichloropyridazine (0.340 g, 2.28 mmol), sodium carbonate (0.726 g, 6.85 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.068 g, 0.059 mmol) were mixed under nitrogen in 1, 2 ═ methoxyethane (H ml) and water (3.8 ml). The reaction mixture was heated (110 ℃) for 12h, cooled to room temperature, diluted with brine and extracted with EtOAc. The combined organic layers were dried to dehydrate 105743-8 min (Na)2SO4) Filtered and concentrated in vacuo to a crude solid, which was dissolved in DCM and extracted into 1n hcl (aq). The DCM layer was discarded and the aqueous layer was basified with 1n naoh (aq) and re-extracted with EtOAc. The EtOAc layer was dried via dehydration, slap 2SO4), filtered, and concentrated in vacuo to give the title compound (0.395 g) oMS (ESI +) M/z206(M + H) +. preparation 24: 5-Oxazol-5-yl-pyridin cun-ylamine
Step 1. conversion of 5- (3-Arachnocampa Ding oxazole (21.2 mmol) to its corresponding N-oxide with m-chloroperbenzoic acid (46.9 mmol) in chloroform (40 mL) at room temperature (3 hours) calcium hydroxide (109 mmol) and DCM (250 mL) were added to the reaction mixture and stirred for 45 minutes, then the solid was filtered off and the filtrate was concentrated to afford the N-oxidized intermediate (2.9 g, 17.9 mmol).
Step 2. tetrabutylammonium nitrate (6.54 g, 21.6 mmol) in DCM (90 ml) was cooled in an ice-water bath under nitrogen. Trifluoroacetic anhydride (3.0 ml, 21.6 mmol) was added to this solution and the resulting mixture was stirred for 20 minutes, then the product of step 1 (in 90 ml DCM) was added and the resulting slurry was first stirred in an ice-water bath and then allowed to warm to room temperature for 2 hours. The mixture was then heated (40. C) for 9 hours, cooled to room temperature, and treated with saturated aqueous NaHCO 3. The mixture was then extracted with DCM (3 × 250 ml) and the combined organic layers were dried over anhydrous lang a2SO4, filtered and concentrated in vacuo to afford, after purification (SGC with MeOH: DCM in 1: 10 ratio), 5-quino-oxide-donitro-3-pyridine) -oxazole (0.73 g, 3.53 mmol).
Step 3. the gentamicin (N koh-nitro-3-naphthyridine) - [ oxazole ] (0.159 g, 0.77 mmol) from step 2 was treated with MeOH (30 mL) and Raney nickel 2800 suspension {05743 ● 8 ㄩ (2 mL) and the mixture was shaken under hydrogen (45psi) on a Parr apparatus for 6 hours. Filtration (celite) yielded the title compound. MS (ESI +) M/z162(M + H) +.11 preparation of 25: quinolin-5-yl-amino acid eicosanoid ester
6-aminoquinoline (0.5 g, 3.5 mmol) was treated with phenyl chloroformate (0.597 g, 3.81 mmol) and TEA (1 mL) in DcM at room temperature for 4 hours. Saturated aqueous NaHCO3 solution and water were added thereto, and the mixture was extracted with DcM. The combined organic layers were washed with brine, dehydrated and dried O ↓a2SO4), filtered and concentrated in vacuo to afford, after purification (SGC, from 2: 3 to 7: 3 ratio using EtOAc: hexane gradient eluent'), the title compound oMS (ESI +) M/z265(M + H) +. d 26: 1-eicosyl-azetidin-3-ylamines
Methanesulfonic acid 1 ═ benzylazetidin-3-yl ester (14.8 g, 47 mmol, Oakwood product) was dissolved in anhydrous DMF (60 ml) and sodium bunanide (9.0 g, 138 mmol) was added to this solution. The mixture was heated (80 ℃) for 18 h' to room temperature and then treated with water (20 ml) and saturated aqueous NaHCO3 (20 ml). The resulting mixture was extracted with DCM (4X 60 ml) and the organic layer was washed with Na2SO4And (5) dehydrating and drying. Solvent removal yielded crude oil (H g), which was redissolved in THF (85 ml) and treated with triphenylphosphine (15 g, 57 mmol). After stirring at room temperature (30 minutes; gas evolution and some exothermicity were observed),the mixture was heated to reflux (6 hours) and then cooled back to room temperature, followed by the addition of NH40H (7 ml), and reflux again (5 hours). After cooling to room temperature, the solvent was removed and the residue was treated with 3n hcl (35 ml) to obtain pH 1. The resulting acidic solution was extracted with DcM (3 × 10574350 ml) and the organic layer was discarded. The aqueous layer was then basified to pH10 with solid potassium hydroxide, followed by another extraction with DCM (3 × 75 ml). The aqueous layer was then saturated with solid sodium chloride and re-extracted with DCM (3 × 75 ml). The combined organic layers were washed with Na2SO4Dried by dehydration, filtered and concentrated to give crude 1 ═ benzylazetidine-in-amine (9.0 g, 37.8 mmol) oMS (ESI +) z (M + H) +239.
The following preparation examples illustrate the preparation of the examples of tables 1-16, including the helmet group coupling method used. Light 27
Integral 1.20: 3-removing
taurosyl-H12-dideoxy-6-O-cun-onyl-12 n-exaggerate ylcarbonyl-1-18-naphthyridin-4-yl-tetrazine-potyimino) -erythromycin A
The final crude solid from preparation 1 (1.20 g, 1.06 mmol 3-descladinosyl, 11, 12, dideoxy-6-o-methyl-3-oxo-12, n- (oxycarbonyl- (azetidin-3-yl) -imino) -erythromycin A) was taken up in dry THF (10 mL), 1,&naphthyridine -carboxaldehyde (0.20 g, 1.3 mmol), TEA (0.44 ml, 3.2 mmol), acetic acid (0.095 ml, L6 mmol), powdered 4a molecular sieve (3 g) and the slurry was heated and stirred at 47 ℃ for 4 hours. At this point, sodium triacetoxyborohydride (0.33 g, 1.6 mmol) was added and heating continued for an additional 30-60 minutes, then the heat source was removed and the reaction flask was allowed to return to room temperature overnight with continuous stirring. Next, the reaction mixture was diluted with DCM and filtered to remove solids. To the filtrate was added saturated aqueous NaHCO3 (15 ml) and water (15 ml), and the resulting mixture was extracted with DCM (5 × 30 ml). The solid filtrate was washed into a separatory funnel and extracted as filtrate. Make it combined withOrganic layer dehydration drying (Na)2SO4) Filtered and concentrated 105743 ● 8 eggplant under vacuum.
Purification (SGC, using DCM: MeOH: NH40H gradient eluent at 96: 4: 0.5 to 93: 7: 0.5 ratio) yielded the title compound (0.557 g after conversion to the diformate salt with excess formic acid in MeOH and concentration in vacuo). d, preparing 28: 3-removing
Labyrin sugar U-H1 ethylenedioxy-6-o-certain-3-oxo-121L high basic carbonyl cosmetic-1-S, 18-piperidine- -ethylpiperazino-certain-imino, Rhodomyrtus, A
Courage 1.23; blood 3-depletion
ladinosyl-H12-di-cored O-yl-3-keto tamper-121 f.cloth homoyl carbonyl-1-R-18- -pyridin-4-min-ethyl-azetidin-3-yl) -imino) -erythromycin A (example 1.25);
the final crude solid from preparation 1 (4.21 g, 3.72 mmol, 3-descladinosyl-H, 12-dideoxy-6-O ≡ methyl 3 ≡ keto ≡ 12, H- (oxycarbonyl ≡ (azetidin-3-yl) -imino) -erythromycin a) was treated with anhydrous THF (35 ml), ㄩ 1,8 ] naphthyridin-4-yl, ethanone (0.7 g, 4.07 mmol), acetic acid (0.33 ml, 5.8 mmol), TEA (1.55 ml, H.1 mmol) and powdered 4 angstrom molecular sieve (4.5 g) and the slurry was taken up at 49. Heat and stir for 4 hours under C. At this point, sodium triacetoxyborohydride (2.35 g, 11 mmol) was added and heating continued for an additional hour, then the heat source was removed and the reaction flask was allowed to return to room temperature overnight with continuous stirring. Then, the solid was filtered off, and a saturated aqueous NaHCO3 solution (15 ml) and water (15 ml) were added to the filtrate, and the layers were separated. The aqueous layer was re-extracted with DCM (5 × 40 ml). The solid filtrate was washed into a separatory funnel and extracted as filtrate. The combined organic layers were dried (Na)2SO4) Filtered and concentrated under vacuum to give 4 g of a crude mixture of diastereomers. 105743 Tian 4 ●
The diastereoisomers were fractionated (RP-HPLC, using a gradient from 8 to30% a in B over 10 min). The more polar absorption peak (absorption peak 1) elutes at 4.00 minutes (1.1 grams collected), while the less polar absorption peak (absorption peak 2) elutes just after 4.38 minutes (1.0 grams collected). Absorption Peak 1 can be from EtOAc, MeOH, MeOWater, EtOH, etoke water, IPA, or water/water recrystallization. Recrystallization from EtOAc gave the appropriate crystals for X-ray spectroscopic analysis and the structure was unambiguously confirmed as 3-descladinosyl-11, 12 ═ deoxy-6 ═ O-methyl-3-oxo-12, H ═ oxycarbonyl- (1- (R) - (1,&naphthyridin-4-yl) -ethyl) -azetidin-yl) ═ imino) brennomycin a (example 1.25). Absorption peak 2 was determined by extrapolation to be 3-descladinosyl 1, 12-dideoxy-6-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (S) - (1, 8-naphthyridin-4-yl) "yl) azetidin-yl) -imino) -erythromycin a (example 1.23). Soaring 29
,1.33: in taking off
Latrine glycosyl emetic 112 ═ desmut-2-fluoro-O-yl ═ 3-keto-emetic 2 n-boryl carbonyl-deaf 18-oxazidin-4-yl-parent-azide tetra jai ═ yl) -imino) -erythromycin a
Step 1: the free base of 3-decladinosyl-11, 12-dideoxy-O azepine-3-oxo-12, 1L (oxycarbonyl- (1- ((1, 8-naphthyridine des) -methyl) -azetidin-3-yl) -imino) -erythromycin a (0.10 g, 0.12 mmol) was dissolved in anhydrous DCM (1.5 ml). TEA (0.069 ml, 0.50 mmol) and acetic anhydride (0.015 ml, 0.16 mmol) were added and the reaction was allowed to stand overnight. Saturated aqueous NaHCO3 and water (1: 1) were added to the mixture and the organic layer was separated. The aqueous layer was re-extracted with DCM (3X 2 ml) and the combined organic layers were dried (Na)2SO4) Filtered and concentrated under vacuum to give the crude intermediate.
Step 2: the intermediate from step 1 was dissolved in anhydrous DMF (3 mL) and 105743 Wu free water toluene (3 mL) and cooled in a dry ice/acetone bath with the same procedure asWhile maintaining a positive pressure of nitrogen. Solid potassium bis (trimethylsilyl) amine (0.042 g, 0.21 mmol) was weighed under nitrogen and added quickly to the cooled solution, which was then stirred while cooling for 1 hour. Then, solid twenty (chloromethyl) -4-fluoro-1, 4 ═ diazobicyclo [2.2.2 ] octane bis (tetrafluoroborate) was added (0.062 g, 0.176 mmol), and the reaction was warmed to room temperature over 1 hour. DCM (20 ml) was added followed by saturated aqueous NaHCO3 (5 ml) and water (5 ml) and the layers were separated. The aqueous layer was re-extracted with DCM (2 × 10 ml). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated under vacuum.
And step 3: the crude product from step 2 was dissolved in MeOH (100 ml) and heated (32 ℃) overnight. After concentration in vacuo, the crude mixture was purified by RP ═ HPLC to give the title compound (0.023 g, 0.028 mmol). Thin 30
Yan 2.06: 3-removing
latrine-H12 ═ des κ -6-O-yl-3-oxo-12H-afternoon ylcarbonyl-1-apiin-5-yl-aminocarbonyl certain azetidin-3 ═ yl) -imino) -erythromycin a
The final crude solid from preparation 1 (0.076 g, 0.067 mmol) was treated with TEA (1.0 ml) and phenyl quinoline- -yl -methylate (0.030 g, 0.H3 mmol) in anhydrous MeCN and heated (50. C) overnight. The reaction mixture was worked up to dryness in vacuo and purified (RP-HPLC) to afford the title compound. 0
31
Ten 315.3-Shi
labyrisyl-H12-dide-6-O-yl, 3-ketospit-2H-tailylcarbonyl-1-imidazole,' 12-a pyridine- acyl-azetidin-yl) -imino) -erythromycin A
The final crude solid from preparation 1 (0.20 g, 0.18 mmol) was treated with anhydrous MeCN (5 ml), followed by TEA (0.076 ml, 0.54 mmol), and chloro 105743 to imidazoi [1, 2-aI-pyridineCun-sulfonyl (0.039 g, 0.18 mmol) treatment. The reaction was stirred at room temperature for 3 hours, then treated with saturated aqueous NaHCO3 (15 ml), water (15 ml), and extracted with DCM (4 × 30 ml). The combined organic layers were dried (Na)2SO4) Filtered and concentrated under vacuum. Purification by RP-HPLC gave the title compound (0.055 g, 0.065 mmol). ' s
32
- [ integral ] ruffian 14.34: seed stripper
Ten sugar usu-H12-dijie berry-6-alpha
certain-3-oxo-12H-nylcarbonyl ≡ 1-apigenin-8-carbonylazetidin-3-yl ■ imino) -erythromycin A
Step 1: quinoline-8-carboxylic acid (0 lu 182 g, 1.05 mmol) was dissolved in anhydrous DCM (3 ml) to which DMF (0.025 ml) had been added. To this was added oxalyl chloride (0.526 ml, 2M solution in dichloromethane, 1.05 mmol), which was stirred at room temperature for 15 minutes, followed by addition of TEA (0.550 ml, 3.9 mmol) and N-hydroxysuccinimide (0.140 g, 1.22 mmol). The reaction was stirred for an additional 30 min, then treated with water (10 ml), saturated aqueous NaHCO3 (10 ml), and then extracted with DCM (2 × 30 ml). The combined organic layers were dried by dehydration, filter and concentrated to dryness, and redissolved in anhydrous THF (8 ml) and TEA (0.550 ml, 3.9 mmol) which were intended to be used as stock solutions in step 2 below.
Step 2: the 3-decladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, u- (oxycarbonyl- ((azetidin-3-yl) quack) -imino) ═ erythromycin a dihydrochloride (0.050 g, 0.073 mmol) from preparation 2a was treated directly with the stock solution prepared in step 1 above (2 ml) and allowed to react at room temperature for 15 minutes, then treated with water (15 ml), saturated aqueous NaHCO3 solution (10 ml) and then extracted with DCM (3 × 30 ml). Dehydration 105743, 8 red (Na) for combined enhancement of the lumbar intervertebral discs2SO4) And purification (SGC, using DCM: MeOH eluent) to9: 1 ratio) to give the title compound (0.022 g, 0.026 mmol) oMS (ESI +) M/z420(M + H) +.1HNMR (CD30D) delta 8.94(br d, 1H), 8.37(brt, 1H), 8.02(br d, 1H), 7.76(br d, 1H), 7.64(t, 1H), 7.56(M, 1H). ㄩ 33
Yan 10.14: 3-removing
decaglycosyl-H12-dide exaggerate-6-O-cun-onyl 2H-digylcarbonyl-1-pyrazole,' 15-a cun a-R ≡ tetrahydropyrrole-2-yl) -methyl) -imino) -erythromycin a
Step 1 pyrazolo [1, 5-a1 pyridine-ethanecarboxylic acid (0.228 g, 1.41 mmol), EDC (0.455 g, 2.38 mmol), HOBT (0.328 g, 2.38 mmol), and 2-port acetyl-3-descladinosyl 1, 12-dideoxy-6-O ═ methyl-3-oxo-12, H- (oxycarbonyl- (((S) -tetrahydropyrrole ═ 2-yl) -methyl) -imino) -erythromycin a trifluoroacetate (0.80 g) from preparation 6a were mixed in anhydrous DMF (7 ml) at room temperature overnight and then heated (45 ℃) for 2 days. The reaction mixture was treated with saturated aqueous NaHCO3, water, and repeatedly extracted with DCM. The combined organic layers were dried (Na)2SO4) And concentrated to dryness under vacuum.
Step 2 the crude product from step 1 was redissolved in MeOH and heated (40. C) for 3 hours to remove 2 □ acetyl groups and obtain the title compound after RPHPLC purification. ' j ^ 34
Ten ^ ruffian 112.11: 3 ═ take off
D-glycosyl-H12-di-de reverie-O-
-3-oxo-12 n-cauda eliminate oxo mousse-1-koxiu-5 ═ carbonyl, s-tetrahydropyrrole-2-usurf-yl) -imino) -erythromycin a
Step 1 quinoline 5-carboxylic acid (0.04 g, 0.23 mmol) was placed in anhydrous MeCN (1.5 ml) and treated with TEA (0.078 ml, 0.56 mmol), followed by tetrafluoroboric acid O- (N ═ succinimidyl) -N, N ″, N □ tetramethyl (0.056105743 g, 8 ● g, 0.185 mmol), and the mixture was stirred for 3 hours.
Step 2. the 3-descladinosyl core from preparation 6b, 12 ═ deoxy-6-O7 yl-3-oxo-12, H- (oxycarbonyl ═ O (((R) -tetrahydropyrrole ═ 2-yl) -methyl) -imino) -erythromycin a trifluoroacetate (0.075 g, 0.081 mmol) in anhydrous MeCN was added to the mixture from step 1 and the resulting mixture was stirred overnight.
Step 3 to ensure that any undesired esters of 2 □ were split off during step 2, the reaction mixture (from step 2) was treated to dryness under a stream of nitrogen and redissolved in MeOH and then heated (60. c) for 1.5 hours. Purification (Rp-HpLc) yielded the title compound (0.006 g). 1 ^ 35, 11.107: in taking off
ralosyl-H12-dide-6 ═ O-yl-keto-1211-cauyl carbonyl-1-3 nan-oct-car-yl azetidine 3 ═ yl-imino-rhodomyces, a
Step 1: 3-chloro-4-methylquinoline (0.10 g, 0.56 mmol; B. mu. rebuke)&cc.p plus γ plus Bo host e α 1 α 1988, 127, 29), N-bromosuccinimide (0.200 g, 1.13 mmol) and dibenzoyl peroxide (0.040 g, 0.168 mmol) in 3 ml of carbon tetrachloride in a sealed tube at 85. Heating for 2.5 hours under C. Water (3 ml) was added and the product was extracted with DCM (3 × 3 ml). Mixing the organic layer with Na2SO4Dried by dehydration and the solvent evaporated. The Lc-Ms of the residual solid showed a roughly 60: 40 mixture of 3-chloro-4-bromomethylquinoline and starting material. MS (ESI +) M/z 257(M + H) +.
Step 2: this crude product (034 mmol), the final crude solid from preparation 1 (0.22 g, 0.34 mmol), TEA (0.087 ml, 0.67 mmol) in 2 ml MeCN in a microwave reactor at 90. c for 6 minutes. 105743 the reaction mixture was concentrated and the residue was purified (RP-HPLC) to give the title compound (0.050 g, 0.059 mmol). 1 "36: 4-bromo
Group-3-
15-15 pyridine
Step 1: 3, 5-dibromo-4-methylpyridine (100 mg) was placed in a microwave tube followed by CuI (0.01 eq) in 2 ml MeOH, cesium carbonate (2 eq) and 1, 10-azaphenanthrene (0.02 eq). The mixture is at 160. c, heating for 2 hours under microwave irradiation. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the EtOAc layer was washed with Na2SO4And (5) dehydrating and drying. The crude intermediate was 3-bromo-5-methoxy-4-methylpyridine, and the oMS (ESI +) M/z 201 [ M + H1 +) was purified by SGC (EtOAc/hexanes).
Step 2: 3-bromo-5-methoxy-4-methylpyridine (0.76 g) was placed in a single-neck round-bottom flask with NaOtBu (1.4 equiv.), Bqip IAP (0.8 equiv.), pd2(dba)3(0.25 equiv.), and benzhydrylideneamine (1 equiv.) in 20 mL of toluene and refluxed at 150 ℃ for 4 hours. The reaction was partitioned between water and EtOAc and the EtOAc layer was washed with Na2SO4And (5) dehydrating and drying. The product was purified by sGc (EtoAc/hexane) to yield 3-methoxy-4 ═ methyl-N- (diphenylmethylene) pyridin-3-aminomets (ESI +) m/z 302IM + H +.
And step 3: to 5-methoxy -methyl-N- (diphenylmethylene) pyridin-3-amine (0.7 g) in a single-neck round bottom flask was added 14 ml of 1N HCl stop HF (1: 1) and the resulting mixture was taken up at 55. Heating for 1 hour under C. Basified with 1N NaOH to pH9, extracted with DCM, and extracted with Na2SO4Dried and concentrated under vacuum to dryness to give 5-methoxy-4-methyl ㄩ sedentadin-3-ylamine. MS (ESI +) z 139 [ M + H1+.
And 4, step 4: to 3-methoxy-4-methyl 105743 , 5-naphthyridine (0.26 g) dissolved in carbon tetrachloride (6 ml) was added N-bromosuccinimide (1.2 equiv.) and dibenzoyl peroxide (0.3 equiv.) and heated at 80 ℃ for 4 hours. The reaction was partitioned between saturated NaHCO3 and DCM, and the DCM layer was dried over Na2SO4 and concentrated to give the title compound (120 mg). MS (ESI +) bloody stasis z252IM + field +.0 with 37: chlorination of 8-Octaf Oxine-5-sulfonyl
Step 1: adding 10 ml of 2, 3-diamino in acetic acidPhenol (2 g) was combined with 20 ml of 4M sodium acetate and a solution of glyoxal (4.8 g) dissolved in 20 ml of water and the resulting mixture was taken up at 60. c for 1.5 hours. After cooling to room temperature' water (100 ml) was added and the mixture was extracted with EtOAc. Mixing the organic layer with Na2SO4Dehydrated, dried and concentrated to give quinoxaline (gentrin oMs (EsI +) z147IM + lug +.
Step 2: to over scAN-5-ol (0.43 g) dissolved in DMF (6 ml) was added K2CO3(2.5 eq) and KI (0.2 eq). Methyl iodide (1.2 equiv.) was then added dropwise to this mixture. The resulting mixture was then heated to 50 ℃ overnight. The reaction mixture was then partitioned between saturated NaHCO3 and EtOAc, and the EtOAc layer was back-washed with water and brine, and with Na2SO4Dried' and concentrated under vacuum to dryness. The crude material was then purified by SGC (MeOH: DCM) to yield the methoxy chirp Ox m/z 160IM + +.
And step 3: by the method of preparation 10, 5 ═ methoxy chirp was converted into the title compound oMS (ESI +) z259 [ M + H ] +.1 |) f 38: 7-bromo-pyridine,' 23-b-buprenorphine ═ 8-carboxaldehyde
In a Parr shaker flask, 2-amino-5-bromo -methyl-daughter nitropyridine 105743-port 1- (1.63 g, 7.0 mmol; Combi-Blocks) was partially dissolved in MeOH (240 mL) and PtO2 catalyst (29 mg) was added, which was then subjected to H2(45psi) and shaken at room temperature for 1 hour. More catalyst (30 mg) was added and hydrogenolysis continued for an additional 2 hours, then the solids were removed by filtration. The filtrate was concentrated to give crude gentodobromo-2, 3-diamino-4-methyl-3-nitropyridine (1.5 g) oMS (ESI +) Wz203(M + H) +. Then, following a procedure analogous to preparation 37, step 1 and preparation 16, it was converted to the title compound oMS (ESI +) M/z239(M + H) +. preparation 39: in chloro-n, 81 naphthyridine 4-carboxaldehyde
Step 1: 4-methyl-pyrindin-ethylamine (30 g, 0.28 mol) was dissolved in DCM (300 ml) and treated with TEA (41 ml) followed by via a dropping funnel by pivaloyl chloride (38 ml)The treatment lasts 30 minutes. The mixture was stirred at room temperature overnight and then poured into a separatory funnel with water (100 ml) and saturated aqueous NaHCO3 (75 ml). The organic layer was extracted, washed with saturated aqueous NaHCO3 (75 ml), and Na2SO4Dried by dehydration and concentrated to obtain solid 2, 2-methyl-N- (4-methyl, pyridin-2-yl) as a white peony amide (42 g, 0.22 mol) o1HNMR(CDCl3)δ8.09(m，2H)，7.93(br s，1H)，6.83(m，1H)，2.33(s，3H)，1.29(s，9H).
Step 2: 2, 2-dimethyl-N- (4-methyl-pyridin-2-yl) -propionamide (42 g, 0.22 mol) from step 1 was placed in a 3-neck 3-liter flask equipped with an overhead stirrer. To this was added water (650 ml), followed by Na2HPO4(78 g, 0.55 mol), followed by DCM (220 ml). The mixture was stirred and cooled to 0 in an ice bath. c, then slowly bubbling chlorine gas through the sprayed frit. The reaction was monitored by TLC (EtOAc/hexanes 1 few), and was found to be complete after 80 minutes. The reaction mixture was poured into a separatory funnel and extracted. The aqueous layer was re-extracted 2-min 105743 with DCM (2 × 100 ml). Mixing the combined liquid layers with Na2SO4Dried by dehydration and concentrated to a crude solid product which is recrystallized from hexane to yield purified N, (5-chloro-4, methyl-pyridin-2-yl) -2, 2-dimethyl-propionamide (41 g, 0.18 mol).1HNMR(CDCl3)δ8.18(s，1H)，8.12(s，1H)，7.94(br s，1H)，2.35(s，3H)，1.29(s，9H).
And step 3: n- (5-chloro-4-methyl-pyridin ═ ethyl) -2, 2-dimethyl gurgline 5 amide (18.3 g, 0.081 mol) from step 2 was placed in a flame-dried three-necked 1-liter flask equipped with an overhead stirrer under nitrogen. To this solid was added anhydrous diethyl ether (170 ml) and the mixture was stirred until dissolved, at which time it was allowed to cool in a dry ice/acetone bath for 20 minutes (slurry formation). To the resulting slurry, tert-butyllithium (1.7M in pentane, 100 ml) was added dropwise over a period of 8 minutes via a cannula. The flask was removed from the cooling bath and stirred until it reached room temperature, at which time solvent-free 3-dimethylamino-acrolein (10 mm) was addedLiter, 0.10 mole). Stirring the resulting mixture at room temperature under a nitrogen stream overnight; by the morning, a dry powder was created. To this water (80 ml) was added followed by slow addition of concentrated HCl (40 ml) while the flask was cooled in an ice/water bath. After acid addition, the ice bath was removed and the flask was heated to 80 ℃ for 1 hour, cooled in an ice/water bath, and treated with NaOH (solid particles) until basic. Next, the alkaline aqueous mixture was extracted with DCM (4 × 100 ml) -resistant and brine was required to help break the emulsion formed. Adding Na to the combined extract2SO4Dried by dehydration and concentrated in vacuo to give the crude product, which is further purified by SGC (EtOAc eluent) to give pure 3-chloro-4-methyl-I1, 8 ] naphthyridine (10 g, 0.056 mol). Note: due to the weak UV activity, it has been found that monitoring the column fractions in MS instead of UV is more effective. MS (ESI +)105743 towering Tian \34883z179 (M + H) +.1HNMR(CDCl3)δ9.06(m，1H)，8.96(s，1H)，8.34(d，1H)，7.51(m，1H)，2.72(s，3H).
And 4, step 4: dissolving 3-chloro-4-ping 9-yl-I1, 8 ] naphthyridine (3.0 g, 16.7 mmol) obtained from step 3 in 4: 1, oxa-ring: water (30 ml) and selenium dioxide (5.9 g, 50.4 mmol) was added. The reaction mixture was heated (H0 ℃) for 2.5 hours, cooled to room temperature and poured into saturated aqueous NaHCO3 (30 ml) and water (10 ml). The mixture was then treated with DCM (80 ml) and the solid was filtered off over celite and the filter cake was washed with DCM. After separation of the aqueous and organic layers, the aqueous phase was re-extracted with DCM (4 × 80 ml) and the combined organic material was dried to dryness in ad 2SO4) and concentrated. The crude product was chromatographed by SGC (MeCN eluent) to give the title compound 3-chloro 41, 8I naphthyridine-4-carboxaldehyde (1.0 g, 5.2 mmol). Note: due to the weak UV activity, it was found that monitoring the column fractions in MS instead of UV was more efficient, as in step 3. MS (ESI +) M/z193(M + H) +.1HNMR(CDCl3) δ 10.79(s, 1H), 9.28(dd, 1H), 9.17(s, 1H), 9.14(dd, 1H), 7.63(dd, 1H). 2-cyclopropyl-3H-imidazo, 5 ═ b1 pyridine-carboxaldehyde
2-cyclopropyl-7-methyl-3-imidazo [4, 5-b ] pyridine (100 mg, 0.58 mmol; EP0420237A1) was treated with SeO2(160 mg, 1.44 mmol) in 6 ml of hexamethylenediamine in water (4: 1) and subjected to microwave irradiation (300W, normal absorbency) at 180. C, three 20 minute intervals. The mixture was then treated with saturated aqueous NaHCO3 (25 ml) and water (25 ml) and passed through celite, removing the solids by filtration, rinsing with DCM. The filtrate was extracted with DCM (4X 50 ml) and the combined organic extracts were dried to dryness! a2SO4), filtered and concentrated to dryness to give the crude title compound. MS (ESI +) z105743 ● 94 ● 188(M + H) + preparation 41: in methyl-3H-imidazo [4, 5-b-pyridine-7-carboxaldehyde
Step 1: 4-methyl-pyridinum, 3-amine (1.0 g, 8.12 mmol) was treated with formic acid (15 ml) and heated to reflux over 3 hours. After cooling to room temperature, the solution was concentrated under a stream of nitrogen for 48 hours, then diluted with DCM (30 ml) and the solid was filtered off in a buec imer funnel. The filtrate was concentrated and the crude product was chromatographed by SGC (DCM: MeOH: NH40H ═ 90: 10: 1 as eluent) to give purified 7-methyl ∞ 3H-imidazo [4, 5-b1 pyridine (0.325 g, 2.44 mmol) oms (gcms) M/z 133(M) +.
Step 2: reacting 7-methyl-3H-imidazo [4, 5-b)]Pyridine (2.0 g, 15 mmol) was dissolved in acetone (60 ml) and treated with freshly ground KOH (4.21 g), followed by dropwise addition of methyl iodide (10 ml) o10 min, after which the reaction mixture was poured into saturated aqueous NaHCO3 (25 ml) in water (25 ml) and extracted with DCM (4 × 80 ml). The organic layers were combined and washed with Na2SO4Drying by dehydration, filtration and concentration of oSGC (DCM: MeOH: NH40H ═ 96: 4: 1 as eluent) to give 3, 7-dimethylcunx-imidazo [4, 5-b-]Pyridine (1.05 g). 1H NMR (CDCl)3)δ7.94(s，1H)，7.83(d，1H)，6.48(s，1H)，3.04(s，3H)，2.07(s，3H).
And step 3: oxidation with SeO2 as described in preparation 16 gave the title compound oMS (ESI +) M 162(M + H) +. preparation 42: 6-chloro-3-timidazolo, 5-b1 pyridine-7-carboxaldehyde
Step 1: n- (gento-4-methyl-pyridin-yl) swallow, 2 ═ methyl-propionamide (3.0 g, 13.2 mmol) from preparation 39, step 2 was treated with concentrated sulfuric acid (19 ml), stirred for 30 minutes, then cooled in an ice water bath to 105743 ● 9 side at 0 ℃, and fuming red nitric acid (0.67 ml) was added over a 10 minute period. The reaction mixture was heated (35. C) overnight, then diluted with water (40 ml) and extracted with DCM (6 × 50 ml). DCM was removed under vacuum and the residue was redissolved in concentrated HCl (20 ml) and heated to 40 ℃ over 18 hours then 100. C4 hours, and finally 18 hours at 50 ℃. The mixture was cooled to room temperature, diluted with water (50 ml) and extracted with DCM (5 × 40 ml). The aqueous layer was treated with 30% (w/v) aqueous NaOH until pH 12, then extracted with DCM (6 × 60 ml). These latter extracts were combined with Na2SO4Dried by dehydration, filtered and concentrated to give 5-chloro-4-methyl-3-nitro-pyridin-ethylamine (1.0 g) o1HNMR(CDCl3)δ8.15(s，1H)，5.93(br s，2H)，2.49(s，3H).
Step 2: the material from step 1 (1.0 g) was dissolved in MeOH (300 ml) and PtO2(40 mg) was added. The mixture was allowed to receive hydrogen (50psi) for 3.5 hours in a parr shaker, then filtered through celite, and concentrated HCl (1 ml) was added to the filtrate, then concentrated to yield blunt [ chloro-4-methyl-pyridine-2, 3-diamine hydrochloride (1 g) nmr (CDCl)3) δ 7.39(s, 1 linger, 2.29(s, 3H).
And step 3: the material from step 2(1 g) was dissolved in phosphoric acid (20 ml) and then added to formic acid (10 ml) and heated (130. c) for 1 hour, then cooled to room temperature over 3 days. The reaction mixture was then poured into ice (200 g) and the pH adjusted with 30% (w/v) aqueous NaOH until a solid formed. The solids were removed via filtration and rinsed with water. The filtrate (aqueous solution) was concentrated to dryness and extracted repeatedly with hot EtOH. The EtOH extracts were combined and concentrated to a solid (3 g). The solid was extracted with hot MeCN (4 × 80 ml); the combined MeCN extracts were allowed to cool to room temperature and a solid precipitated out. The precipitate was filtered (celite) and the filtrate was concentrated to give 6-chloro pi-methyl-3H-imidazo [4, 5, bI pyridine (0.278105743 g) oMS (ESI +) z 168(M + H) +.
And 4, step 4: the product from step 3 (0.278 g) was subjected to oxidation by SeO2 as in preparation 16 to give the title compound (69 mg). MS (ESI +) M 182(M + H) +. preparation 43: 4-bromomethyl- ping-3 ═ methyl cyanide
Quack-4-quinquack-eye (alternate force. petaby. α corpse. 1989, 322, 5H) was prepared according to the procedure used in preparation 36, step 4, brominating oMS (ESI +) M 249(M +2) +.preparation 44: 3-methyl-benzenediol-4-carboxylic acid methyl aldehyde
Step 1: 2-chloro-methyl-quinoline -carbonyl chloride (200 mg) was synthesized as reported by (B ω o kar M as C plus 2002, 10, 779), dissolved in TI (4 mL) and treated with sodium borohydride (189 mg, 5.0 mmol) under nitrogen. The reaction mixture was stirred for 1 hour, diluted with water, extracted three times with DCM, and extracted with Na2SO4Dried by dehydration, filtered, and evaporated under vacuum to afford 174 mg of crude alcohol. 1HNMR (CDCl)3) δ 8.12(d, 1H), 7.97(d, 1H), 7.65(M, 1H)7.57(M, 1H), 5.16(s, 2H), 2.62(s, 3H). LCMS (ESI +) z208(M) +, 210(M +2) +.
Step 2: a mixture of 170 mg of the alcohol from step 1 (0.819 mmol), 30 ml of EtOH, 0.35 ml of TEA (2.5 mmol) and 100 mg of 10% P at rt was shaken under 15psi of hydrogen for 30 min, filtered through celite using MeOH and evaporated in vacuo. The resulting residue was partitioned between water and DCM, extracted three more times with DCM, washed with brine, and Na2SO4Dried by dehydration, filtered, and evaporated in vacuo to afford 128 mg of the title compound.1HNMR(CDCl3) δ 8.60(s, 1H), 8.19(d, 1H), 8.04(d, 1H), 7.63(M, 1H), 7.56(M, 1H), 5.13(s, 2H), 2.51(s, 3H). LCMS (ESI +) z174(M + H) +.105743 preparation 45: 8-methoxyquinoline-5-carboxaldehyde
Step 1: 5- (hydroxymethyl) quinolinol (6.7 g, 38 mmol) was dissolved in DMF (38 mL) andtreated with potassium carbonate (16 g, u6 mmol) followed by methyl iodide (2.9 ml, 6.8 g, 48 mmol). The mixture was stirred at room temperature overnight, then poured into a separatory funnel with water, and the organic layer was extracted with Na by DCM extraction 3x o2SO4Dried and concentrated to give solid 5-hydroxymethyl ← 8-methoxyquinoline (6.5 g). 1HNMR (CDCl)3)δ8.97(d，1H)，8.51(d，1H)7.49(m，2H)，6.99(d，1H)，5.05(s，2H)，4.09(s，3H).
Step 2: 5-hydroxymethyl-8-methoxyquinoline from step 1 (6.5 g, 34 mmol) was dissolved in 250 ml DCM and treated with 24 g manganese dioxide. After stirring for 24 hours, the mixture was treated with another 6 grams of manganese dioxide and stirred for 24 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give 6 g of the title compound as a brown solid o1HNMR(CDCl3) δ 10.2(s, 1H), 9.69(d, 1H), 9.01(d, 1H), 8.01(d, 1H), 7.61(dd, 1H), 7.16(d, 1H), 4.19(s, 3H). preparation 46: 3-methoxyquinoline-4-carboxaldehyde
Step 1: methyl 3-hydroxycinchoninate O fulga, 1953, 18, 552) (1.53 g, 754 mmol), potassium carbonate (1.15 g, 8.29 mmol) were treated with methyl iodide (470 μ l, 7.54 mmol) in acetone (H ml) and stirred under nitrogen at room temperature overnight. The mixture was diluted with water and extracted into DCM and washed with saturated sodium thiosulfate solution. Mixing the organic substance with Na2SO4Dehydrating, drying, and concentrating. The material was purified by SGC (Combi flash, 10-50% EtOAc-hexane over 40 minutes) to yield methyl 3-methoxycinchoninate o1HNMR(CDCl3) Delta 8.85(s, 1H), 8.07(d, 1H), 7.72(d, 1H), 105743-9 are used in a wet process of 7.61(M, 2H), 4.08(s, 3H), 4.03(s, 1H), MS (ESI +) M/z 218(M + H) +.
Step 2: methyl 3-methoxyquinic acid (427 mg, 1.96 mmol) was cooled to-78 ℃ in toluene (3.9 ml) under a nitrogen atmosphere. 1MDiBAL-H in toluene (5.9 mL, 5.9 mmol) was added dropwise over 5 minutes. The reaction was quenched with water (3.9 ml)And warmed to room temperature, magnesium sulfate and NaHCO3 added in alternating portions, and EtOAc o added the solid was filtered and washed with EtOAc, then concentrated to give the intermediate alcohol (339 mg) o1HNMR(CDCl3)：δ8.67(s，1H)，8.10(d，1H)，8.00(d，1H)，7.55(m，2H)，5.14(s，2H)，3.98(s，3H).
And step 3: the product from step 2 (339 mg, 1.79 mmol) was dissolved in DCM (1.8 ml) and treated with Dess ═ Ma pi in periodinane (760 mg, 1.79 mmol) at room temperature. After completion, the mixture was diluted with DCM and washed with saturated NaHCO3 solution. Then, the organic substance is added with Na2SO4Dehydrating, drying, and concentrating. The material was purified by SGC (0-100% EtOAc: hexanes over 45 min) to give a yellow solid (264 mg) oMS (ESI +) M 188(M + H) +.1HNMR(CDCl3) δ 10.90(s, 1H), 9.02(m, 2H), 8.08(d, 1H), 7.65(m, 2H), 4.21(s, 3H). preparation 47: 3-methoxy-n, 81-naphthyridine-4-carboxaldehyde
Step 1: n- (3-amino-4-methyl. Sodium nitrite (2.33 g, 33.74 mmol) in 40 ml of water was added dropwise to the solution over 25 minutes. The solid was collected by filtration and washed with cold ether. The solid was then transferred to a flask and in MeOH open to air (85 ml) at 55-60. Heat overnight at C. The solvent was removed in vacuo and the crude material 105743-99 ● was dissolved in EtOAc and washed with NaHCO3 solution. Mixing the organic substance with Na2SO4Dried by dehydration, and concentrated after filtration. The intermediate was purified by SGC and purified with EtOAc: hexanes 0 to 25% were eluted over 30 minutes to give 3.16 g of N- (5 ═ methoxy-4-methyl ═ pyridin-2-yl) -2, 2 ═ methyl-propionamidoms (ESI +) M/z (M + H) +223.1HNMR(CDCl3) Δ 8.08(s, 1H), 7.74(s, NH), 7.68(s, 1H), 3 84(s, 3H), 2.22(s, 3H), 1.62(s, NH)2)，1.30(s，9H).
Step 2: conversion of material from step 1 to daughter methoxy-4-methyl ≡ 1, 8I naphthyridine by a process for preparation 39 step 3. 1H NMR (CDCl)3)δ8.98(d，1H)，8.92(s，1H)，8.32(d，1H)，7.45(m，1H)，4.07(s，3H)，254(s，3H).
And step 3: converting the material from step 2 to 3-methoxy-U, 8 ] naphthyridine-4-carboxaldehyde by the method of preparation 16. 1HNMR (CDCl)3) δ 10.84(s, 1H), 9.42(d, 1H), 9.22(s, 1H), 9.03(m, 1H), 7.57(m, 1H)4.25(s, 3H). preparation 48: 4-methyl-n, 81 naphthyridine
The conversion of 4-methyl-pyridin-2-ylamine to 4 ═ methyl-I1, 8 ] naphthyridine is carried out according to known methods (C plus. P plus γ plus. B μ ═ 11971, 19, 1751). Sodium m-nitrobenzenesulfonate (202 g, 897 mmol) was weighed into a 3 l 3-neck flask equipped with an overhead stirrer and the flask was immersed in an ice-water bath, followed by the addition of concentrated sulfuric acid (260 ml), glycerol (145 ml, 1987 mmol), 4-methyl-pyrindin-2-ylamine (50 g, 463 mmol) and finally water (260 ml). The mixture was heated to 120 ℃ for 8 hours and then cooled to room temperature to yield a chocolate brown slurry. Sodium hydroxide (20N in water) was slowly added with cooling (so that the temperature did not exceed 40 ℃) until the pH was close to 10. The resulting slurry was filtered through celite and the filtrate was extracted with DCM (3 × 100 ml). Mixing the organic layer with Na2SO4Dried by dehydration, filtered, and concentrated under vacuum to a black oil. The desired product (7.32 g, 50.8 mmol) was isolated by passage through SGC105743 ㄩ 0, 1 in small (DCM: MeOH 95: 5). preparing: 3-bromo-I1, 81 naphthyridine-4-carboxaldehyde
Step 1: using a procedure analogous to preparation 48, 2-amino-5-bromo-4-methylpyridine gave 3-bromo -methyl-I1, 8 ] -naphthyridino1HNMR(CDCl3)δ9.H(m，2H)，8.43(d，1H)，7.54(m，1H)，2.79(s，3H).
Step 2: a mixture of 3-bromo-4-methyl- [1, 8 j-naphthyridine (1.5 g, 6.7 mmol), hexamethylenedioxide (16 ml) and water (0.6 ml) was mixed with selenium dioxide (3.0 g, 27 mmol)Ear) and processed at 80. Stirring for 1 hour under C. The mixture was cooled to room temperature, diluted with saturated aqueous NaHCO3, extracted 3x with EtOAc, and the combined organic phases were extracted with Na2SO4Dried, filtered and concentrated under vacuum. Filtration through a pad of silica gel eluting with EtOAc afforded 0.70 g of the title compound as a yellow solid o1HNMR(CDCl3) δ 10.62(s, 1H), 9.32(s, 1H), 9.28(d, 1H), 1.18(d, 1 lin, 7.66(dd, 1H). preparation 50: 2-methoxy - "1, 81 naphthyridine-car-yl-ethanone
Step 1: 1- [1, 8I naphthyridin-4-yl-ethanone (250 mg, 1.45 mmol) from preparation 18, 2, 6-dimethylpyrazine, was added. Pyridine (0.254 ml, 2.18 mmol) was treated with trimethylsilyl trifluoromethanesulfonate (0.276 ml, 1.53 mmol) in DCM (3.6 ml) and stirred at room temperature overnight. The mixture was diluted with DCM and washed with saturated NaHCO 3. Mixing the organic substance with Na2SO4Dried by dehydration and concentrated to give 350 mg of 4- (1-trimethylsilyloxy-vinyl) - {1, 81-naphthyridine as an oil oMS (ESI +) M/z 245(M + H) +.
Step 2: to a suspension of iodosobenzene (347 mg, 157 mmol) in MeOH (7.2 ml) in an ice bath was added boron trifluoride etherate (0.200105743 ㄩ 0 ml, 1.57 mmol) followed by 4 ═ 4 (1-trimethylsilyloxy-vinyl) -I1, 8 ] naphthyridine from step 1 (350 mg, 1.43 mmol) in a minimum amount of MeOH. The reaction mixture was allowed to warm to room temperature overnight, then quenched with solid NaHCO3 and diluted with water. Iodobenzene was extracted with EtOAc and the desired material was re-extracted with DCM 2x o the organic layer was Na2SO4Dried by dehydration and concentrated to an orange oil (H0 mg) which contained a 2: 3 mixture of the starting material and the desired title compound oMS (ESI +) z203(M + H) +. preparation 51: 5-bromomethyl ≡ quinoline-8-carbonitrile
Step 1: mu.o.kappa.pi.eC of 5-bromo-2-methylaniline was added 2002, knife 6, 173) (8.9 g, 48 mmol) with water (27 ml), concentrated sulfuric acid (27 ml), glycerol (19 g, 206 mmol), 3-nitrobenzenesulfoneSodium (21 g, 23 mmol) and heated to 120 deg.f. C, over 8 hours, then to 150 ℃ over 4 hours. The mixture was cooled to room temperature, quenched with ice, carefully basified with solid sodium hydroxide, and buffered with solid NaHCO 3. The mixture was extracted twice with EtOAc and the organic layer was taken over Na2SO4Dehydrating, drying, and concentrating. Purification by SGC (Combi flash, 5-40% EtOAc-hexanes over 40 min) afforded 5.33 g of gemfibromethylfield ═ bromoquinoline. 1HNMR (CDCl)3)δ9.05(d，1H)，8.34(d，1H)，7.94(d，1H)，7.49(dd，1H)，7.24(d，1H)，2.65(s，3H).
Step 2: 5-methyl-8-bromoquinoline (01.5 g, 6.78 mmol) was treated with Pd2(dba)3(0.62 g, 0.67 mmol), diphenylphosphinodicyclopentadienyliron (0.752 g, 1.36 mmol), zinc cyanide (2.77 g, 23.7 mmol), cuprous iodide (0.064 g, 0.34 mmol), and degassed DMF (45 mL, nitrogen purged prior to use) in a Schlenk flask under nitrogen. The mixture was heated to 80 deg.f. And C, standing overnight. After cooling to room temperature, the mixture was poured into 4: 1: 4 saturated ammonium chloride: ammonium hydroxide (37%): water (90 ml), extracted 3X with EtOAc and the organic layer was washed with Na2SO4Dehydrating, drying, and concentrating. The material was purified by SGC and eluted with 5 ═ 45% EtOAc in hexanes over 30 minutes to give 1.05 g of 5-methyl (m-8-carbonitrile o)1HNMR(CDCl3)δ9.10(d，1H)，8.39(d，1H)，8.01(d，1H)，7.58(m，1H)，7.43(m，1H)，2.76(s，3H).
And step 3: brominating the material from step 2, according to the method of preparation 36, step 4, to give the title compound o1HNMR(CDCl3) δ 9.16(m, 1H), 8.55(d, 1H), 8.08(d, 1H), 7.66(m, 1H), 4.88(s, 2H). 4-formyl quinoline-8-carbonitriles
Step 1: 2-bromoaniline (5.16 g, 30 mmol) dissolved in acetic acid and concentrated sulfuric acid was treated with a solution of methyl vinyl ketone in acetic acid. The reaction mixture was heated to 90 deg.f. And C, the time is 14 hours. Pouring the cooled mixture into water, alkalifying with sodium hydroxide, and addingAnd (4) extracting the EtOAc. Mixing the organic substance with Na2SO4Dried by dehydration and concentrated, purified by SGC (Combi flash, 0 inch 00% EtOAc: hexanes over 30 minutes) followed by recrystallization from hot hexanes to afford 4-methyl-8 ═ bromoquinoline (2.3 g)1HNMR(CDCl3) δ 8.92(d, 1H), 8.08(d, 1 Tian, 8.01(d, 1H), 7.45(t, 1H), 7.32(d, 1H), 2.71(s, 3H).
Step 2: 4-methyl-8-bromoquinoline (0.1 g, 0.47 mmol) was treated in a Schle Shanr flask under nitrogen with Pd2(dba)3(0.049 g, 0.047 mmol), diphenylphosphinodicyclopentadien iron (0.052 g, 0.094 mmol), zinc cyanide (0.19 g, 1.6 mmol), cuprous iodide (0.005 g, 0.024 mmol), and degassed DMF (2.3 mL, purged with nitrogen before use). The mixture was heated to 80 ℃ over 2 hours. After cooling to room temperature, the mixture was diluted with water, extracted 3x with EtOAc, and the organic layer was taken over Na2SO4Dried by dehydration, and concentrated to give 0.1 g of gentamicin-8-carbonitrile.1HNMR(CDCl3)δ8.89(d，1H)，8.04(d，1H)，8.02(d，1H)，7，41(m，1H)，7.27(m，1H)，2.70(s，3H).
And step 3: using preparation 16, the material from step 2 was converted to the title compound o1HNMR(CDCl3) δ 10.43(s, 1H), 9.40(d, 1H), 9.38(d, 1H), 8.24(d, 1H), 7.94(d, 1H), 7.80(t, 1H) · jj · j · 53: 22-diketo, 23-dihydro-1H cun lambda 6-yao ',' C mouth, thiophene ∞ rhino carboxylic acid
Aldehydes
Step 1: a solution of methyl 3, 4-bis (bromomethyl) benzoate (997 mg, 3.10 mmol) in EtOH (16 ml) and water (4 ml) was treated with sodium sulfide nonahydrate (745 mg, 3.10 mmol). The solution was heated to reflux for 2 hours with rapid stirring and then cooled to room temperature. The mixture was then concentrated to dryness in vacuo and the residue was suspended in DCM (50 ml). The slurry was filtered and the solid was washed with additional DCM. Adding Na to the filtrate2SO4Dehydrating, drying, filtering, andconcentration in vacuo afforded 2, 1-dihydrobenzo thiophene ═ 5-carboxylic acid methyl ester (581 mg) as a yellow oil ohihnmr (CDCl)3)δ7.88-7.94(m，2H)，7.31(d，1H)，4.29(s，4H)，3.92(s，3H).MS(ESI+)m2z197IM+H】+.
Step 2: a solution of the sulfide from step 1 (577 mg, 2.97 mmol) in DCM (24 ml), MeOH (24 ml) and water (16 ml) was treated with an oxygen generator (oxone) (2.37 g, 3.85 mmol, 1.3 eq) and the reaction was stirred at rt overnight. The mixture was then filtered through a pad of celite, and the pad was washed with additional DCM (2 × 20 ml). The filtrate layers were separated and the aqueous layer was extracted with DCM (2 × 25 ml). Adding Na to the combined organic extracts2SO4Dried, filtered, and concentrated under vacuum. The crude residue formed was purified by SGC (gradient 80: 20 to 50: 50 hexane but tOAc), 105743 ㄩ 04-to give methyl 2, 2-diketo-2J-dihydrobenzo thiophene-3-carboxylate (288 mg) as an off-white solid:1HNMR(CDCl3) δ 8.05(d, 1H), 8.01(s, 1H), 7.41(d, 1H), 4.42(d, 4H), 3.94(s, 3H). MS (ESI +) z 227IM + H1+.
And step 3: a solution of the ester from step 2 (288 mg, 1.27 mmol) in DCM (10 ml) was cooled to-78 ℃ under nitrogen and treated dropwise with LiAlH4(1.0M in hexane, 1.50 ml, 1.50 mmol) over 5 minutes. The mixture was then stirred at-78 ℃ for 90 minutes, then warmed to room temperature and stirred for an additional 1 hour. Then, water (1 ml) was added and vigorous gas evolution was found. The mixture was stirred for 10 minutes, then 2N NaOH (1 ml) was added followed by additional water (3 ml). The mixture was stirred for 30 min, diluted with EtOAc (50 ml), and Na2SO4And (5) dehydrating and drying. Subsequent filtration and concentration of the filtrate in vacuo gave the desired alcohol intermediate (310 mg), which was used directly. This alcohol was dissolved in DCM (13 ml) and the solution treated with MnO2(463 mg, 5.33 mmol). After stirring at room temperature for 1.75 hours, the slurry was filtered through a pad of celite, and the pad was washed repeatedly with DCM. The filtrate was then put under vacuumConcentration and the residue was purified by SGC (gradient 75: 25 to 50: 50 hexane abuse OAc) to give the title compound (25 mg) as a pale yellow solid:1HNMR(CDCl3)δ10.02(s，1H)，7.85-7.92(m，2H)，7.53(d，1H)，4.45(d，4H).13C NMR(CDCl3) δ 190.8, 137.8, 136.8, 132 □ 6, 130 □ 3, 127.0, 126.9, 56.9, 56.6.MS (ESI +) m/z 197IM + tian +. di 1 device 54: chlorination of night ',' pupil ≡ 5-sulfonyl
Step 1: a solution of 2-bromonitroaniline (5.27 g, 24.3 mmol) in 98% formic acid (30 mL) was heated to reflux under nitrogen for 90 min. The cooled reaction mixture was then poured into cold water (600 ml), 105743 ㄩ 0 which gave a yellow precipitate. The solid was isolated by filtration and the filter cake was washed with cold water (2 × 200 ml). Subsequent drying under vacuum overnight afforded N-formylcun-bromo-5-nitroaniline (5.84 g, 98%) as a yellow solid: 1HNMR (DMSO-d6) δ 10.14(br s, 1H), 9.01(d, J ═ 2.4Hz, 1H), 8.46(s, 1H), 7.98(d, J ═ 8.8Hz, 1H), 7.91(dd, J ═ 8.8, 2.5Hz, 1H); 13CNMR (DMSO-d6) delta 161.2, 146.9, 136.6, 134.0, 120.6, H9.8, 116.7.
Step 2: a solution of formamide (5.83 g, 23.8 mmol) from step 1 and sodium sulfide nonahydrate (8.60 g, 35.8 mmol) in EtOH (120 ml) was heated to reflux under nitrogen for 2 hours. After this time, the reaction was allowed to cool to room temperature and then poured into cold water (600 ml). The resulting solution was cooled in an ice bath and acidified to pH1 with 37% HCl. The solution was allowed to cool in the ice bath for a further 1 hour, during which time an orange precipitate formed. The solid was isolated by filtration and dried under vacuum to give 5-nitrobenzophenone oxazole as an orange solid (2.28 g). The filtrate was extracted with EtOAc (3X 200 mL) and the combined organic extracts were extracted with Na2SO4Dry by dehydration, filter and concentrate under vacuum to give additional 5-nitrobenzophenone oxazole (0.89 g) as an orange solid, which on nmr and 1f C analysis showed the same product on both recoveries; the combined yield was 3.17 g o1HNMR(CDCl3)δ9.19(s，1H) 9(d, 1H), 8.35(dd, 1H), 8.12(d, 1H);13CNMR(CDCl3)δ157.3，153.1，147.0，140.2，122.5，120.1，H 9.3.MS(ES I+)m/z 181IM+HI+.
and step 3: a solution of the material from step 2 (1.17 g, 6.47 mmol) in 37% HCl (15 mL) was heated to 40. C, treated with tin (II) chloride dihydrate (4.39 g, 19.4 mmol) and stirred at this temperature for 30 minutes. The reaction was then poured into saturated aqueous NaHCO3 (250 ml) and extracted with EtOAc105743 ㄩ 06 ● (3 × 100 ml). Adding Na to the combined organic extracts2SO4Dried, filtered and concentrated under vacuum. The crude residue formed was purified by SGC (gradient 75: 25 to 0: 100 hexane swing oac) to give 4(0.214 g) as an orange solid:1HNMR(CDCl3) δ 8.91(s, 1H), 7.69(d, J ═ 85Hz, 1H), 7.41(d, J ═ 2.2Hz, 1H), 6.87(dd, J ═ 8.5, 2.2Hz, 1H), 4.12(br s, 2H); MS (ESI +) z 151 [ M + H1+.
And 4, step 4: a solution of aniline from step 3 (0.217 g, 1.45 mmol) in glacial acetic acid (2 ml) was added dropwise to 37% HCl (2 ml). The mixture was cooled to 0 ℃ via an ice/salt bath and a solution of sodium nitrite (0.H0 g, 1.59 mmol) in water (1.1 ml) was added dropwise. The mixture was then stirred at-10 ℃ for 60 minutes. While this diazotization was progressing, a second flask containing glacial acetic acid (2 ml) and cuprous chloride (0.029 g, 0293 mmol) was treated with sulfur dioxide gas until the mixture became blue-green in color. The mixture was allowed to cool to 10 deg.f. And C, adding the diazotization reactant in portions within 15 minutes. Vigorous gas evolution was found. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was then poured into cold water (100 ml) and the aqueous layer was extracted with EtOAc (3 × 50 ml). The combined organic extracts were washed with water (2X 50 ml), saturated aqueous N IC03 (3X 25 ml) and brine (3X 25 ml) and then Na2SO4Dried, filtered and concentrated under vacuum. The crude solid formed is purified by SGC (90: 10 hexane-abuse tOAc) to obtain the targetThe title compound (0.123 g) was obtained as an off-white solid: melting point H0-H2 ℃;1HNMR(CDCl3)δ9.24(s，1H)，8.83(d，1H)，8.23(d，1H)，8.11(dd，1H).13CNMR(CDCl3) δ 157.5, 152.7, 142.6, 141.0, 123.4, 123.1, 122.8.MS (ESI +) cutting z 234, 236IM + lugs +. 55: gasification of 4-ethylkappa-3-OxoJiang + Sulfonyl
Step 1: at 60. Ethane iodide (1.93 ml, 38.4 mmol) was added dropwise over 15 minutes to a stirred mixture of 4-nitroguaiacol 1(5.00 g, 29.6 mmol) and K2CO3(6.21 g, 44.3 mmol) in DMF (30 ml) under nitrogen. After 2 hours, the reaction was cooled to room temperature and diluted with water (100 ml) and methyl tert-butyl ether (250 ml). The organic layer was washed with water (25 ml), brine (2 × 20 ml), and Na2SO4Dried by dehydration, filtered and concentrated in vacuo to give 2-ethoxy-5-nitrobenzyl ether (5.74 g) as a pale yellow solid. Melting point 88-90. C, performing a chemical reaction on the mixture to obtain a reaction product,1HNMR (DMSO-d6) delta 7.89(dd, 1H), 7.73(d, 1H), 7.16(d, 1H), 4.17(q, 2H), 3.88(s, 3H), 1.37(t, 3H), 13cNMR (DMso-d6) delta 153 means away from 9, 148.6, 140.5, 117.6, n1.5, 106.4, 64.6, 55.9, 14.4.MS (ESI +) z 198{ M + lug +.
Step 2: a suspension of 2-ethoxy-5-nitrobenzylether from step 1 (5.50 g, 27.9 mmol) in 10% Pd/C (1.0 g) in 1: 1 EtOH: EtOAc (50 mL) was shaken under an atmosphere of H2 (35-40psi) for 30 minutes. The reaction mixture was filtered through celite and concentrated in vacuo to give 4-ethoxy-3-methoxyaniline (4.82 g, 100%) as a brown solid: melting point 54 ═ 56 ℃.1H NMR (DMSO-d6) Δ 6.61(d, 1H), 6.25(d, 1H), 6.03(dd, 1H), 4.65(s, 2H), 3.82(q, 2H), 3.66(s, 3H), 1.22(t, 3H);13CNMR(DMso-d6)δ143.6，138.8，H6.6，105.1，99.9，65.0，55.1，15.1；MS(ESI+)m/z 168【M+H】+.
and step 3: to a solution of 4-ethoxy-3-methoxyaniline from step 2 (2.35 g, 14.05 mmol) in glacial acetic acid (5 ml) was added concentrated HCl (15 ml). The mixture was cooled to 0 in an ice/salt bath.c and a solution of sodium nitrite (1.06 g, 15.36 mmol) in water (2.5 ml) was added dropwise. 105743 ㄩ 08 ● then mixed the mixture at-10. Stirring for 90 minutes under C. While this diazotization reaction was progressing, a second flask containing glacial acetic acid (16 ml) was saturated with sulfur dioxide gas for 10 minutes, then cuprous chloride (0.278 g, 2.81 mmol) was added, followed by additional sulfur dioxide gas, until the mixture turned blue-green. The mixture was allowed to cool to 10 ℃ and the diazotisation mixture was added in portions over 25 minutes. The resulting mixture was allowed to warm to room temperature overnight. The reaction mixture was then poured into ice-cold water (100 ml) and the aqueous layer was extracted with EtOAc (4 × 50 ml). The combined organic extracts were washed with water (2 × 50 ml), saturated aqueous NaHCO3 (4 × 50 ml) and brine (3 × 50 ml), then Na2SO4Dried, filtered and concentrated under vacuum. The resulting dark red oil was purified by chromatography (Biotage, gradient 100: 0 to 80: 20 hexane abuse tOAc, over 850 mL) to yield 48 mg of impure product as an orange semisolid. This semi-solid was triturated with hexane to give the title compound (34 mg) as a pale yellow solid. Melting point 72-73 ℃.1HNMR(CDCl3) δ 7.66(dd, 1H), 7.44(d, 1H), 6.97(d, 1H), 4.21(q, 2 p, 3.96(s, 3H), 1.52(t, 3H).13CNMR(CDCl3)δ154.3，149.5，135.7，121.7，n1.3，109.3，65.1，56*4，14.5.
Other non-limiting embodiments are shown in tables 1-16. On each of the heads, the macrocyclic lactone template structure of the following example is shown. Template variables are defined in the table for each embodiment. These tables list (1) the example number, (2) the variable name (C-2 fluorinated compound is shown as 2-F in the name window of the table entry. see preparation 29) (the compound shown as an asterisk in the name window is a single diastereomer in an unidentified absolute configuration), (3) M +1 or M/2(IM +21 ) MS data (unless otherwise indicated), (4)1HNMR spectroscopic data were run as CD30D (unless otherwise indicated), and (5) the preparative method 105743 ㄩ 0 camel method of coupling helmet base reagents with templates was given the preparative number, which is describedConditions for preparing the subject compounds are described. In the case where a 2' -acetate protecting group is present, this group is removed as a final step, as is the case in preparation 34, step 3. Compounds are prepared as formates unless otherwise indicated.
Chromatographic purification is typically performed using reverse phase high performance liquid chromatography (RP-HPLC, Shimadzu instrument) using a gradient elution with acetonitrile (0.1% formic acid) and water (0.1% formic acid) solvent system. Evaporative light scattering detection systems were used to aid in the RP ═ HPLC compound imaging and collection procedure. Other purifications were performed by normal phase medium pressure SGC.
TABLE 1
Example # 2-R2Name (R) MS .HNMR Preparation of #
1.01 Benzyl radical m 757 7.43(m，5H) .
1.02 (pyridin-2-yl) methyl m vomit 758 858(d，1H)；7.84(m，1H)；7.42(d，1H)；7.38(m，.H) 27
1.03 (pyridin-3-yl) methyl m-1758 8.58(s，1H)；8.53(d，.H)；7.88(d，.H)；7.46(m，1H) 27
1.04 (pyridin-4-yl) methyl m-.758 8.48(dd，2H)；7.4.(d，2H) 27
1.05 (quinoline-8-tomb) methyl 8.0 8.98(d，1H)；8.4.(d，.H)；8.03(d，.H)；7.87(d，.H) 27
1.06 (quinolin-5-yl) methyl m-.808 8.90(d，.H)；8.72(d，.H)；8.08(d，.H)；778(m，.H) 27
1.07 (quinolin-6-yl) methyl M/2406 8.85(d，1H)；8.38(d，.H)；8.03(d，1H)；7.98(bs，.H)；779(d，.H)；757(m，.H) 27
1.08 3, 4 Difluorobenzyl m-1793 736 cun.24 (m, 2H); 7.20(bs, 1H) 27
1.09 (1H-benzo [ d1 imidazol-2-yl) methyl m-1797 7.52(dd，2H)；7.20(dd，2H) 27
Example king Gas R2Name one MS 1HNMR Preparation of a phantom
1.10 (1-pyridin-2-Yl) -pyrazol-3-Yl) methyl m 824 CDCl3：8.62(bs，1H)；8.41(bs，H)；8.0L7.92(m，2H)；7.31(bs，1H)；6.61(bs，1H) 27
1.11 (1H-benzimidazol-7-yl) methyl M 400 8.27(s，1H)；7.65(dd，1H)；7.36-7.32(m，2H) 27
1.12 (quinol-8-yl) methyl m，1809 9.0L8.96(m，2H)；820(d，1H)；7.99(d，1H)；7.91(m，1H) 27
1.13 (benzoxazol-7-yl) methyl M/2401 8.53(s, 1/2H); 8.18(s, 1/2H); 7.75(d, 1 H) Jiang.45 (m, 1H); 7.36(d, 1 H) 27
1.14 4-cyanobenzyl radical 784 7.76(d，2H)；7.58(d，2H) 27
1.15 3-cyanobenzyl radical m 782 7.76(bs，1H)；7.74-7.68(m，2H)；7.56(t，1H) 27
1.16 (quinolin-4-yl) methyl m spit 808 CDCl3：8、80(d，1H)；8.20(d，1H)；803(d，1H)；7.79(t，1H)；7.76(t，1H) 27
1.17 (1, 8-Nalidin-3-yl) methyl m 809 9.08(dd，1H)；8.53-8.48(m，2H)；7.70(dd，1H)；7.63(d，1H) 27
1.18 (1H-pyrazol-5-yl) methyl m 747 7.69(d，1H)；6，43(d，1H) 27
1.19 (1H-pyrazol-4-yl) methyl m 747 7.80(s，2H) 27
1.20 (L8-Nalidin-4-yl) methyl W2406 9.05(dd，1H)；9.00(d，1H)；8.75(dd，1H)；7.68(m，1H)；7.61(d，1H) 27
1.21 1R- (pyridin-4-yl) ethyl m 772 850(dd，2H)；7.48-7.40(m，2H) 28
1.22 1S- (pyridin-4-yl) ethyl m-1772 8.46(dd，2H)；7.40(d，2H) 28
1.23 1S- (1, 8-naphthyridin-4-yl) ethyl 825 9.06(d，1H)；9.03(d，1H)；8.90(d，1H)；7.73(d，1H)；7.68(m，1H) 28
1.24 (pyrido [2, 3-b) pyrin-8-yl) methyl M 407 9.14-9.n(m，2H)；9.04(d，1H)；7.88(d，1H) 27
1.25 1R- (1, 8-naphthyridin-4-yl) ethyl 825 9.08(d, 1H); 9.02(d, 1H); 8.91(d, 1H); 7.71 cun 68(m, 2H) 28
1.26 (1, 5-Nalidin-4-yl) methyl m am Tu 809 9.05(dd，1H)；8.99(d，1H)；8.48(dd，1H)；7.8&7.82(m，2H) 27
1.27 (1, 6-Nalidin-4-yl) methyl 811 9.13(m，1H)，8.67(d，1H)，8.41(d，1H)，7.91(d，1H)，7.60(m，1H) 27
1.28 (Quinolin-6-yl) methyl 8n 8.84(d，2H)8.1(m，2H)7.84(d，1H) 27
1.29 (indazol-3-yl) methyl 799 7.20(t，1H)；7.42(t，1H)；7.54(d，1H)；7.83(d，1H) 27
1.30 (isoquinolin-4-yl) methyl 811 7.76(t，1H)；7.92(t，1H)；8.18(d，1H)；828(d，1H)；8.49(s，1H)；9.26(s，1H) 27
1.31 (isoquinolin-3-yl) methyl 8n 7.73(t，1H)；7.80(t，1H)；7.83(s，1H)；7.95(d，1H)；8.12(d，1H)；9.29(s，1H) 27
1.32 1R- (1, 8-Nalidin-4-yl) ethyl (2F template) 843 9.05(m，1H)；899(d，1H)；8.91(d，1H)；7.69-7.65(m，2H) 28
1.33 (1, 8-Nalidin-4-yl) methyl (2F template) M 415 9.04(dd，1H)；8.99(d，1H)；8.74(dd，1H)；7.66(dd，1H)；7.59(d，1H) 27
1.34 (2-methyl-thiazolo [5, 4-b ]]Pyridin-5-yl) methyl 831 8 Lobster 10(d, 1H)7.46(d, 1H) 27
1.35 (Thiazolo [4, 5-b ]]Pyridin-7-yl) methyl 831 9.64(s，1H)；8.82(s，1H)；7.74(s，1H) 27
1.36 (6-chloro-1H-quinolin-2-one-4-yl) methyl 860 7.90(s，1H)；756(d，1H)；7.37(d，1H)；6.67(s，1H) 27
1.37 1R- (1, 5-naphthyridin-4-yl) ethyl M/2413 9.03(dd，1H)；8.96(dd，1H)；8.44(m，1H)；7.84-7.79(m，2H) 28
1.38 1S (1, 5-naphthyridine-4-Grave) Ethyl group M/2413 9.05(m, 1H); 8.99(m, 1H); 8.49(m, 1H); 7.87 cun 81(m, 2H) 28
1.39 (2-Methoxyquinolin-4-yl) methyl group 840 6.96(s，1H)；7.45(t，1H)；7.63(t，1H)；7.82(d，1H)；8.00(d，1H) 27
Example # 2-R2-name MS 1HNMR Preparation of #
1.40 (2-Hydroxyquinolin-4-yl) methyl 827 7.87(d，1H)；7.57(t，1H)；7.39(d，1H)；732(t，1H)；6.64(s，1H) 27
1.41 (1- [ 3-fluorophenyl)]Pyrazol-4-yl) methyl 843 7.09(t，1H)；7.53(m，1H)；7.65(m，2H)；7.80(s，1H)；8.52(s，1H) 27
1.42 (1H-3- [ 4-fluorophenyl)]-pyrazol-4-yl) methyl 843 7.25(t，2H)；7.64(m，2H)；7.88(s，1H) 27
1.43 3- (pyridin-2-yl) -benzyl 836 7.45(m，1H)；7.56(m，2H)；7.92(m，2H)；8.05(d，1H)；8.08(s，1H)；8.68(m，1H) 27
1.44 3- (3-Ethyl- [1, 2, 4 ]]Oxadiazol-5-yl) benzyl 855 7.68(t，1H)；7.72(d，1H)；8.16(d，1H)；8.22(s，1H) 27
1.45 (6- [ pyrazol-1-yl)]Pyridin-3-yl) methyl 826 6.51(t，1H)；7.75(d，1H)；7.95(d，2H)；8.43(s，1H)；8.58(d，1H) 27
1.46 (2- [ 3-methyl- (1, 2, 4) oxadiazol-5-yl)]Pyridin-4-yl) methyl 842 7.56(d，1H)；8.14(s，1H)；8.67(d，1H) 27
1.47 3- (-Oxazol-5-yl) benzyl 826 7.46(d，1H)；7.53(t，1H)；7.60(s，1H)；7.80(d，1H)；7.85(s，1H)；830(s，1H) 27
1.48 4- (pyridin-2-yl) benzyl 836 7.42(m，1H)；7.60(d，2H)；7.92(m，2H)；8.06(d，2H)；8.64(d，1H) 27
Example # 2-R2Name (R) MS 1HNMR Preparation of #
1.49 4- (pyridin-3-yl) benzyl 836 758(m，1H)；7.62(d，2H)；7.78(d，2H)；8.14(d，1H)；8.59(s，1H)；8.86(s，1H) 27
1.50 4- (Pyridopin-2-yl) benzyl 837 755(m，2H)；8.10(d，1H)；8.14(s，1H)；8.58(d，1H)；8.72(m，1H)；9.16(m，1H) 27
1.51 (2- [ phenyl group)]-thiazol-5-yl) methyl 842 7.50(m，3H)；7.79(s，1H)；7.94(m，2H) 27
1.52 (1H-2- [ phenyl)]-imidazol-5-yl) methyl 825 731(s，1H)；7.42(m，1H)；7.48(t，2H)；7.90(d，2H) 27
1.53 3-([1，2，4]Triazol-1-yl) benzyl 825 6.56(m，1H)；7.38(d，1H)；7.54(t，1H)；7.76(m，1H)；7.82(s，1H)；8.26(d，1H) 27
1.54 (2- [ phenyl group)]-thiazol-3-yl) methyl M/2422 7.42(m，3H)；7.52(s，1H)；7.94(m，2H) 27
1.55 1- (4- [ imidazol-1-yl)]Phenyl) ethyl 839 7.13(s，1H)；7.49-7.56(m，5H)；8.12(m，1H) 28
1.56 3-([1，2，3]Triazol-1-yl) benzyl 826 7.44(d，1H)；7.55(t，1H)；7.78(d，1H)；7.90(d，1H)；8.54(d，1H) 27
1.57 4- (imidazol-1-yl) benzyl 825 7.16(s，1H)；7.54-7.64(m，5H)；8.18(s，1H) 27
1.58 4- (isoxazol-5-yl) benzyl 826 7.55(d，2H)；7.58(s，1H)；7.80(d，2H)；8.28(s，1H) 27
1.59 3- (imidazol-1-yl) benzyl 825 7.24(bs，1H)；7.50(d，1H)；7,60(t，1H)；7.66(d，1H)；7.74(s，1H) 27
1.60 3- (pyrazol-1-yl) benzyl 825 654(t，1H)；738(d，1H)；754(t，1H)；7.72-7.76(m，2H)；7.82(s，1H)；8.25(d，1H) 27
1.61 1- (quinolin-4-yl) propyl 838 CDCl3：7.62(t，1H)；7.85(d，1H) 28
1.62 1- (quinolin-4-yl) ethyl (.) 824 CDCl3：8.26(t，1H)；8.90(q，1H) 28
1.63 1- (quinolin-4-yl) ethyl (.) 824 CDCl3：8.90(q，1H)；9.00(d，1H) 28
1.64 1- (quinolin-4-yl) butyl (.) 852 CDCl3：7.77(t，1H)；8.25(d，1H) 28
1.65 1- (quinolin-4-yl) butyl (.) 852 CDCl3：7.62(t，1H)；7.80(t，1H) 28
1.66 Phenyl- (pyridin-3-yl) methyl (#) 836 CDCl3：7.56(t，1H)；8.66(s，1H) 28
1.67 Phenyl- (pyridin-3-yl) methyl (#) 836 CDC h：848(t，1H)；8.62(s，1H) 28
1.68 Phenyl- (pyridin-4-yl) methyl (#) 836 CDCl3：758(d，1H)；8.66(d，1H) 28
1.69 Phenyl- (pyridin-4-yl) methyl (#) 836 CDCl3：7.47(q，2H)；8.55(d，1H) 28
1.70 8-Methoxyquindox-5-methyl 839.7 7.22(d，1H)，7.67(m，2H)，8.66(d，1H)，8.86(d，2H) 27
1.71 3-Methoxyquindox-4-methyl 839.7 8.92(s，1H)，8.21(d，1H)，8.03(d，1H)，7.68(t，2H) 27
1.72 3-methoxy-1, 8-naphthyridine-4-methyl 841.0 7.59(m，1H)，8.71(d，1H)，9.03(d，1H)，9.06(s，1H) 27
Example # Second R2Name (R) MS 1HNMR Preparation of #
1.73 Quinoline-3-carbonitrile -methyl 835(M+1) 8.95(s，1H)，839(d，1H)，8.10(d，1H)，7.82(t，1H)，7.67(t，1H) 35
1.74 7-bromopyrido [3, 2-b ]]Pirphine methyl 892 9.26(s，1H)，9.09(d，1H)，9.05(d，1H) 27
1.75 3-bromine-1, and the salt is a salt,&naphthyridine ═ methyl 888.8 7.71(m，1H)，8.86(dd，1H)，9.06(m，1H)，9.14(s，1H) 27
1.76 3-chloro ═ 1, 8-naphthyridine substituted methyl 845 CDCl3：9.06(dd，1H)，8.99(s，1H)，8.73(dd，1H)，7.52(dd，1H) 27
1.77 In bromopyridine-4-methyl 839 8.61(br s，1H)，8.44(dd，1H)，7.45(d，1H) 27
A
Example # Second R2Name (R) MS 1HNMR Preparation of #
1.93 to 3-methyl-3H-imidazo [4, 5-b]Pyridine-7-methyl M/2408 841(br s, 1H) 8.31(d, 1H), 8.28(s, 1H), 7.23(d, 1H) 27
1.94 1H-ang-2 (3H) sulfone-5-methyl 849 7.4(m，1H)，73(m，2H) 27
1.95 Quinoline-8-carbonitrile-4-methyl 834.7 7.62(d，1H)，7.74(t，1H)，8.24(d，1H)，8.96(d，1H) 27
1.96 Quinoline-8-carbonitrile □ 5-methyl group 834.7 7.70(m，2H)，8.20(d，1H)，8.76(d，1H)，9.20(d，1H) 35
1.97 2-ethoxy -1-methyl 852.8 7.46(t，1H)，7.48(d，1H)，7.62(t，1H)，7.90(d，1H)，8.04(d，1H) 27
1.98 In methyl quinoline-4-methyl 824(M+1) 8.72(s，1H)，8.33(d，1H)，8.03(d，1H)，7.59(m，2H) 27
1.99 3-methyl rebuke 8-naphthyridine -methyl 825(M+1) 9.03(d，1H)，893(s，1H)，8.82(d，1H)，7.52(dd，1H) 27
1.100 6-chloro-3H-imidazo [4, gentamia]Pyridine pi-methyl M/2418 8.41(s，1H)，839(s，1H)，8.33(s，2H) 27
1.101 3-methoxyspit, 5-naphthyridine-4 cun 9 yl M+1841 CDCl3：8.40(m，2H)；8.98(d，1H) 35
1.102 6-methoxy; 2-methoxy 839 CDCl3：8.78(d，1H)；8.61(d，1H)；1.15(d，1H)，7.48(d，1H)，7.46(m，1H) 27
1.103 2, 4-Dichlorobenzene -methyl 826 7.52(s，1H)；7.45(dd，1H)；7.36(dd，1H) 27
1.104 Benzo [ d ] dioxolen-3-methyl M+1802 6.6&6.93(m3H) 27
1.105 Tributine methoxy caoxine-8-methyl 840 7.84(d，1H)；7.30(d，1H) 27
1.106 3-bromo , 5-naphthyridine early group M+2890 9.09(s，1H)；900(d，1H)；838(dd，1H)；779(m，1H) 27
1.107 3-chloroquinoline -methyl M+1844 8.52(d，1H)；8.03(d，1H)；7.64(t，1H)；757(t，1H)；7.24(s，1H) 35
1.108 3-ethoxy-1, 8-diazepam-4-methyl M+1855 8.24(s，3H)，8.96(d，1H)，9.10(s，1H) 27
TABLE 2
Example # R-name of 7 MS 1HNMR Preparation of #
2.01 Isoquinoline-4-carboxyl m-1822 931(d，1H)；8.52(d，1H)；8.24-8.12(m，2H)；7.89(t，1H)；7.75(t，1H) 33
2.02 2-methyl-3H-benzo [ d1 imidazole-4-carboxy M 414 7.63(bs，1H)；7.38(m，1H)；7.24(m，1H) 33
2.03 N- ( -yl) aminocarbonyl 838 7.88(d，1H)；7.80(m，2H)；7.60(d，1H)；750(m，3H) 30
2.04 N- ( cun-yl) aminocarbonyl 838 7.98(s，1H)；7.71(m，3H)；7.40(m，2H)；7.33(dd，1H) 30
2.05 N, (quinolin-6-yl) aminocarbonyl 839 CDCl3：7.98(d，1H)；8.05(d，1H) 30
2.06 N- (quinolinyl) aminocarbonyl 839 CDCl3：7.98(d，1H)；8.39(d，1H) 30
2.07 N-recruit- (4-fluorophenyl) -1H-pyrazol-5-yl) aminocarbonyl 872 CDCl3: 7.75(t, 2H); 8 xi 05(s, 1H) 30
2.08 N- (mother-of-pear 5-methylpyridine asparagus-yl) -1H-pyrazole-5 ═ yl) aminocarbonyl 867 CDCl3：7.90(t，1H)；8.39(s，1H) 30
2.09 N quinolyl) aminocarbonyl 839 CDCl3：7.62(d，1H)；7.65(t，1H) 30
2.10 N- ((quinolinyl) methyl) aminocarbonyl 853 CDCl3：7.66(t，1H)；7.98(t，1H) 30
2.11 N-quinolino-yl) methyl) aminocarbonyl 853 CDCl3：7.72(t，！H)；7.80(d，1H) 30
2.12 4- (leathery methyl-1, 2, 4-sigma diazol 3-yl) benzoyl 855 CDCl3：7.78(m，2H)；8.12(m，2H) 33
2.13 4- (1H-pyrazole □ Grave) benzoyl 839 6.54(s, 1H); 7.74 cun.87 (m, 5H); 8.31(s, 1H) 33
2.14 4- (1H-imidazol-1 ═ yl) benzoyl 839 7.16(s, 1H); 7.65-7.71(m, 3H); 7.79 cun.84 (m, 2H); 8.23(m, 1H) 33
2.15 Car (1H-1, 2, 4 ═ triazole tomb) benzoyl 841 7.8&930(m，2H)；797-8.03(m，2H)；9.86(d，1H) 33
2.16 3- (5 ═ methyl ,2, ca oxadiazol cun-yl) benzoyl 855 7.60(m，1H)；7.82(m，1H)；8.17(m，1H)；8.25(d，1H) 33
2.17 3- (3, 3-dimethyl-1H-pyrazol-icosanyl) benzoyl 867 6.08(s，1H)；7.5&7.60(m，4H) 33
2.18 2- (gentodomethyl ,2, thiadiazol 3-yl) pyridine-4-carboxylic acid 856 7.78(m，1H)；826(d，1H)；8.82(m，1H) 33
2.19 Yan (1H-tetrazol-1-yl) pyridine-4-carboxyl 842 7.73(m，1H)；825(d，1H)；8.72(m，1H)；9.96(s，1H) 33
2.20 6- (1H-pyrazol-1 ═ yl) pyridine cun-carboxyl 840 6.54(s，1H)；7.78(s，1H)；8.04(m，1H)；8.22(m，1H)；8.65(m，1H)；8.73(m，1H) 33
2.21 2-Phenylacetyl 787 732 cun 23(m, 5H) 33
2.22 (S) -2-Phenylbenzoyl 801 7.32 cun 21(m, 5H) 33
TABLE 3
Example # Second R2Name (R) MS 1HNMR Preparation of #
3.01 Pyridine 3 abstruse acyl group 810 8.96(d，1H)；8.81(dd，1H)；8.25(m，1H0；7.76(dd，1H) 31
3.02 Hawthorn seed -sulfonyl 859 8.73(d，1H)；8.24-8.16(m，2H)；7.99(d，1H)；7.68-7.57(m，3H) 31
3.03 Quinoline-8 □ sulfonyl 860 9.04(dd，1H)；8.44-8.39(m，2H)；821(dd，1H)；7.70(t，1H)；7.61(dd，1H) 31
3.04 Isoquinoline-leathery sulfonyl group M 431 936(s，1H)；8.62-8.58(m，2H)；8.4&8.41(m，2H)；7.84(t，1H) 31
3.05 Benzo [1, 2, 5] oxadiazole-4-sulfonyl 851 8.21(d，1H)；8.08(d，1H)；7.68(t，1H) 31
3.06 Benzo [1, 2, 51 diazole-4-sulfonyl 867 8.31(dd，1H)；8.24(dd，1H)；7.82(t，1H) 31
3.07 2-fluorobenzenesulfonyl 827 7.82(m，1H)；7.69(m，1H)；7.37(m，2H) 31
3.08 3-fluorobenzenesulfonyl 827 7.65(m，2H)；757(m，1H)；7.44(m，1H) 31
3.09 Vehicular fluorobenzene sulfonyl group 827 7.89(m，2H)；7.35(m，2H) 31
3.10 3-cyanophenylsulfonyl group 834 8.21(s，1H)；8.n(m，1H)；8.03(m，1H)；7.81(t，1H) 31
3.n 4-cyanophenylsulphonyl 834 7.99(s，4H) 31
3.12 Gemfibrozil ═ phenyl-1H-pyrazole ═ 4-sulfonyl group 889 753-757(m，5H)；7.96(s，1H) 31
3.13 4-phenyl-sulfonyl-5-oxazolyl 876 7.74(s，1H)；7.93(d，2H)；8.01(d，2H)；836(s，1H) 31
3.14 4- (4, 5-hydro-6-methyl-O, 5-keto-1, 2, 4-oxo-2 (3H) benzenesulfonyl 934 7.91 cun 96(m, 4H) 31
3.15 H-imidazo [1, 2-a ]]Pyridine cun-sulfonyl 849 8.89(d，1H)；8.51(s，1H)；7.72(d，1H)；758(m，1H)；7.18(m，1H) 31
A
Embodiment support R of2Name (R) MS 1HNMR Preparation of #
3.I6 6- (1H-pyrazol-1-yl) pyridine-3-sulfonyl 876 8.70(s，1H)8.60(m，1H)7.74(m，1H)6.46(m，1H) 31
3.17 Imidazo [1, 2-a ]]Pyrimidine 3-sulfonyl 850 928(dd，1H)；8.78(dd，1H)；8.42(s，1H)；7.30(dd，1H) 31
3.18 2-cyanophenylsulphonyl 834 8.03(m，2H)；7.84(m，2H) 31
3.19 Timonaico [1, 5-a ]]pyridine-L sulfonyl group 849 8.88(d，1H)；8.45(s，1H)；7.72(d，1H)；7.58(m，1H) 31
3.20 4- (2, 3, 4, 5-tetrahydro-cun, 5 ═ keto, 2, motrinophen-6-yl) benzenesulfonaldehyde group 920 7.6 blunt; straightforward; leathers 8.65(m, 4H) 31
3.21 1- (pyridin-2-yl) -1H-pyrazole low carbonyl 876 9.0(s，1H)8.37(sJH)8.08(s，1H)8.04(d，1H)7.85(m，1H)7.29(m，1H) 31
3.22 2, 3-dihydro-ethanophenonebenzo [ d ] σ oxazole-5-sulfonyl 866 7.73(m，2H)7.17(d，1H) 31
3.23 4- (methylsulfonyl yl) benzenesulfonyl 887 8.16(d，2H)8.07(d，2H)3.09(s，3H) 31
3.24 2, 3-dihydrobenzo [ b ] cyclopenta-sulfonyl group 876 A 31
3.25 2- (methylsulfonyl) benzenesulfonyl 887 ● 31
3.26 4- (pyridin-4-yloxy) benzenesulfonyl 902 A 31
3.27 4- (peeling-3-yloxy) benzenesulfonyl group 902 A 31
3.28 1, 2-methyl-1H-cadaveric oxazole-methanesulfonyl 827 A 31
3.29 3, 5-dimethyl-1-octacosyl pyrazole-4-sulfonyl 827 A 31
3.30 1, 2,3, 4-tetrahydro cun, 4-diketopyrimidine ≡ 5 deacylated 843 A 31
3.31 2, 4 ═ methoxybenzenesulfonyl 869 A 31
3.32 3, 5-dimethyl-iso-sigma Azole acyl 828 A 31
3.33 5- (Isosigma Azol-3-yl) Phenosulfonyl 882 830(d，1H)7.65(d，1H)7.59(d，1H)6.54(d，1H) 31
3.34 4- (spiroxy) benzenesulfonyl group 902 8.22(m，1H)7.87(d，2H)7.69(dd，1H)7.28(d，2H)7.06(dd，1H)6.95(d，1H) 31
3.35 3- (. omega. -sito-winter-yl) benzenesulfonyl 876 CDCl3：7.80(d，1H)；7.82(d，1H) 31
3.36 3- (1 icosanol-3-yl) benzenesulfonyl group 875 CDCl3: 7.80(d, 1H) Jiang.98 (d, 1H) 31
Example # R of2Name (R) MS 1HNMR Preparation of #
3.37 to 2-methoxy peeling-wangshengBase of 840 835(m，1H)，8.19(m，1H)，7.01(m，1H) 31
3.38 6-methoxypyridin cun-sulfonyl 840 8.63(d，1H)，7.96(dd，1H)，6.85(d，1H) 31
3.39 4- (1H-pyrazole-gemini) benzenesulfonyl group 875 CDCl3：7.95(d，2H)，7.88(d，2H)，7.60(m，1H)，6.66(dd，1H) 31
3.40 In (3-methylisoxazole O-yl) benzenesulfonyl 890 CDCl3: 7.96(m, 2H), 7.65(dd, 1H), 7 school 41(m, 2H) 31
3.41 From (1, 2, 4-oxadiazolidinyl-yl) benzenesulfonyl 877 CDCl3：7.60(t，1H)；7.80(d，1H) 31
3.42 2-keto dihydro | -5-sulfonyl 864 CDCh：7.73(d，1H)7.68(s，1H)6.93(d，1H) 31
3.43 2, 3-dihydro-2-ketobenzo [ d ] oxazole-5-sulfonyl 866 CDCl3：7.68(m，2H)7.12(d，1H) 31
3.44 4- (1-alphosp-1-yl) benzenesulfonyl 875 6.55(t，1H)；7.75(d，1H)；7.94(d，2H)；8.09(d，2H) 31
3.45 4- (1, 2, 3- -diazol-4 ═ yl) benzenesulfonyl 893 8.02(d，2H)；8.43(d，2H)；9.49(s，1H) 31
3.46 3-fluoro-4 ≡ morpholinylbenzenesulfonyl 911 753(dd，1H)，7.47(dd，1H)，6.97(t，1H) 31
3.47 4- (3, 5-methyl-1H-pyrazole-1 ═ methylYl) benzenesulfonyl 903 7.92(d，2H)，7.65(d，2H)，6.00(s，1H) 31
3.48 6-cyanopyridine-fountanesulfonyl 835 8.12(d，2H)；8.42(d，2H)；9.11(s，1H) 31
3.49 5, cyano ═ 1-sulfonyl 884 9.06(d，1H)850(d，1H)8.41(d，1H)8.0(d，1H)τ77(dd，1H)7.70(dd，1H) 31
3.50 3-cyano - (1H' diazol-1-yl) benzenesulfonyl 900 8.36(d，1H)8.26(s，1H)8.14(d，1H)8.09(d，1H)7.85(d，1H)6.59(dd，1H) 31
3.51 4- (2-methyl-2H-tetrazol-5-yl) benzenesulfonyl 891 834(d，2H)8.0(d，2H)4，42(s，3H) 31
3.52 4- (1H-1, 2, 4-oxazol-1-yl) benzenesulfonyl 876 8.73(s，1H)8.13(s，1H)8.05(d，2H)7.95(d，2H) 31
3.53 4- (1H-imidazole-1 tomb) -3-tosyl 889 7.86(s，1H)7.80(d，1H)7.75(bs，1H)7.43(d，1H)7.24(bs，1H)7.15(bs，1H)233(s，3H) 31
3.54 4- (6-methylbenzo [ d1 azol-yl) benzenesulfonyl 956 8.25(d，2H)7.95(m，3H)7.69(s，1H)730(d，1H) 31
3.55 Che (2H-Tu, 2, 3-triazol-2-yl) benzenesulfonyl 876 829(d，2H)7.95(d，2H)7.81(s，2H) 31
Example # R of2Name (R) MS 1HNMR Preparation of #
3.56 4- (1, 3, 4-oxadiazolidinyl) benzenesulfonyl 877 8.05(d，2H)；835(d，2H)；9.10(s，1H) 31
3.57 3H-benzo [ d1I1, 2, 31 triazole-5-sulfonyl 850 ？.84(d，2H)；8.05(d，2H)；8.43“1H) 31
3.58 3- (1H-pyrazol-1-yl) benzenesulfonyl 875 N (m, 1H); 8.04 billet.02 (m, 2H); 7.74(m, 1H); 7.70(d, 1H); 7.63(m, 1H); 6.47(m, 1H) 31
359 3- (1, 2, 4-oxadiazole ● 5-yl) benzenesulfonyl 877 CDCl3：7.60(t，1H)；7.94(d，1H) 31
3.60 3- (gentodol, 3, 4-oxadiazolidic acid ● -yl) benzenesulfonyl 891 CDCl3：7.92(t，1H)；8.04(d，1H) 31
3.61 "3-methyl-1, 3, oxadiazol-2-yl) benzenesulfonyl group 891 CDCl3：8.03(d，2H)；8.28(d，2H) 31
3.62 3- (1, 3, 4- σ oxadiazol-yl) benzenesulfonyl group 877 CDCl3：7.70(t，1H)；7.95(d，1H) 31
3.63 3- (1, 2, 3- diazole-vehicular group) benzenesulfonyl group 893 CDCl3：7.75(t，1H)；7.95(d，1H) ● -31
3.64 3-cyano- "1H-imidazol-1-yl) benzenesulfonyl 899 7.25(s，1H)；770(s，1H)；7.89(d，1H)；8.24(d，1H) 31
3.65 Fou (σ σ sit-2-yl) benzenesulfonyl 876 CDCL：7.63(t，1H)；7.95(d，1H) 31
3.66 3- (2-methylpyrimidin-4-yl) benzenesulfonyl 901 CDCl3：&70(d，1H)，8.38(dd，1H)，827(m，1H)，7.97(m，1H)，7.69(dd，1H)，7.59(d，1H) 31
3.67 3- (pyrimidin-4-yl) benzenesulfonyl 887 CDCl3：927(s，1H)，8.81(m，1H)，853(s，1H)，8.40(dd，1H)， 31
3.68 3- (entrmethyl oxazole-winter-yl) benzenesulfonyl 890 CDCl3：7.60(t，1H)；7.80(d，1H) 31
3.69 4- (1H-1, 2, 3-triazol-1-yl) benzenesulfonyl 876 8.77(s，1H)8.25(d，2H)8.09(d，2H)7.97(s，1H) 31
3.70 3-cyano-4- (2H ,2, 3-triazol-seven) benzenesulfonyl 901 8.11(s，2H)；8.25(dd，1H)；8.38(s，1H)；8.47(d，1H) 31
3.71 3-cyano-4- (2H-1, 2, 4-triazole, 1-yl) benzenesulfonyl 901 8.13(d，1H)；8.28(m，2H)；8.45(s，1H)；924(s，1H) 31
3.72 3- (pyridaphen-3-yl) benzenesulfonyl M 444 CDCl3，9.20(m，1H)，8.51(d，1H)，8.44(s，1H)，7.99(d，2H)，7.74(dd，1H)，7.61(m，1H) 31
3. Is to 4-methoxy-3- (-oxazol-5-yl) benzenesulfonyl 906 CDCl3：7.10(d，1H)；7.90(d，1H) 31
3.74 3- (L-methyl H-pyrazole-5-sulfonyl) benzene 889 CDCl3：7.50(d，1H)；7.65(d，1H) 31
Example # R of2Name (R) MS 1HNMR Preparation of the ocean
3.75 one 5- ({ cunningen-yl) } pyridine-3-sulfonyl 877 CDCl3：9.11(s，1H)，8.99(s，1H)，834(s，1H)，8.01(s，1H)， 31
376 to Car (1, 3, 4, oxadiazol-2-yl) benzenesulfonyl 893 9,13(s，1H)8.20(d，2H)7.98(d，2H) 31
3.77 3-cyano-4, fluorobenzenesulfonyl 852 8 noise 14(dd, 1H), 8' 1(m, 1H), 7.41(m, 1H) 31
3.78 4- (6-Chlorodirphine-yl) benzenesulfonyl group 921 7.95(d，1H)；8.06(d，2H)；8.37(d，1H)；8.45(d，2H) 31
3.79 Benzo [ dI Azole Heart Sulfonyl group 866 8.04(d，1H)；832(d，1H)；8.72(s，1H)；9.51(s，1H) 31
3.80 5- (1H-oxazol -yl) pyridinum-sulfonyl 876 CDCl3：9.24(s，1H)，8.94(s，1H)，8.43(d，1H)，8.05(d，1H)，7.77(s，1H)，653(dd，1H) 31
3.81 3-fluoro - (1H-imidazol-1, yl) benzenesulfonyl 893 8.0(bs，1H)，τ77(m，2H)，7.61(m，1H)，7.4(bs，1H)，52(bs，1H) 31
3.82 4- (1 type imidazole -yl) benzenesulfonyl 875 8.0(bs，1H)，7.98(d，2H)，7.60(d，2H)，7.4(bs，1H)，7.3(bs，1H) 31
3.83 2, 3-dihydroemeth-on-5-sulfonyl 849 7.44(d，1H)；759(d，1H)；7.65(s，1H) 31
3.84 (5-yl-1-Tahitezol-1) benzenesulfonyl radical 877 796(d，2H)；833(d，2H) 31
3、85 1H-Homozole-6-sulfonyl 849 7.58(d，1H)；8.02(d，1H)；8.09(s，1H)；8.17(s，1H) 31
3.86 3-fluoro - (1H-pyrazol-L-yl) benzenesulfonyl 893 8.23(m, 1H), 8.15(t, 1H), 7.74(m, 3H), 6.49(dd, 1 Tian) 31
3.87 1H-ZI | Azole-5-Sulfonyl 849 837(s，1H)，8.20(s，1H)，7.86(d，1H)，7.57(d，1H) 31
3.88 3- (Sigma Ozzolaouch) Benzenesulfonyl group 894 CDCl3：739(t，1H)；7.80(q，1H) 31
3.89 Quinoline-6-sulfonyl 861 821(m，2H)；832(d，1H)；8.58(s，1H)；9.03(m，2H) 31
3.90 Entrymethylbenzo [ d ] Azole-5-sulfonyl 880 7.84(d，1H)；8.20(d，1H)；8.33(s，1H) 31
3.91 -2-sulfonyl 859 8.44(s，1H)，8.0(m，2H)，7.9(m，2H)，7.6(m，2H) 31
3.92 Phthalazine □ 5-sulfonyl 861 CDCl3：10.43(s，1H)，9.60(s，1H)，8.54(d，1H)，820(d，1H)，8.03(dd，1H) 31
3.93 Then oxo-5 ═ sulfonyl 861 CDCl3：9.01(d，1H)，8.91(d，1H)，850(d，1H)，8.30(d，1H)，7.84(dd，1H) 31
3.94 L methyl-1 twenty humming | oxazole-5-sulfonyl 863 8.33(s，1H)，8.12(s，1H)，7.85(d，1H)，7.52(d，1H) 31
Example # R of2Name (R) MS 1HNMR Preparation of #
3.95 1, 3-dihydrobenzo [ c ] ne, 2-diketo [ cI ] thiophene □ 5-sulfonyl 899 7.85(d，1H)，7.79(s，1H)，7.50(d，1H) 31
3.96 Ethylmethyl ≡ 2H ≡ indazole-5 ═ sulfonyl 863 832(s，1H)8.n(s，1H)7.83(d，1H)752(d，1H)4.08(s) 31
3.97 6-Bulkylimidazo [2, 1-b1 deep oxazole □ 5-sulfonyl 888.8 8.02(d，1H)，7.43(d，1H) 31
3.98 Zha Oxixiu □ 5-sulfonyl (2-F template) 879(M+1) 9.01(d，1H)，8.91(d，1H)，8.51(d，1H)，831(d，1H)，7.84(t，1H) 31
3.99 3-cyano-4-ethoxybenzene ≡ 1-sulfonyl 876(M-1) 8.01(s，1H)，8.03(d，1H)，7.38(dd，1H) 31
3.100 Quinoline-5-sulfonyl M+1859 9, 18(dd, 1H); 8.39(t, 2H) 31
3.101 8-methoxyquinoline-5-sulfonyl M+1889 8.15(d，1H)；9.00(d，1H) 31
3.102 8-ethoxyquinoline-L-sulfonyl M+1903 759(m，1H)；8.12(d，1H) 31
3.103 3-cyano -ethoxybenzene-L sulfonyl (2-F template) 896 8.43(s，1H)，8.n(br s，1H)，8.04(dd，1H)，7.38(d，1H) 31
3.104 Benzo [ d ] iso oxazole-6-sulfonyl 865 9.01(s，1H)，8.54(s，1H)，8.25(d，1H)，7.91(d，1H) 31
3.105 Che ethoxy-3-methoxybenzene □ -sulfonyl 882 7.43(d，1H)，731(s，1H)，6.94(d，1H) 31
3.106 5-chloro-entrimethoxybenzene ≡ L sulfonyl 873 7.90(s，1H)，7.48(d，1H)，7.00(d，1H) 31
3.107 3-chlorobenzene-1-sulfonyl 843 7.88(s，1h)，7.78(d，1h)，7.60(d，1h)，7.5(m，1h) 31
3.108 4-acetamidophenyl-1-sulfonyl 865 One by one 31
3.109 3- (cyanomethoxy) 4-methoxybenzene-1-sulphonyl 894M+1 759(d，1H)；7.49(s，1H)；7.25(d，1H) 31
3.n0 To (4-fluorophenoxy) benzene □ L sulfonyl 918 7.84(d，2H)，7.1(m，6H) 31
3.n1 8-methylquinoline □ 3-sulfonyl 874 9.00(d，2H)；834(d，1H)；7.8(d，1H) 31
3.112 Quanma methoxy (methoxy) polyoxy (ruby) sychone sulfonyl group M+1890 7.10(d，1H)；850(d，1H) 31
3.113 8- (Difluoromethoxy) quinoline-L-sulfonyl M+1926 8.35(d，1H)；9.00(d，1H) 31
3.114 &Methylquinoxaline □ 3-sulfonyl group M+1894 7.57(d，1H)；7.49(s，1H)，7.24(d，1H) 31
Example # R of2Name (R) MS 1HNMR Preparation of #
3.115 4- (2-ketotetrahydro-oxazol-3-yl) benzene-1-sulfonyl 894 7.89(d，2H)，7.79(d，2H) 31
3.116 1, 3-dimethylcun, 1, 3-benzo -diazole-2, heptadioxide-5-sulfonyl M+1929 7J2(d，1H)，731(s，1H)；7.53(d，1H) 31
3.117 3-ethyl-1-methyl-1H-Calzazole delta-sulfonyl 890 7.82(d，1H)；7.69(d，1H) 31
TABLE 4
Example # R of2Name (R) MS 1HNMR Preparation of #
4.01 Benzhydryl group 849 CDCl3：734(d，2H)；7.56(t，2H) 2a
4.02 2, 5-difluorobenzoyl group 822 CDCl3：8.76(s，1H)；7.89(d，1H) 33
4.03 Nicotinamide acyl 787 CDCl3：8.86(s，1H)；7.89(s，1H) 33
4.04 (pyridin 3-yl) methyl 773 CDCl3：876(s，1H)；7.65(d，1H) 27
4.05 Isonicotinyl radical 787 CDCl3：8.65(d，1H)；7.88(d，1H) 33
4.06 3-cyanobenzoyl 811 CDCl3：856(s，1H)；7.54(d，1H) 33
4.07 3-cyanophenylsulfonyl group 848 8.10(dt，2H)；7.84(t，1H) 31
4.08 3-cyanobenzyl radical M/2400 7.77(s, 1H) Jiang 58(t, 1H) 27
4.09 (pyrazole ● Genobutyl in trace 1) methyl M 382 7.66(s，1H)；6.39(s，1H) 27
4.10 (Pixol 3-yl) methyl M/2413 8.83(s，1H)；8.41(s，1H)；8.03(d，1H)；7.98(d，1H) 27
4.n (1H-hum | On □ 3-yl) methyl M 407 7.70(d，1H)；752(s，1H)；7.41(d，1H)；7.18(t，1H)；7.16(t，1H) 27
4.12 (quinoxalin cun-yl) methyl M 413 8.83(s，1H)；8J5-8.09(m，2H)；7.86-7.82(m，2H) 27
4.13 (quinolino-4-yl) methyl M 413 878(bs, 1H); 8.17(d, 1H); 8.01(d, 1H); 7.78(t, 1 field; 7.62(t, 1H); 7.48(bs, 1H) 27
Example # R of2Name (R) MS 1HNMR Preparation of #
4.14 (quinolin-6-yl) methyl M 413 8.91(bs, 1H); 8.41(d, 1H); 8.10 □ □ 8.05.05 (m, 2H); 7 debt 80(d, 1H); 7.59(m, 1H) 27
4.15 (quinolinyl; gemfibrogen) methyl 824 891(bs, 1H); 8.72(d Slow 1H); 8.18(d 1H); 7.79(t, 1H); 7.72(d, 1H); 7.62(m, 1H) 27
4.16 (1H-benzo [ d1 imidazol-heptanyl) methyl M/2407 7.53(bd，2H)；7.21(bd，2H) 27
4.17 (quinoxalin-8-yl) methyl M/2413 8.99(bs，2H)，8.20(d，1H)；7.99(d，1H)；7.90(t，1H) 27
4.18 (1H pyrrolo [2, wang b ] pyridin-3-yl) methyl 8.18(d，1H)；8.n(d，1H)；7.44(s，1H)；7.12(dd，1H) 27
4.19 (1H-pyrrolo [2, 3-c)]Pyridin-3-yl) methyl 813 8.96(s，1H)；8.24(d，1H)；8.15(s，1H)；8.08(d，1H)；7.95(s，1H) 27
4.20 (1 Benzimidazol-7-yl) methyl M 407 8.56(s, 1H); 759(d, 1H); 7.30 cun 20(m, 2H) 27
4.21 (L (3-fluorophenyl) H-pyrazol-4-yl) methyl M 429 7.66(s，1H)；7.60-7.43(m，3H)；7.03(t，1H) 27
4.22 (1-Cabuxazole O-yl) methyl m-18u 7.81(d，1H)；754(d，1H)；7.40(t，1H)；7.20(t，1H) 27
4.23 (6 chloro-1 style hum | azol-yl) methyl m-1845 779(d，1H)；757(s，1H)；7.18(dd，1H) 27
4.24 (icosaprolo [1, 2-a ]]Pyrazin-6 yl) methyl 813 8.81(bs，1H)；7.52(bs，1H)；7.11(d，1H)；6.98(d，1H) 27
4.25 (H-imidazo [1, 2-a ]]Pyridin-6-yl) methyl m 8n 8.63(s，1H)；7.91(s，1H)；7.63-7.57(m，2H)；737(d，1H) 27
4.26 (imidazo [1, 2-a ] pyrimidine swallow tomb) methyl 814 8.94(dd，1H)；8.61(dd，1H)；7.83(s，1H)；7.14(dd，1H) 27
4.27 (imidazo [1, 2-a)]Pyrimidine-ethyl) methyl 814 8.80(d, 1H); 8 mince 60(bs, 1H); 7.95(d, IH); 7.05(m, 1H) 27
4.28 (imidazo [1, piece a)](ii) phenyl) methyl M/2408 9.00(s，1H)；8.53(dd，1H)；7.95(d，1H)；7.86(s，1H) 27
4.29 ( -2-yl) methyl M/2412 8.15(d，1H)；8.00-7.92(m，2H)；7.65(m，1H)；7.60-7.49(m，2H) 27
4.30 (L (pyridin-3-yl) -1H-pyrazol cun-yl) methyl W2421 9.02(s，1H)；853(s，1H)；8.51(m，1H)；8.24(m，1H)；7.88(s，1H)；7.57(m，1H) 27
4.31 (L (pyridin-2-yl) -1 vestige pyrazol cun-yl) methyl M 421 8.61(d，1H)；8.42(bs，1H)；8.00-7.90(m，2H)；731(bs，1H)；6.58(d，1H) 27
Example # 2-R2Name one MS 1HNMR Preparation of #
4.32 Quinoline-5-carboxy (free base) M 420 CDCl3：8.93(bs，1H)；8.57(bd，1H)；8.14(d，1H)；7.64(t，1H)；758(dd，1H)；7.44(m，1H) 33
4.33 Quinoline near-carboxyl (free base) M/2420 CDCl3：8.96(bs，1H)；8.14(bs，1H)；7.42(bs，1H) 33
4.34 Quinoline field-carboxyl (free base) M/2420 8.96(bd，1H)；8.39(bt，1H)；8.01(bd，1H)；7.79(bs，1H)；7.63(bt，1H)；7.58(m，1H) 32
4.35 H □ pyrazolo [1, 5-a]Pyridine-3-carboxyl (free base) M 414 8.61(bd，1H)；8.23-8.19(m，2H)；7.42(bt，1H)；7.02(bt，1H) 33
4.36 (Pixiu ≡ Hawai)&Radical) methyl 824 8.98(dd，1H)；8.38(dd，1H)；8.03(m，1H)；7.89(d，1H)；7.65-7.56(m，2H) 27
4.37 Quinoline-4-carboxylic acid 838 8.90(d，1H)；8.09-8.04(m，2H)；7.82(t，1H)；7.71(m，1H)；7.54(dd，1H) 33
4.38 ir O-carboxy 838 9.06(bt，1H)；8.62(m，1H)；8.10(d，1H)；8.05(d，1H)；7.87(m，1H)；7.76(m，1H) 33
4.39 Isoquinoline, 3-carboxy 838 9.22(d, 1H); 8.40(d, 1H); 8.12(m, 1H); 8.02(m, 1H); 7.8 vehicle 7.72(m, 2H) 33
4.40 1, 8-naphthyridine-2-carboxy 839 9.10(m，1H)；8.60-8.48(m，2H)；8.18(m，1H)；7.71(m，1H) 33
4.41 1,6 naphthyridine carboxy 839 9.36(s, 1H); 8.74(d, 1/2H); 8.70(d, 1 H); 8.64(dd, 1H); 8.21 cun 92(m, 2H) 33
4.42 (H ═ pyrazolo [1, 5-a)]Pyridin-3-yl) methyl M 407 8.55(d，1H)；8.10(s，1H)；7.83(d，1H)；735(t，1H)；6.97(t，1H) 27
4.43 (1H, pyrazolo [3, 4-b ] pyrid cun-yl) methyl M∫2812 8.53(dd，1H)；8.30(m，1H)；7.26(dd，1H) 27
4.44 (6-cadaverinyl-1H, benzo [ dI imidazol cun-yl) methyl m-1825 821(d，1H)；7.51(d，1H)；7.20(d，1H) 27
4.45 1H imidazo [4, 5-b]Pyridine-non-carboxylic acid groups M 415 8.52-8.44(m，2H)；7.74(d，1H) 33
4.46 Benzo [ d ] sigma Azole, 7-Carboxylic acid W2415 8.67 .83(m, 4H) 33
A 4.47 Isoquinoline, 4 ═ carboxyl 838 9.31(bs，1H)；8.52(d，1H)；8.19(m，1H)；8.n(bt，1H)；7.89(t，1H)；7.78(t，1H) 33
TABLE 5
Example # 2-R2Name (R) name MS 1HNMR Preparation of #
5.01 Quinoline-carboxalkyl Tetrahydropyrrole □ -yl W2469 8.92(m, 1H); 8.10 billet ·.04(m, 2H); 7.83(m, 1H); 7.72(m, 1H); 7.56(m, 1H) 33
5.02 one Quinoline ● 5-carboxy tetrahydropyrrole-L radical M/2469 8.89(bs, 1H); 8.57(m, 1H); 8.13(d, 1H) Jiang 82(m, 1H); 7.75(m, 1H) 33
5.03 (1H, pyrrolo [2, 3, b)]Pyridin-3-yl) methyl 2-methyl tetrahydro pyrrolyl M/2464 8.21(d，1H)；8.15(d，1H)；7.53(s，1H)；7.15(dd，1H) 27
5.04 (quinolin-8-yl) methyl 2-Methyltetrahydropyrrolyl M/2469 8.99(dd，1H)；8.39(dd，1H)；8.05(d，1H)；7，90(d，1H) 27
5.05 (1H-Georo [2, 3-b)]pyridino-O-yl) methyl 2- (3-fluorophenyl) tetrahydro pyrrolyl M 504 8.25(dd，1H)；8.17(dd，1H)；7.65(s，1H)；7.34(m，1H)；7.19(m，1H) 27
5.06 (1H-pyrrolo [2, 3-b ]]Pyrido-yl) methyl 2-o-fluorophenyl) tetrahydropyrrolyl M 504 8.2L8.14(m，2H)；7.66(m，1H)；7.32(m，1H)；7.2L7.18(m，2H)；7.01(d，1H) 27
5.07 Quinoline-&Carboxyl group Tetrahydropyrrole □ ═ yl M 469 8.95(m，1H)；8.36(m，1H)；8.02(m，1H)；7.78(m，1H)；7.65(m，1H) 33
5.08 (quinolinylmethyl) methyl Tetrahydropyrrole tomb 923 8.99(dd, 1H); 8.39(dd, 1H); 8.04(d, 1H); 7,90(d, 1H); 7.66 cun.59 (m, 2H) 27
5.09 (isoquinoline Grave) methyl Tetrahydropyrrole-1 ═ yl M/2462 8.45(d, 1H); 8.07(d, 1H); 7.97(d, 1H); 7.82 cun.73 (m, 3H) 27
5.10 (1H-pyrrolo [2, 3-b ]]Pyridine cun □ radical) methyl Tetrahydropyrrol-1-yl M/2457 826(dd，1H)；8.20(dd，1H)；7.68(s，1H)；7.20(m，1H) 27
A 5.n (1H-benzo [ dI imidazol-2-yl) methyl Peeling by four degrees in a row of -yl M (457) 752(dd，2H)；7.20(m，2H) 27
A 5.12 (1H □ pyrazolo p, 4 pyridin-3-yl) methyl Tetrahydrocyclolusol-yl m 9n 856(d，1H)；831(d，1H)；729(m，1H) 27
A primary record
Example # R of2Name (R) R beta name MS 1HNMR Preparation of #
5.13 (quinoline-&Radical) methyl Azetidine ≡ 1-yl M/2+41474 9.00(bs，1H)；8.05(bd，1H)；7.91(m，1H)；7.66-7.60(m，2H) 27
5.14 (benzo [ d1 oxazol-2-yl) methyl Tetrahydropyrrole -yl M 465 7.96(d，1H)；7.90(d，1H)；7.47(t，1H)；739(t，1H) 27
TABLE 6
Example # Second R2Name (R) MS 1HNMR Preparation of #
6.01 (quinolin-6-yl) methyl 419 CDCl3：8.95(d，1H)；8.12(d，1H) 27
6.02 (quinolin-5-yl) methylBase of 838 CDCl3：835(s，1H)；8.40(d，1H) 27
6.03 (1H-pyrrolo [2, 3-b ] pyridin-3-yl) methyl group 827 CDCl3：6.80(s，1H)；7.38(s，1H) 27
6.04 (Pixoquinol. sigma. -yl) methyl group 839 CDCl3：7.95(d，1H)；8.38(s，2H) 27
6.05 (quinoxaline-infinity 8-yl) methyl group 839 CDCl3：7.90(t，1H)；8.20(q，2H) 27
6.06 (quinolinesulfonyl) methyl 838 CDCl3：7.78(d，1H)；8.18(d，1H) 27
6.07 (quinoxalin cun-yl) methyl 839 CDCl3：7.78(d，2H)；8.25(q，2H) 27
6.08 (5-fluoro-1H grind 3-yl) methyl 844 CDCl3：736(q，2H)；7.60(s，1H) 27
6.09 (3-phenyl-1H-pyrazole ═ yl) methyl 853 CDCl3：7.48(q，3H)；8.00(s，1H) 27
6.10 (1H-indacen-5-yl) methyl 826 CDCl3：7.40(d，1H)；7.62(s，1H) 27
6 n (1 benzo [ d ] imidazole [ identical to ] ethyl) methyl 827 CDCl3：7.60(d，2H)；8.38(s，3H) 27
6.12 Quinoline-3-carboxylic acid 852 CDCl3：7.80(t，1H)；8.14(d，1H) 33
6.13 Quinoline -carboxy 852 CDCl3：8.10(q，2H)；8.25(s，1H) 33
6.14 Quinoline □ nonanecarboxylic acid 852 CDCh：8.60(t，1H)；8.20(t，1H) 33
6.15 Quinoline-6, carboxyl 852 CDCl3：7.50(q，1H0；8.39(d，1H) 33
6.16 Ir oxo-7-carboxyl group 852 CDCl3：8.20(d，1H)；8.20(s，1H) 33
Example # R-name of MS 1HNMR Preparation of #
6.17 argon ion&Carboxyl group 852 CDCl3：7.40(q，1H)；818(d，1H) 33
6.18 1H-benzo [ d1 imidazolo-carboxy 841 CDCl3：7.40(q，1H)；8.60(d，1H) 33
6.19 Benzo [ d ] Azole-Swityl carboxyl group 858 CDCl3：8.20(s，1H)；8.24(d，1H) 33
6.20 Isoquinoline-carbonoyl 852 CDCl3：7.62(t，1H)；8.03(t，1H) 33
6.21 6- (1H Se an ancient type of spoon Azole -yl) pyridine-ethylcarboxyl 868 CDCl3：7.79(s，1H)；8.00(d，1H) 33
6.22 H pyrazolo [1, 5 ═ a]Pyridine-2-carboxylic acid group 843 CDCl3：758(s，1H)；7.80(d，1H) 33
6.23 1H-pyrrolo [2, 3-b]Pyridine cun-carboxyl 841 CDCh：7.15(q，1H)；8.00(d，1H) 33
6.24 Icosapyrazolo [1, 5-a1 pyridine, 3-carboxyl 843 CDCl3：7.38(t，1H)；8.40(d，1H) 33
TABLE 7
Example # R of2Name (R) MS 1HNMR Preparation of #
7.01 (quinolin-5-yl) methyl M 421 CDCl3：8.90(d，1H)；8.53(d，1H)；8.03(d，1H)；7.64(dd，1H)；7.52(d，1H) 27
7.02 (quinolin-6-yl) methyl M 421 CDCl3：8.91(d，1H)；8.21(d，1H)；8.09(dJ H)；7.92(s，1H)；7.74(d，1H) 27
7.03 (quinoxalin-6-yl) methyl M/2421 CDCl3: 8.84(d, 2H); 8 net 13(s, 1H); 8.10(d, 1H)；7.93(d，1H) 27
7.04 (1H-pyrrolo [2, 3-b ]]Pyridin-3-yl) methyl M 415 CDCl3：8.60(d，1H)；8.24(m，1H)；7.96(s，1H)；7.64(d，1H) 27
7.05 Quinoline-6-carboxylic acid group M 428 CDCl3：9.21(d，1H)；8.55(d，1H)；8.36(d，1H)；8.36(d，1H)；8，13(d，1H)；8.04(s，1H) 33
7.06 Quinoline-8-sulfonyl M 446 CDCl3：9.09(d，1H)；8.41(d，1H)；820(d，1H)；8.01(d，1H)；7.60(dd，1H)
7.07 (2, 5-dimethyl-1H-imidazole -yl) methyl M 404 CDCl3：2.47(s，3H)；229(s，3H) 27
Example # R of2Name (R) MS 1HNMR Preparation of Benzhan
7.08 (1H-benzo [ dI imidazol cunen-yl) methyl M 415 CDCl3：8.19(s，1H)；7.78(d，1H)；7.23(dd，1H)；7.16(d，1H) 27
7.09 1, 2,3, 4-tetrahydro-2, 4-diketopyrimidine (Hongcolone) M∫2412 CDCl3：7.15(s，1H) 27
7.10 (4- (pyrimidin-yl) phenyl) methyl M 434 CDCl3：8.79(d，2H)；8.42(d，2H)；7.47(d，2H)；7.18(dd，1H) 27
7.11 (iso-sigma -sigma Sagityl) methyl M/2391 CDCl3：8、16(s，1H)；6.18(s，1H) 27
7.12 (4- (pyrimidine-5 tomb) phenyl) methyl M 434 CDCl3：9.20(s，1H)；8.95(s，2H)；755(d，2H)；7.47(d，2H) 27
7.13 (L (pyridin-yl) emeth-pyrazol-yl) methyl M/2429 CDCh：9.03(s，1H)；8.56(d，1H)；8.24(s，1H)；8.06(d，1H)；7.79(s，1H)；7“42(dd，1H) 27
7.14 Iso ping, 5-sulfonyl M 446 CDCl3：9.34(s，1H)；8.70(d，1H)；8.50(d，1H)；8.42(d，1H)；8.23(d，1H) 31
7.15 3, 5-methyl-1H-Yin Siro-4-sulfonyl 857 CDCh：2.50(s，6H) 31
7.16 2, 3-dihydro-ketobenzo [ d1 oxazole cardiosulfonyl 896 CDCl3：7.65(d，1H)；7.64(s，1H)；724(d，1H) 31
7.17 1，&Naphthyridine-2-carboxy M/2428 CDCl3：9.15(m，1H)；8.27(m，3H)；753(m，1H) 33
7.18 Pixoxifolin -carboxyl group 855 CDCl3：8.88(d，2H)；8.36(s，1H)；8.14(d，1H)；8、06(d，1H) 33
7.19 ir hearts carboxyl group M/2428 CDCl3：8.93(d，1H)；8.60(dd，1H)；8.14(d，1H)；7.66(m，2H)；7.48(dd，1H) 33
7.20 Quinoline metallurgical grade-carboxyl group W2428 CDCl3：9.15(d，1H)；8.16(d，1H)；7.85(d，1H)；7.78(d，1H)；7.55(dd，1H) 33
7.21 Quinoline cun-carboxyl M 428 CDCl3：9.01(d，1H)；8.18(m，2H)；7.90(s，1H)；7.87(d，1H)；7.51(dd，1H) 33
7.22 Zhao's linus-carboxyl M∫2428 CDCl3：922(s，1H)；8.44(s，1H)；8.13(d，1H)；8.02(d，1H)；7.79(dd，1H) 33
7.23 Hetero ir oxo -carboxyl group M/2428 CDCl3：927(s，1H)；8.58(s，1H)；820(d，1H)；8.00(d，1H)；7.79(dd，1H) 33
7.24 Iso &Carboxyl group M∫2428 CDCl3：9.64(s，1H)；8.57(dd，1H)；7.86(d，1H)；7.66(m，3H) 33
7.25 1, 8-naphthyridine-3-carboxy M 428 CDCl3: 9 para 17(s, 1H); 8.28(m, 3H); 753(m, 1H) 33
726 1H-pyrrolo [2, 3-pyrido-2-carboxy M 422 CDCl3：8.43(d，1H)；8.01(m，1H)；7.13(m，1H)；6.91(s，1H) 33
7.27 lH pyrrolo [2, 3-c]Pyridine-2-carboxylic acid group M/2422 CDCl3：9.02(s，1H)；8.31(m，1H)；7.71(m，1H)；7.02(s，1H) 33
Example # R of2Name (R) MS 1HNMR Preparation of #
7.28 1H-benzo [ d ] imidazole-2-carboxy M/2422 CDCl3：7.68(m，2H)；7.31(m，2H) 33
7.29 H, imidazo [1, 2-a]Pyridine-2-carboxylic acid group M 422 CDCl3: 8.13(m, 1H); n (s, 1H); 7.61(dd, 1H); 7 west 19(d, 1H); 6.81(dd, 1H) 33
7.30 Azolo [1, 5-a ] H]Pyridine-ethylcarboxyl M 422 CDCl3：8.37(d，1H)；7.55(dd，1H)；6.97(m，3H) 33
7.31 6- (1H-pyrazol-1-yl) pyridine ≡ 3-carboxy 870 CDCl3：8.69(d，1H)；8.58(s，1H)；8.n(d，1H)；8.00(d，1H)；7.75(s，1H) 33
7.32 1H-pyrrolo [3, piece b]Pyridine-entrifurboxyl group “2422 CDCl3：8.52(d，1H)；7.80(d，1H)；723(m，1H)；697(d，1H) 33
TABLE 8
Example # Second R2Name (R) MS 1HNMR Preparation of #
8.01 (1H-benzo [ d ]]Imidazol-4-yl) methyl 813 730(m，2H)；7.62(m，1H)；822(s，1H)；9.06(d，1H) 27
8.02 (benzo [ d ]]Thiazol-2-yl) methyl 831 7.93(t，1H)；7.50(t，1H)；7.94(d，1H)；8.00(d，1H) 27
TABLE 9
Example # one Gas R2Name one MS 1HNMR Preparation of #
9.01 ( ping-4-yl) methyl M 413 756(d，1H)；7.60(t，1H)；7.76(t，1H)；8，02(d，1H)；8.28(d，1H)；8.78(d，1H) 27
9.02 (Quinoline □ 5, yl) methyl M 413 7.52(m，1H)；7.62(d，1H)；7.72(t，1H)；7.96(d，1H) 27
9.03 (1H-pyrrolo [2, 3-b ]]Pyridin-3-yl) methyl 813 722(m，1H)；7.68(s，1H)；8.22(d，1H)；8.28(d，1H) 27
9.04 (Quinolin-3, Yl) methyl M 413 7.64(t，1H)；7.80(t，1H)；7.96(d，1H)；8.04(t，1H)；8.40(s，1H)；8.90(s，1H) 27
9.05 (1，&Naphthyridin-4-yl) methyl 825 7.61(m，2H)；8.86(d，1H)；898(d，1H) 27
9.06 (1H-benzo [ d1 imidazol 4-yl) methyl 814 7.38(m，2H)；7.70(t，1H)；831(s，1H) 27
9.07 (isoquinolin-5-yl) methyl 824 7.72(t，1H)；7.92(d，1H)；820(m，2H)；8.52(d，1H) 27
9.08 Isoquinoline-nonanesulfonyl 874 7.88(t，1H)；8.48(m，2H)；8.64(d，1H)；8.68(d，1H) 31
9.09 (1H-ZI | Azole-based) methyl 813 7.24(t, 1H) Jiang.46 (m, 2H); 7.56(d, 1H); 7.88(d, 1H) 27
9.10 (isoquinolin-4-yl) methyl 824 7.76(t，1H)；7.85(t，1H)；8.16(d，1H)；8.32(d，1H)；8.45(s，1H) 27
Watch 10
Example # R of2Name (R) MS 1HNMR Preparation of #
10.01 (isoxazolo) methyl radical 777 83(s，1H)；6.37(s，1H) 27
10.02 (1H ,2, 3-triazol-4 ═ yl) methyl 777 7.95(s，1H) 27
10.03 (isoquinolin-5-yl) methyl 837 9.4(s，1H)；8.61(d，1H)；83(d，1H)；8.21(d，1H)；7.9(m，2H) 27
10.04 (quinolin-4-yl) methyl 837 8.79(d, 1H); 83(d, 1H); 8.02(d, 1H); 75(m, 2H) chicks; 7.64(m, 1H) 27
Example # R of2Name (R) Ms 1HNMR Preparation of #
10.05 (quinolin-8-yl) methyl 837 9.03(d，1H)；8.5(d，1H)；8.09(d，1H)；7.66(m，2H) 33
10.06 Quinoline-pinocarboxyl 851 8.89(d，1H)；8.48(s，1H)；844(d，1H)；8.11(s，1H)；7.59(dd，1H) 33
10.07 Quinoline-3-carboxylic acid 852 8.98(s，1H)；8.03(m，2H)；7.89(t，1H)；7.67(t，1H) 33
10.08 Quinoline cun-carboxyl 852 CDCl3：7.58(t，1H)；7.96(d，1H) 33
10.09 Isoquinoline-3, carboxy 852 cDch：7.60(t，1H)；8.u(d，1H) 33
10.10 Ir oxo-4-carboxyl group 852 CDCl3：7.88(d，1H)；7.98(t，1H) 33
10.n Quinoline-8-carboxylic acid 852 CDCl3：7.76(t，1H)；8.10(q，4H) 33
10.12 Zha σ ir-6, carboxyl 853 CDCl3：8.05(d，1H)；8.18(d，1H) 33
10.13 (1 Tolpyrazole ═ L-yl) pyridine O-carboxyl group 868 CDCl3：7.70(s，1H)；8.00(t，1H) 33
10.14 H-pyrazolo [1, 5-a]Radical of pyridino-C 841 CDCl3：7.98(d，1H)；750(q，1H) 33
10.15 Zhao's linus-carboxyl 852 CDCl3：7.48(q，1H)；7.82(d，1H) 33
10.16 1, 8-naphthyridine methyl 853 CDCl3：7.58(q，1H)；7.80(d，1H) 33
10.17 isoquinoline-L Carboxylic acid 852 CDCl3：7.62(t，1H)；7.80(t，1H) 33
10.18 1H-benzo [ d ] imidazolo-carboxy 843 CDCl3：7.25(t，2H)；8.36(d，1H) 33
10.19 Entrazone (trifluoromethyl), 1, 6-naphthyridine-3-carboxyl 921 CDCl3：8.10(t，1H)；8.98(d，1H) 33
10.20 Ixaxol-4-carboxyl 852 CDCl3：7.80(t，1H)；8.05(d，1H) 33
10.21 Zha sigma xixi-carboxyl group 853 CDCl3：7.80(t，1H)；8.05(t，1H) 33
10.22 Benzo [ d1 deep. Tetra-7-carboxy 858 CDCl3：7.52(t，1H)；7.70(t，1H) 33
10.23 Benzo [ dI oxazole pi-carboxy 842 CDCl3：7.60(d，1H)；8.40(d，1H) 33
10.24 3H-imidazo [4, 5-c ]]Pyridine cun-carboxyl M 422 CDCl3：7.60(d，1H)；8.42(d，1H) 33
10.25 3H-imidazo [4, 5-b ]]Pyridine-ethylcarboxyl M 422 CDCl3：6.89(t，1H)；7.10(t，1H) 33
10.26 9H, purine ≡ 9H&Carboxyl group “2421 CDCl3：8.79(s，1H)；8.40(s，1H) 33
10.27 1 Bitumo-2-carboxyl (second F template) 859 CDCl3：730(q，2H)；7.60(t，2H) 33
1028 H rebuke Azolo [1, 5-a ]]Pyridine cun-carboxyl (2 ═ F template) 859 CDCl3：6.88(t，1H)；7.05(t，1H) 33
10.29 Isoquinoline -carboxy (2-F template) 870 CDCl3：8.00(d，1H)；821(d，1H) 33
Example # ● R of2Name (R) MS 1HNMR Preparation of #
10.30 1, 8-naphthyridine-2-carboxyl (2-F template) 871 CDCl3：751(q，1H)；8.03(d，1H) 33
10.31 1H benzo [ dI imidazole-heptacarboxyl 859 CDCl3：730(q，2H)；7.60(t，2H) 33
10.32 1H- | Azole-5 ═ carboxyl 841 CDC3：7.42(d，1H)；7.60(d，1H) 33
10.33 Pixex [ sigma ] button 5-carboxyl 853 CDC3：7.80(m，4H)；8.18(d，1H) 33
10.34 1H-pyrrolo [2, 3-c]Pyridine-seven carboxyl 841 CDCh：7.40(d，IH)；8.20(q，1H) 33
10.35 2-methyl-4 ═ keto, 4-icosapyrido [1, 2-a ]]Pyrimidine-7-carboxy 884 CDCl3：7.50(d，1H)；7.98(d，1H) 33
10.36 1-benzyl-2-hydrogen-ethano-pyridine-carboxyl 908 CDCl3：7.38(t，2H)；7.50(q，2H) 33
10.37 Isoquinoline-&Carboxyl group 852 CDCl3：7.60(m，4H)；8.50(q，2H) 33
1038 1，&Triazine O-carboxyl 853 CDCl3：7.50(m，2H)；7.80(d，1H) 33
10.39 The beginning of the seven-methyl group ,&has the advantages of pyridine-3-carboxyl 867 CDCl3：7.40(q，1H)；8.20(s，}H) 33
10.40 Yan (trifluoromethyl) -1, 8-naphthyridine O ═ carboxyl 921 CDCl3：7.40(m，2H)；8.35(d，1H) 33
10.41 2-methyl-1, 6-naphthyridine-3-carboxyl 867 CDCl3：8.40(s，1H)；8.70(d，1H) 33
10.42 1H □ pyrrolo t3, 2-b]Pyridine-ethylcarboxyl 841 CDCl3：7.80(q，2H)；8.51(t，2H) 33
10.43 Imidazo [1, 2-a ] pyrimidine carboxyls 842 CDCl3：7.00(q，2H)；8.61(t，1H) 33
10.44 Then, after reaction, is]Pyridine-7-carboxylic acid group 859 CDCl3：7.58(q，1H)；8.80(q，1H) 33
10.45 H-zolo [1, 5-a]Pyridine O-carboxyl M/2421 CDCl3：7.28(t，1H)；8.40(d，1H) 33
10.46 Isoquinoline, 3-sulfonyl 888 CDCl3：7.86(t，1H)；8.20(d，1H) 31
10.47 Relatively voluminous heart sulfonyl group 888 CDCl3：7.62(t，1H)；8.00(d，1H) 31
10.48 1, 2-dihydro-6-capsuloxy-pyrido-O-carboxy M 416 CDCl3：7.80(d，1H)；8.40(s，1H) 33
10.49 1, 6-naphthyridine-2-carboxy M∫2472 CDCl3：928(s，1H)；8.76(d，1H)；836(m，1H)；8.04(m，1H) 33
10.50 3 zaimidazo [4, 5-b]And E. Having a fixed clip-carboxyl group 842 CDCl3：6.96(d，1H)；7.45(d，1H) 33
10.51 Radix seu folium Amaranthi Prinosi [1, 5] can be varied independently 842 CDCl3：6.80(q，2H)；8.00(s，1H) 33
10.52 1-Eicoseno [ d1 imidazole-4-carboxyl 841 CDCh：7.80(q，2H)；820(s，1H) 33
10.53 Pyrazolo [1, 5-a]Pyrimidine, seven-carboxyl 842 CDCl3：6.81(q，2H)；8.45(d，1H) 33
10.54 Icosano [1, ethap-pyridine-2, carboxyl M 421 CDCl3：7.19(t，1H)；7.58(d，1H) 33
Example # R of2Name (R) MS 1HNMR Preparation of #
10.55 1H-pyrrolo [2, 3-bI pyridine-2-carboxyl 841 CDCl3：7.02(q，2H)；7.96(d，1H) 33
TABLE 11
Example # R of2Name (R) MS 1HNMR Preparation of #
11.01 (quinoline-blume) methyl group 839 8.8 shared 8.87(m, 2H); 7.98(d, 1H); 7.73(dd, 1H); 7.64 σ.62(m, 2 print) 27
11.02 (quinoxaline coreRadical) methyl 839 8.87(d，2H)；8.09-8.07(m，2H)；7.96(d，1H) 27
11.03 (quinolin-3-yl) methyl 837 8.2(s，1H)；8.4(s，1H)；8.0(d，1H)；7.9(d，1H)；7.7(t，1H)；7.6(t，1H) 27
n.04 (quinolin-entryl) methyl 837 8.3(d，1H)；8.1(d，1H)；7.9(d，1H)；7.8(t，1H)；7.6(m，2H) 27
11.05 (1H ═ pyrrolo [2, in b)]Pyridine cun-yl) methyl 826 8.3(d，1H)；82(d，1H)；7.7(s，1H)；7.2(t，1H) 27
n.06 (L-methyl ═ 1H-benzo [ d ] imidazol-2-yl) methyl 840 7.53(d，1H)；7.45(d，1H)；7.29(t，1H)；7.2(t，1H)；3.92(s，3H) 27
11.07 (6-methoxypyridin-3-yl) methyl 817 8.2(s，1H)；7.75(d，1H)；6.82(d，1H)；3.9(s，3H) 27
11.08 (6-methoxypyridine-ethyl) methyl m-1816 7.7(t，1H)；7.0(d，1H)；6.8(d，1H)；395(s，3H) 27
11.09 (2-methoxypyridine ● 3-yl) methyl 817 8.0(d, 1 field; 7.7(d, 1H); 6.9(m, 1H); 3.92(s, 3H) 27
11.10 (isoquinolin-1-yl) methyl m-1835 8.48(d，1H)；8.12(d，1H)；7.97(d，1H)；77(m，3H) 27
11.11 (wa forest 31052y) methyl m-1835 823(d，1H)；83(d，1H)；8、0(d，1H)；7.8(t，1H)；7.65(t，1H)；7.6(d，1H) 27
11.12 (blowing. Table-base) methyl group 837 9.0(m，1H)；8.41(d，1H)；8.0(d，1H)；7.87(d，1H)；7.62(m，1H) 27
11.13 (isoquinolin, 5-yl) methyl 837 9.29(s，1H)；8.59(d，1H)；8.2(m，2H)；7.9(d，1H)；7.7(t，1H) 27
Example # 2 rogue 2 name one MS 1HNMR Preparation of #
11.14 (1, (pyridine-ethyl) H, pyrazole ═ 4, yl) methyl 853 8.63(s，1H)，8.42(d，1H)；7.94(m，2H)；7.3(m，1H)；6.6(d，1H) 27
11.15 (L (pyridin-yl) Twenty-4-yl-pyrazol-4-yl) methyl 853 9.0(s，1H)；85(m，2H)；8.3(d，1H)；7.9(s，1H)；7.6(m，1H) 27
n.16 H-pyrazolo [1, 5, a ]]Pyridine, ethylcarboxyl M 421 7.88(m，2H)；7.20(m，1H)；7.64(m，1H)；8.51(s，1H) 33
11.17 Hetero ir to carboxyl M/2427 7.64(mJH)；7.81(m，1H)；8.00(d，2H)；8.52(s，1H)；8.96(s，1H) 33
n.18 Quinoline derivativesQuinoline carboxylic acid radical M/2427 756(m，1H)；7.84(m，1H)；8.04-8.10(m，2H)；8.44(d，1H)；8.88(s，1H) 33
TABLE 12
Example # Second R2Name (R) MS 1HNMR Preparation of #
12.01 (6-methoxypyridine-ethyl) methyl 817 7.7(t，1H)；7.1(d，1H)；6.8(d，1H)；3.94(s，3H) 27
12.02 (2-methoxypyridin-3-yl) methyl 818 8.2(d，1H)；7.86(d，1H)；τ03(m，1H)；4.01(s，3H)； 27
12.03 (6 Quaternary oxypyridin-3-yl) methyl group 817 8.1(s，1H)；7.0(d，1H)；6.8(d，1H)；3.88(s，3H) 27
12.04 (isoxazol ≡ 5-yl) methyl group 777 83(s，1H)；636(s，1H) 27
12.05 Quinoline cun ≡ carboxyl M 427 8.97(bs，1h)；8.55(bs，1H)；8.07-8.00(m，2H)；7.83(t，1H)；7.66(t，1H) 33
12.06 Quinoline-6-carboxylic acid group 852 8.90(m，1H)；8.43(d，1H)；8.14(d，1H)；8.08(m，1H)；7.88(d，1H)；7.58(dd，1H) 33
12.07 1，&Naphthyridine-2, carboxyl M 427 9.14(d，1H)；8.61(m，1H)；8.53(d，1H)；832(m，1H)；7.72(m，1H) 33
12.08 Quinoline □ carboxy 852 8.90(d, 1H); 8.08(d, 1H); 7.83(m, 1H); 7.70(m, 1H) Jiang.58 (d, 1H) 33
Example # 2-R2Name one MS 1HNMR Preparation of #
12.09 Iso Pan-carboxy 852 924(bs，1H)；8.13(bs，2H)；8.01(m，1H)；7.82(t，1H)；7.74(m，1H) 33
12.10 Relatively ir oxo-8-carboxyl 852 8.86(bs, 1 H); 8.80(bs, 1 H); 835(d, 1H); 7.98(d, 1H); 7.82(m, 1H); 7.63(m, 1H) 33
12.11 Quinoline-5-carboxylic acid group 852 8.89(dd，1H)；8.34(d，I H)；8.09(d，1H)；7.82(m，1H)；7.69(m，1H) 34
12.12 Quinoline-7-carboxylic acid group 852 8.91(m，1H)；8.43(m，1H)；8.14(bs，1H)；8.05(d，1H)；7.72(d，1H)；7.61(dd，1H) 33
Watch 13
Example # Xuan R2Name (R) MS 1HNMR Preparation of #
13.01 (1H-pyrrolo [2, 3-b1 pyridine-potyyl) methyl 827 82(dd，2H)；τ6(s，1H)；7.2(m，1H) 27
13.02 3- (aminomethyl) -1H, pyrrolo [3, 2-c)]Pyridin-6 (5H) ═ one 842 7.9(s，1H)；7.8(s，1H)；7.7(s，1H) 27
13.03 (1 pyrrolo [2, 3-c ] asparagus-methyl group 827 8.9(s，1H)；8.2(s，1H)；8.0(d，2H) 27
13.04 2- (aminomethyl) quinoline-tetrol 853 8.25(d，1H)；7.47(d，1H)；7.38(t，1H)；736(d，1H)；7,1(d，1H) 27
13.05 (pyridine cun-phenyl) methyl 863 871(d, 1H); 8.03(d, 2H); 7 to 9(m, 2H); 7.61(d, 2H) Jiang 4(m 1H) 27
13.06 (isoxazole geminyl) methyl 777 8.3(s，1H)；6.39(s，1H) 27
13.07 (1H-1, 2, 3-triazole-vehicle-yl) methyl 777 7.8(s，1H) 27
13.08 (entriphenyl oral H-miasma sit, 4-yl) methyl m 850 7.8(d，2H)；7.41(m，2H)；7.39(t，1H)；7.1(s，1H) 27
13.09 1, N-naphthyridine-2-carboxyl 853 7, 93-8.00(m, 2H); 8.68(m, 1H); 8.73(m, 1H); 9.37(s, 1H) 33
River 10 Relatively ir oxo-3-carboxyl 852 7.70(t，1H)；7.82(t，1H)；8.07-8.10(m，2H)；852(s，1H)；9.01(s，1H) 33
Example # one R-name of 7 MS 1HNMR Preparation of #
13.11 Quinoline-&Carboxyl group 851 8.9(s，1H)；8.39(d，1H)；8.0(d，2H)；7.79(d，1H)；7.6(m，1H) 33
13.12 Quinoline-carboxyl-swallows M 427 τ 60(m, 1H) jiang.88 (m, 1H), 8.08(m, 1H); 8.14(m, 1H); 8.45(m, 1H); 8.92(m, 1H) 33
13.13 OxiranIs not identical to ethylcarboxy 853 7.89(m，2H)；8.12(m，2H)；922(s，1H) 33
13.14 Benzo [ d1 [ sigma ] carbaryl 858 7.64(t，1H)；7.77(d，1H)；8.16(d，1H)；9.31(s，1H) 33
13.15 1H Se an ancient type of spoon pyrrolo [2, 3-b]Pyridine carboxyl group M/2421 7.07(d，1H)；7.15(m，1H)；8.12(d，1H)；8.33(m，1H) 33
13.16 Lean on pyrazolo [1, gentamia]Pyridine cun-carboxyl 841 6.95(m, 2H); 721(m, 1H) Jiang 66(d, 1H); 8.61(dd, 1H) 33
13.17 Hetero ir oxo-4-carboxyl group 852 7.76-7.90(m，3H)；8.20(m，1H)；8.47(s，1H)；9.31(d，1H) 33
TABLE 14
Example # R of2Name (R) MS 1HNMR Preparation of #
14.01 (1H □ pyrrolo [2, 3, b)]pyridino-O-yl) methyl 857 822(s，1H)；8.19(d，1H)；7.21(m，2H) 27
Watch 15
Example # R-name of today MS 1HNMR Preparation of #
15.01 (quinoxalin-8-yl) methyl 852 8.92(s，1H)；8.86(s，1H)；8.1(d，1H)；7.9(d，1H)；7.82(m，1H) 27
15.02 (quinoline-vehicle-yl) methyl M 426 8.75(d，1H)；8.32(d，1H)；8.0(d，1H)；7.73(t，1H)；7.62(t，1H)；755(d，1H) 27
15.03 (Pixol-3-yl) methyl m-1849 8.83(s, 1H); 8.27(s, 1H); 8.0(d, 1H); 792(d, 1H) Jiang.74 (t, 1H) Jiangxi 61(t, 1H) 27
15.04 (6-these-capsyloxypyridin-3-yl) methyl groups 831 8 times 0(s, 1H); 7.8(d, 1H); 6.9(d, 1H); 3.9(s, 3H) 27
15.05 (6-methoxypyridin-2-yl) methyl M 416 7.72(t，1H)；7.04(d，1H)；6.83(d，1H)；3.97(s，3H) 27
15.06 (2-methoxypyridin-3-yl) methyl 831 7.29(d，1H)；7.8(d，1H)；7.1(m，1H)；4.03(s，3H) 27
15.07 (4- (pyrid "2-yl) phenyl) methyl 878 8.6(d，1H)；7.87(m，4H)；7.45(d，2H)；7.38(t，1H) 27
15.08 (2-phenyl-1H-imidazole □ 5-yl) methyl 866 7.83(d，2H)；7.42(m，2H)；7.36(t，1H)；7.1(s，1H) 27
15.09 (Iso-sigma Azole ● 5, Yl) methyl 791 8.51(s，1H)；6.70(s，1H) 27
15.10 (1H-Tu, 2, 3-triazol-4-yl) methyl 791 7.82(s，1H) 27
TABLE 16
Example # 2-R2Name one MS 1HNMR Preparation of #
16.01 Tert-butyloxycarbonyl radical 808 CDCl3：428(t，2H)；3.82(t，1H) 8
16.02 Nicotinamide acyl 814 CDCl3：8.69(s，1H)；8.23(d，1H) 33
16.03 2, 5-fluorobenzoyl 849 CDCl3：8.28(s，1H)；7.89(d，2H) 33
16.04 (pyridin-3-yl) methyl 800 CDCh：8.34(s，1H)；7.98(d，1H) 27
16.05 3-cyanobenzoyl 838 CDCl3：8.57(s，1H)；8.68(d，1H) 33
Biological Properties
As described above, macrolides, including ketolides, are generally known as species that have antibacterial activity in many cases. Although not limiting to the invention, it is believed that macrolides are bound to subunits of bacterial ribosomes, resulting in inhibition of protein synthesis. Thus, while the activity and mechanism of action of erythromycin, clarithromycin, and other macrolides are known, at least generally, the invention is not bound or limited by any theory.
In some embodiments, the compounds of the invention exhibit broad antibacterial activity and/or are effective against a variety of infectious species of interest. For example, using standard microtiter medium serial dilution experiments, the compounds of the invention have been found to exhibit a useful degree of activity against a wide range of pathogenic microorganisms, including species of staphylococcus aureus (s.aureus), streptococcus pneumoniae (s.pneumo.), moraxella mucosae, streptococcus pyogenes (s.pyo.) and haemophilus influenzae (Hin £), including drug-resistant species. Thus, the compounds of the present invention are useful, for example, in the treatment and/or prevention of a variety of diseases caused by pathogenic bacteria in humans and animals.
Strains containing genes with the names em selenium, em Mi or ecm C are resistant to some macrolide, lincosamide and streptogramine B antibiotics, which generally attenuate binding through members of all three antibiotic species due to the modification (methylation) of the 23S rRNA molecule by the Erm methyl group. Other macrolide efflux containing species have also been described. For example, msrA encodes an efflux system component in staphylococcus that prevents the entry of some macrolides and streptogramines, while meL E encodes a transmembrane protein that appears to only efflux macrolides. Inactivation of macrolide antibiotics can occur and can be mediated by phosphorylation of either the 2 "hydroxyl group (mph) or by cleavage of the macrolide (ester-cure). "AcrAB" or "AcrAB-like" indicates that an intrinsic multidrug efflux pump system is present in the species.
The activity against bacterial and protozoan pathogens is demonstrated by the ability of the compounds to inhibit the growth of defined pathogenic species. The assays described herein include a test list of strains that are combined to include multiple target pathogenic species, including representatives that have been characterized as having macrolide resistance mechanisms. The bacterial pathogens comprising the screening test list are shown in the table below. In many cases, both macrolide-sensitive parent species and macrolide-resistant species derived therefrom are available to provide a more accurate assessment of the ability of compounds to evade resistance mechanisms. The assay is performed in a microtiter plate and is read according to performance criteria of an antimicrobial susceptibility test; 14 th edition of information supplement (M100 core 14), guidelines published by the National Committee for Clinical Laboratory Standards (NCCLS); MIC was used to compare species. First, the compound was dissolved in DMso as to prepare a 40 mg/ml stock solution. Table 17 lists the data obtained for the compounds of tables 1 to 16. Bacterial species name
Macrolide resistance mechanism streptococcus pyogenes 1079 streptococcus pneumoniae 1016 streptococcus pneumoniae 1095 streptococcus pneumoniae 1175 haemophilus influenzae 1218em { (sensitivity) emBme s (sensitivity).
Example # Streptococcus pneumoniae 1016 (ug/ml) Streptococcus pneumoniae 1095 (mug/ml) Streptococcus pneumoniae n75(μ g/ml) Streptococcus pyogenes 1079(μ g/ml) Haemophilus influenzae 1218 (mug/ml)
1.01 ＜0.06 ＜0.06 0.12 ＞64.00 0.5
1.02 ＜0.06 0.12 0.12 > 64 west 00 0.25
1.03 ＜0.06 ＜0.06 2 ＞64.00 0.5
1.04 ＜0.06 0.12 05 ＞64.00 0.25
1 orange 05 ＜0.06 ＜0.06 0.12 64 0.25
1.06 ＜0.06 ＜0.06 ＜0.06 4 1
1.07 ＜0.06 ＜0.06 0.25 16 Loal portion
1.08 ＜0.06 0.5 0.25 ＞64.00 ●
1.09 ＜0.06 ＜0.06 0.25 ＞64.00 ●
1.10 ＜0.06 ＜0.06 0.12 ＞64.00 ●
1.n ＜0.06 ＜0.06 0.5 4 ＜0.06
1.12 ＜0.06 ＜0.06 ＜0.0ε 2 0.25
1.13 ＜0.06 0.12 1 64 0.25
1.14 ＜0.06 1 0.5 ＞64.00 025
1.15 ＜0.06 ＜0.06 0.25 ＞64.00 0.25
1.16 ＜0.06 ＜0.06 0.25 4.25 0.5
1.17 ＜0.06 ＜0.06 0.25 ＞64.00 0.12
1.18 ＜0.06 1 2 ＞64.00 0.25
1.19 ＜0.06 0.12 4 ＞64.00 0.5
1.20 ＜0.06 ＜0.06 0.12 1 0.25
1.21 ＜0.06 ＜0.06 0.5 32 2
1.22 ＜0.06 1 1 ＞64.00 16
1.23 ＜0.06 ＜0.06 0.25 16 0.5
1.24 ＜0.06 ＜0.06 0.25 4 1
1.25 ＜0.06 ＜0.06 0.25 1 0.5
1 feeding pill ＜0.06 ＜0.06 .●＜0.06 1 0.38
1.27 ＜0.06 ＜0.06 0.5 2 0.5
1.28 ＜0.06 ＜0.06 4 8 0.5
1.29 ＜0.06 ＜0.06 1 2 0.5
1.30 ＜0.06 ＜0.06 ＜0.06 4 1
1.31 ＜0.06 ＜0.06 2 64 1
1.32 ＜0.06 ＜0.06 0.25 0.12 0.5
1.33 ＜0.06 ＜0.06 ＜0.06 0.25 0.25
1.34 ＜0.06 ＜0.06 0.12 32 0.5
1.35 ＜0.06 ＜0.06 0.12 4 1
1.36 ＜0.06 ＜0.06 0.12 8 0.5
1.37 ＜0.06 ＜0.06 0.25 4 1
1.38 ＜006 ＜0.06 0.25 4 1
1.39 ＜0.06 ＜0.06 0.25 16 1
1.40 ＜0.06 ＜0.06 0.25 32 0.5
1.41 ＜0.06 ＜0.06 ＜0.06 ＞64.00 0.12
142 ＜0.06 ＜0.06 0.25 ＞64.00 2
1.43 ＜0.06 ＜0.06 ＜0.06 16 2
1.44 ＜0.06 ＜0.06 0.5 ＞64.00 16
1.45 ＜0.06 ＜0.06 0.5 16 4
1.46 ＜0.06 ＜0.06 0.25 ＞64.00 8
1.47 ＜0.06 ＜0.06 ＜0.06 64 0.25
1.56 ≡ ＜0.06 ＜0.06 ＞64.00 1
1.57 Hum ＜0.06 ＜0.06 64 1
1.61 < 0 Electricity 06 ＜0.06 0.25 8 4
1.62 ＜0.06 ＜0.06 ＜0.06 2 0.5
1.63 ＜0.06 ＜0.06 0.12 2 1
1.64 ＜0.06 ＜0.06 ＜0.06 1 1
1.65 ＜0.06 ＜0.06 < 0 tragic index 06 8 1
1.66 ＜0.06 0.5 ＜0.06 64 2
1.67 ＜0.06 ＜0.06 ＜0.06 16 0.5
1、68 ＜0.06 4 ＜0.06 32 4
1.69 ＜0.06 ＜0.06 ＜0.06 8 1
1.70 ＜0.063 ＜0.063 ＜0.063 2 1
1.71 ＜0.063 ＜0.063 ＜0.063 ＜0.063 1
1.72 ＜0.063 ＜0.063 ＜0.063 ＜0.063 1
1.73 ＜0.063 ＜0.063 ＜0.063 0.125 2
1.74 < 0 063 ＜0.063 ＜0.063 0.5 1
1.75 ＜0.063 ＜0.063 ＜0.063 ＜0.063 1
1.76 ＜0.063 ＜0.063 ＜0.063 0125 0.5
1.77 ＜0.063 ＜0.063 ＜0.063 1 0.5
1.78 ＜0.063 ＜0.063 ＜0.063 4 1
1.79 ＜0.063 ＜0.063 ＜0.063 4 1
1.80 ＜0.063 1 0.125 16 4
1.81 ＜0.063 0.5 ＜0.063 4 4
1.82 ＜0.063 ＜0.063 ＜0.063 4 0.5
1.83 ＜0.063 ＜0.063 ＜0.063 4 1
1.84 ＜0.063 ＜0.063 ＜0.063 8 2
1.85 ＜0.063 ●● ● A 16 2
1.86 ＜0.063 0.125 ＜0.063 1 1
1.87 ＜0.063 ●● ● 8 0.5
1.88 ＜0.063 One by one ■ 8 0.5
1.89 ＜0.063 0.5 ＜0.063 1 4
1.90 ＜0.063 0.125 ＜0.063 2 2
1.91 ＜0.063 0.125 ＜0.063 8 1
1.92 ＜0.063 0.125 ＜0.063 2 2
1.93 ＜0.063 ＜0.063 1 1 2
1.94 ＜0.063 0.5 0.25 4 1
1.95 ＜0.063 1 ＜0.063 1 2
1.96 ＜0.063 ＜0.063 ＜0‘063 1 1
1.97 ＜0.063 ＜0.063 ＜0.063 2 0.5
1.98 ＜0.063 ＜0.063 ＜0.063 0.25 2
1.99 ＜0.063 ＜0.063 ＜0.063 0.5 1
1.100 ＜0.063 ＜0.063 ＜0.063 0.125 0.5
1.101 ＜0.063 0.125 ＜0.063 0.25 2
1.102 ＜0.063 ＜0.063 ＜0.063 1 2
1.103 ＜0.063 ＜0.063 0.125 16 0.25
1.104 ＜0.063 ＜0.063 0.125 ＞64 0.25
1.105 ＜0.063 ＜0.063 0.125 8 1
1、106 ＜0.063 < 0 face 063 ＜0.063 0.25 1
1.107 ＜0.063 ＜0.063 ＜0.063 0.25 1
1.108 ＜0.063 ＜0.063 0.125 0.5 1
2.01 ＜0.06 32 0.25 ＞64.00 4
2.02 ＜0.06 ＞64.00 2 ＞64.00 2
2.03 ＜0.06 8 ＜0.06 ＞64.00 2
2.04 ＜0.06 8 ＜0.06 32 8
2.05 ＜0.06 16 ＜0.06 64 0.5
2.06 ＜0.06 16 0.25 ＞64.00 0.5
2.07 ＜0.06 4 32 16 16
2.08 ＜0.06 1 16 32 8
2.09 ＜0.06 16 0.25 ＞64.00 8
2.10 ＜0.06 8 0.25 ＞64.00 2
2.11 ＜0.06 2 0.12 ＞64.00 0.5
2.12 ＜0.06 2 0.25 ＞64.00 32
2.13 ＜0.06 2 0.12 ＞64.00 8
2.14 ＜0.06 2 0.25 ＞64.00 4
2.15 ＜0.06 8 0.5 ＞64.00 8
2.I6 ＜0.06 16 0.25 ＞64.00 64
2.17 ＜0.06 ＞64.00 0.25 ＞64.00 ＞64.00
2.18 ＜0.06 ＞64.00 0.5 ＞64.00 32
2.19 ＜0.06 ＞64.00 0.5 > 64 sip 00 32
2.20 ＜0.06 1 0.12 ＞64.00 16
3.01 ＜0.06 ＜0.06 ＜0.06 4 0.25
3.02 ＜0.06 ＜0.06 ＜0.06 0.5 0.12
3.03 ＜0.06 ＜0.06 ＜0.06 1 0.12
3.04 ＜0.06 ＜0.06 ＜0.06 0.12 0.25
3.05 ＜0.06 2 ＜0.06 16 0.25
3.06 ＜0.06 ＜0.06 ＜0.06 1 0.12
3.07 ＜0.06 ＜0.06 ＜0.06 16 0.5
3.08 to ＜0.06 ＜0.06 ＜0.06 16 0.5
3.09 ＜0.06 ＜0.06 0.25 16 0.25
3.10 ＜0.06 ＜0.06 ＜0.06 4 0.25
3.11 ＜0.06 ＜0.06 0.5 8 0.25
3.12 ＜0.06 1 ＜0.06 64 4
3.13 ＜0.06 0.12 ＜0.06 4 0.25
3.14 ＜0.06 1 1 ＞64.00 1
3.15 ＜0.06 ＜0.06 ＜0.06 1 0.25
3.16 ＜0.06● ＜0.06 ＜0.06 1 0.5
3.17 ＜0.06 ＜0.06 0.12 4 0.5
3.18 ＜0.06 1 ＜0.06 2 0.12
3.19 ＜0.06 ＜0.06 ＜0.06 1 0.25
3.20 ＜0.06 ＜0.06 2 8 0.5
3.2i ＜0.06 ＜0.06 ＜0.06 ＞64.00 Roll 1
3.22 ＜0.06 4 0.5 1 0.25
3.23 ＜0.06 0.25 ＜0.06 ＞64.00 1
3.24 ＜0.06 1 ＜0.06 32 0.25
3.25 ＜0.06 ＜0.06 0.25 ＞64.00 1
3.26 ＜0.06 ＜0.06 8 64 4
3.27 ＜0.06 ＜0.06 ＜0.06 32 1
3.28 ＜0.06 ＜0.06 4 ＞64.00 1
3.29 ＜0.06 ＜0.06 0.5 8 0.25
3.30 1 ＞64.00 32 ＞64.00 32
3.31 ＜0.06 2 0.12 4 0.5
3.32 ＜0.06 0.5 0.12 32 2
3.33 ＜0.06 ＜0.06 ＜0.06 8 0.5
3.34 ＜0.06 1 0.12 64 16
3.35 ＜0.06 ＜0.06 ＜0.06 1 0.12
3.36 ＜0.06 ＜0.06 ＜0.06 1 0.25
3.37 ＜0.06 4 ＜0.06 16 0.5
3.38 ＜0.06 1 ＜0.06 64 0.5
3.39 ＜0.06 ＜0.06 ＜0.06 0.25 0.5
3.40 ＜0.06 ＜0.06 ＜0.06 4 2
3.41 ＜0.06 ＜0.06 ＜0.06 8 0.25
3.42 ＜0.06 ＜0.06 0.5 2 2
3.43 ＜0.06 < 0 west 06 0.5 1 0.5
3.44 ＜0.06 ＜0.06 ＜0.06 0.12 0.25
3.45 ＜0.06 ＜0.06 ＜0.06 0.12 0.25
3.46 ＜0.06 0.5 ＜0.06 32 2
3.47 ＜0.06 0.5 ＜0.06 64 8
3.48 ＜0.06 1 ＜0.06 ＞64.00 0.5
3.49 ＜0.06 ＜0.06 ＜0.06 0.5 0.5
3.50 ＜0.06 ＜0.06 ＜0.06 0.25 1
3.51 ＜0.06 ＜0.06 ＜0.06 0.5 2
3.52 ＜0.06 0.12 0.12 4 2
3.53 ＜0.06 ＜0.06 0.25 64 4
3.54 ＜0.06 4 4 8 ＞64.00
3.55 ＜0,06 ＜0.06 ＜0.06 ＜0.06 1
3.56 ＜0.06 ＜0.06 ＜0.06 0.5 1
3.57 ＜0.06 ＜0.06 8 4 1
3.58 ＜0.06 ＜0.06 ＜0.06 4 1
3.59 ＜0.06 8 8 64 16
3.60 ＜0.06 ＜0.06 0.12 4 2
3.61 ＜0.06 2 0 12 2 2
3.62 ＜0.06 ＜0.06 0.5 8 2
3.63 ＜0.06 ＜0.06 ＜0.06 0.25 ＜0.06
3.64 ＜0.06 ＜0.06 ＜0.06 32 0.5
3.65 ＜0.06 ＜0.06 ＜0.06 1 0.12
3.72 ＜0.06 ＜0.06 ＜0.06 1 1
3.75 ＜0.06 ＜0.06 ＜0.06 16 1
3.76 ＜0.06 ＜0.06 ＜0.06 0.12 0.5
3.77 ＜0.06 ＜0.06 ＜0.06 8 1
3.78 ＜0.06 < 0 06 ＜0.06 64 4
3.79 ＜0.06 ＜0.06 ＜0.06 1 0.25
3.80 ＜0.06 ＜0.06 ＜0.06 4 ＞64.00
3.81 ＜0.06 ＜0.06 ＜0.06 4 1
3.82 ＜0.06 ＜0.06 ＜0.06 2 0.25
3.83 ＜0.06 ＜0.06 ＜0.06 32 1
3.84 1 ＞64.00 16 ＞64.00 32
3.85 ＜0.06 ＜0.06 ＜0.06 1 0.25
3.86 ＜0.06 ＜0.06 ＜0.06 1 1
3.87 ＜0.06 ＜0.06 ＜0.06 0.19 0.19
3.88 ＜0.06 ＜0.06 ＜0.06 8 2
3.89 ＜0.06 ＜0.06 ＜0.06 8 1
3.90 ＜0.06 ＜0.06 ＜0.06 8 0.25
3.91 ＜0.06 ＜0.06 ＜0.06 4 0.12
3.92 ＜0.06 ＜0.06 ＜0.06 4 1
3.93 ＜0.06 ＜0.06 ＜0.06 1 0.25
3.94 ＜0.06 0.I2 ＜0.06 0.25 0.25
3.95 ＜0.06 ＜0.06 ＜0.06 0.12 0.5
3.96 ＜0.06 0.12 2 1 1
3.97 Is one 0.25 ＜0.063 1 0.125
3.98 ＜0.063 ＜0.063 ＜0.063 0.25 0.25
3.99 ＜0.063 ＜0.063 ＜0.063 0.25 1.41
3.100 ＜0.063 ＜0.063 ＜0.063 0 west 125 0.5
3.101 ＜0.063 ＜0.063 ＜0.063 ＜0.063 0.125
3.102 ＜0.063 ＜0.063 ＜0.063 ＜0.063 1
3.103 ＜0.063 ＜0.063 ＜0.063 0.5 2
3.104 ＜0.063 ＜0.063 ＜0.063 1 ＜0.063
3.105 ＜0.063 ＜0.063 ＜0.063 1 0.25
3.106 ＜0.063 ＜0.063 ＜0.063 0.5 0.5
3.107 ＜0.063 ＜0.063 ＜0.063 1 025
3.108 ＜0.063 ＜0.063 0.5 0.25 1
3.109 ＜0.063 ＜0.063 ＜0.063 0.125 < 0 net of birds 063
3.110 ＜0.063 ＜0.063 ＜0.063 4 2
3.1n < 0 xi 063 ＜0.063 ＜0.063 1 0.5
3.H2 ＜0.063 ＜0.063 0.25 0.125 2
3,n3 ＜0.063 ＜0.063 ＜0.063 0.5 1
3.114 ＜0.063 0.I25 ＜0.063 1 0.25
3.115 ＜0.063 ＜0.063 0.125 0.25 1
3.116 ＜0.063 ＜0.063 ＜0.063 0.5 0.5
3.n7 ＜0.063 ＜0.063 ＜0.063 1 1
4.01 ＜0.00 0.39 0.39 6.25 6.25
4.02 0.01 0.5 0.5 100 3.12
4.03 0.02 0.39 0.78 ＞100.00 1.56
4.04 ＜0.06 16 0.25 ＞64.00 0.5
4.05 0.02 2 1 ＞64.00 4
4.06 0.02 12.5 0.39 ＞100.00 3.12
4.07 ＜0.06 24 0.19 ＞64.00 1
4.08 ＜0.06 32 ＜0.06 ＞64.00 0.12
4.09 ＜0.06 32 0.5 ＞64.00 0.12
4.10 ＜0.06 1 ＜0.06 16 ＜0.06
4.11 ＜0.06 4 2 64 1
4.12 ＜0.06 8 0.12 64 1
4.13 ＜0.06 0.5 ＜0.06 32 1
4.14 ＜0.06 ＜0.06 ＜0.06 8 0.5
4.15 ＜0.06 ＜0.06 ＜0.06 32 0.25
4.16 ＜0.06 2 0.25 ＞64.00 0.5
Playing articles 4.17 ＜0.06 0.5 0.12 64 0.25
4.18 ＜0.06 0.12 0.5 8 0.25
4.19 ＜0.06 ＜0.06 1 64 0.5
4.20 ＜0.06 0.12 0.25 16 0.25
4.21 ＜0.06 2 ＜0.06 64 0.5
4.22 ＜0.06 2 0.25 32 0.12
4.23 ＜0.06 4 0.12 16 ＜0.06
4.24 ＜0.06 0.5 ＜0.06 64 0.5
4.25 ＜0.06 0.38 0.31 64 0.62
4.26 ＜0.06 2 2 ＞64.00 0.25
4.27 ＜0.06 ＞64.00 4 ＞64.00 1
4.28 ＜0.06 8 1 ＞64.00 0.25
4.29 ＜0.06 2 ＜0.06 16 0.12
4.30 ＜0.06 ＞64.00 0.25 ＞64.00 0.5
4.31 ＜0.06 32 ＜0.06 ＞64.00 0.5
4.32 ＜0.06 0.5 ＜0.06 64 1
4.33 ＜0.06 1 0.25 64 1
4.34 ＜0.06 1 1 ● 0.25
4.35 ＜0.06 1 0.12 ＞64.00 1
4.36 ＜0.06 0.25 ＜0.06 ＞64.00 ＜0.06
4.37 ＜0.06 0.25 ＜0.06 ＞64.00 0.5
4.38 ＜0.06 2 ＜0.06 ＞64.00 2
4.39 ＜0.06 8 ＜0.06 ＞64.00 4
4.40 ＜0.06 8 0.5 ＞64.00 4
4.41 ＜0.06 0.25 ＜0.06 ＞64.00 2
4.42 ＜0.06 0.5 ＜0.06 ＞64.00 0.12
4.43 ＜0.06 0.12 1 ＞64.00 0.25
4.44 ＜0.06 0.5 ＜0.06 8 0.25
4.45 ＜0.06 ＞64.00 4 ＞64.00 16
4.46 ＜0.06 0.5 ＜0.06 64 I
4.47 ＜0.06 0.19 0.12 ＞64.00 0.75
5.01 ＜0.06 0.5 ＜0.06 64 2
5.02 ＜0.06 0.25 ＜0.06 16 4
5.03 ＜0.06 ＜0.06 ＜0.06 0.5 2
5.04 ＜0.06 ＜0.06 ＜0.06 4 1
5.05 ＜0.06 2 0.5 4 8
5.06 ＜0.06 ＜0.06 ＜0.06 0.25 2
5.07 ＜0.06 0.25 ＜0.06 16 4
5.08 ＜0.06 0.25 ＜0.06 16 2
5.09 ＜0.06 1 ＜0.06 64 2
5.10 ＜0.06 ＜0.06 ＜0.06 2 1
5.11 ＜0.06 1 ＜0.06 32 1
5.12 ＜0.06 2 0.5 64 8
5.13 ＜0.06 16 0.12 ＞64.00 1
5.14 ＜0.06 4 ＜0.06 32 4
6.01 ＜0.06 0.5 0.5 ＞64.00 1
6.02 ＜0.06 ＜0.06 0.25 32 2
6.03 ＜0.06 ＜0.06 0.12 16 0.5
6.04 ＜0.06 025 025 ＞64.00 1
6.05 ＜0.06 ＜0.06 0.12 ＞64.00 1
6.06 ＜0.06 05 0.5 ＞64.00 1
6.07 ＜0.06 1 0.5 ＞64.00 4
6.08 ＜0.06 ＜0.06 0.25 16 0.5
6.09 ＜0.06 ＜0.06 0.25 ＞64.00 0.5
6.10 ＜0.06 0.25 0.12 ＞64.00 1
6.11 ＜0.06 0.25 ＜0.06 ＞64.00 1
6.12 ＜0.06 0.25 0.12 ＞64.00 ●
6.13 ＜0.06 8 ＜0.06 ＞64.00 ●
6.14 ＜0.06 8 0.25 ＞64.00 ●
6.15 ＜0.06 8 2 ＞64.00 ●
6.16 ＜0.06 0.12 0.12 ＞64.00 ≡
6.17 ＜0.06 ＞64.00 0.12 ＞64.00 A
6.18 ＜0.06 0.25 0.25 ＞64.00 ●
6.19 ＜0.06 i 0.5 ＞64.00 ●
6.20 ＜0.06 64 0.5 ＞64.00 ＝
6.21 ＜0.06 16 0.5 ＞64.00 ■
6.22 ＜0.06 4 0.5 ＞64.00 ●
6.23 ＜0.06 ＜0.06 0.25 64 ●
6.24 ＜0.06 4 0.25 More than oolitic and 00 ■
7.01 ＜0.06 ＜0.06 ＜0.06 ＞64.00 1
7.02 ＜0.06 0.12 0.12 ＞64.00 0.5
7.03 ＜0.06 0.12 0.12 ＞64.00 0.5
7.04 ＜0.06 ＜0.06 1 32 0.5
7.05 ＜0.06 2 1 ＞64.00 1
7.06 ＜0.06 32 0.5 ＞64.00 0.5
7.07 0.12 8 4 ＞64.00 16
7.08 ＜0.06 ＜0.06 0.25 ＞64.00 0.25
7.09 0.5 64 16 ＞64.00 16
7.10 ＜0.06 64 1 ＞64.00 2
7.11 ＜0.06 4 0.5 ＞64.00 2
7.12 ＜0.06 ＞64.00 0.5 ＞64.00 2
7.13 ＜0.06 1 1 ＞64.00 2
7.14 ＜0.06 1 0.12 ＞64.00 0.25
7.15 ＜0.06 ＞64.00 4 ＞64.00 2
7.16 ＜0.06 64 4 ＞64.00 1
7.17 ＜0.06 ＜0.06 0.5 ＞64.00 1
7.18 ＜0.06 0.25 0.25 ＞64.00 2
7.19 ＜0.06 0.12 0.25 ＞64.00 1
7.20 ＜0.06 2 1 ＞64.00 0.5
7.21 ＜0.06 0.5 1 ＞64.00 2
7.22 ＜0.06 ＜0.06 0.12 ＞64.00 1
7.23 ＜0.06 0.5 0.5 ＞64.00 2
7.24 ＜0.06 2 1 ＞64.00 2
7.25 ＜0.06 ＜0.06 2 ＞64.00 1
7.26 ＜0.06 0.12 0.25 ＞64.00 0.5
7.27 ＜0.06 ＜0.06 1 ＞64.00 1
7.28 ＜0.06 ＜0.06 0.25 ＞64.00 2
7.29 ＜0.06 0.25 8 ＞64.00 1
7.30 ＜0.06 0.25 0.25 ＞64.00 8
7.31 ＜0.06 4 0.12 ＞64.00 8
7.32 ＜0.06 ＜0.06 2 ＞64.00 2
8.01 ＜0.06 ＞64.00 0.25 ＞64.00 8
8.02 ＜0.06 8 0.5 32 16
9.01 ＜0.06 0.5 0.12 32 1
9.02 ＜0.06 ＜0.06 0.12 8 0.5
9.03 ＜0.06 ＜0.06 0.5 1 0.12
9.04 ＜0.06 ＜0.06 ＜0.06 32 0.5
9.05 ＜0.06 0.5 0.5 8 8
9.06 ＜0.06 ＜0.06 ＜0.06 4 0.25
9.07 ＜0.06 ＜0.06 0.12 2 1
9.08 ＜0.06 4 0.12 16 0.25
9.09 ＜0.06 0.25 0.12 2 0.12
9.10 ＜0.06 8 0.25 64 0.5
10.01 ＜0.06 0.25 0.5 ＞64.00 1
10.02 ＜0.06 0.25 2 ＞64.00 1
10.03 ＜0.06 0.25 0.25 64 8
10.04 ＜0.06 ＜0.06 ＜0.06 16 0.5
10.05 ＜0.06 < 0 spray 06 0.12 ＞64.00 4
10.06 ＜0.06 ＜0.06 0.12 64 2
10.07 ＜0.06 ＜0.06 0.25 ＞64.00 2
10.08 ＜0.06 ＜0.06 2 ＞64.00 2
10.09 ＜0.06 ＜0.06 1 ＞64.00 2
10.10 ＜0.06 ＜0.06 1 ＞64.00 4
10.11 ＜0.06 0.5 4 ＞64.00 16
10.12 ＜0.06 ＜0.06 0.12 32 2
10.13 ＜0.06 0.5 0.5 ＞64.00 16
10.14 ＜0.06 ＜0.06 0.12 32 0.25
10.15 ＜0.06 ＜0.06 0.25 ＞64.00 2
10.16 ＜006 ＜0.06 0.25 ＞64.00 0.25
10.17 ＜0.06 ＜0.06 0.12 ＞64.00 0.5
10.18 ＜0.06 ＜0.06 ＜0.06 16 0.25
10.19 ＜0.06 ＜0.06 0.12 ＞64.00 8
10.20 ＜0.06 ＜0.06 0.12 64 2
10.21 ＜0.06 ＜0.06 0.12 ＞64.00 2
10.22 ＜0.06 0.12 2 64 2.5
10.23 ＜0.06 ＜0.06 1 ＞64.00 8
10.24 ＜0.06 ＜0.06 1 ＞64.00 2
10.25 ＜0.06 ＜0.06 0.5 ＞64.00 4
10.26 ＜0.06 ＜0.06 1 ＞64.00 2
10.27 ＜0.06 ＜0.06 0.25 8 2
10.28 ＜0.06 ＜0.06 0.12 16 1
10.29 ＜0.06 ＜0.06 0.12 16 2
10.30 ＜0.06 ＜0.06 0.12 32 2
10.31 ＜0.06 ＜0.06 ＜0.06 16 0.25
10.32 ＜0.06 ＜0.06 0.5 ＞64.00 1
10.33 ＜0.06 ＜0.06 0.25 ＞64.00 2
10.34 ＜0.06 0.12 0.12 ＞64.00 2
10.35 ＜0.06 0.25 1 ＞64.00 32
10.36 ＜0.06 4 0.5 ＞64.00 16
10.37 ＜0.06 ＜0.06 ＜0.06 16 0.5
10.38 ＜0.06 ＜0.06 0.5 ＞64.00 1
10.39 ＜0.06 ＜0.06 0.5 ＞64.00 2
I 0.40 ＜0.06 ＜0.06 ＜0.06 ＞64.00 2
10.41 ＜0.06 ＜0.06 ＜0.06 ＞64.00 2
10.42 ＜0.06 ＜0.06 ＜0.06 64 0.5
10.43 ＜0.06 ＜0.06 0.25 ＞64.00 1
10.44 ＜0.06 ＜0.06 0.12 ＞64.00 1
10.45 ＜0.06 ＜0.06 ＜0.06 ＞64.00 1
10.46 ＜0.06 ＜0.06 ＜0.06 64 1
10.47 ＜0.06 0.12 ＜0.06 64 2
10.48 ＜0.06 4 0.5 ＞64.00 1
10.49 ＜0.06 2 2 ＞64.00 8
10.50 ＜0.06 0.5 2 ＞64.00 8
10.51 ＜0.06 ＜0.06 0.5 ＞64.00 1
10.52 ＜0.06 ＜0.06 ＜0.06 64 0.25
10.53 ＜0.06 ＜0.06 0.12 ＞64.00 1
10.54 ＜0.06 ＜0.06 0.25 64 1
10.55 ＜0.06 ＜0.06 ＜0.06 32 1
11.01 ＜0.06 ＜0.06 0.25 16 1
11.02 ＜0.06 ＜0.06 0.25 4 0.5
11.03 ＜0.06 ＜0.06 0.5 64 2
n.04 ＜0.06 ＜0.06 0.12 64 1
11.05 ＜0.06 ＜0.06 0.5 4 0.5
11.06 ＜0.06 2 2 ＞64.00 4
11.07 ＜0.06 ＜0.06 0.25 16 1
11.08 < 0 heart 6 ＜0.06 0.25 ＞64.00 0.5
11.09 ＜0.06 4 16 ＞64.00 4
11.10 ＜0.06 ＜0.06 ＜0.06 64 0.12
11.11 ＜0.06 0.12 0.12 8 1
11.12 ＜0.06 ＜0.06 ＜0,06 ● ＜0.06
n.13 ＜0.06 ＜0.06 ＜0,06 Common Japanese mackerel 0.25
n.14 ＜0.06 0.25 0.25 32 2
n.15 ＜0.06 ＜0.06 0.5 64 2
11.16 < 0 Electricity 06 8 05 ＞64,00 8
n.17 ＜0.06 8 2 ＞64.00 4
11.18 ＜0.06 8 2 ＞64.00 2
12.01 ＜0.06 2 1 ＞64.00 8
12.02 ＜0.06 8 8 ＞64.00 16
12.03 ＜0.06 ＞64.00 0.5 ＞64.00 4
12.04 ＜0.06 4 1 ＞64.00 2
12.05 ＜0.06 1 1 ＞64.00 4
12.06 ＜0.06 0.25 1 ＞64.00 2
1Z08 < 0 house 06 1 2 ＞64.00 16
12.09 ＜0.06 1 1 ＞64.00 2
12.10 ＜0.06 0.5 2 ＞64.00 8
12.11 ＜0.06 0.5 1 ＞64.00 8
12.12 ＜0.06 Less than 0 toxin 06 1 ＞64.00 2
13.01 ＜0.06 0.25 1 ＞64.00 1
13.02 0.12 16 4 64 16
13.03 ＜0.06 1 4 ＞64.00 2
13.04 ＜0.06 1 0.25 64 1
13.05 ＜0.06 16 0.5 ＞64.00 4
13.06 ＜0.06 ＞64.00 0.5 ＞64.00 2
13.07 ＜0.06 ＞64.00 4 ＞64.00 2
13.08 ＜0.06 4 0.5 64 2
I3.09 ＜0.06 ＞64.00 1 ＞64.00 4
13.10 ＜0.06 ＞64.00 0.25 ＞64.00 4
13.11 ＜0.06 16 4 ＞64.00 4
13.12 ＜0.06 ＞64.00 0.5 ＞64.00 4
13.13 ＜0.06 ＞64.00 0.5 ＞64.00 I6
13,14 ＜0.06 2 ＜0.06 ＞64.00 1
13.15 ＜0.06 2 0.12 ＞64.00 4
13.16 ＜0.06 ＞64.00 1 ＞64.00 16
13.17 ＜0.06 ＞64.00 025 ＞64.00 4
14.01 ＜0.06 32 1 ＞64.00 4
15.01 ＜0.06 ＞64.00 0.25 ＞64.00 32
15.02 ＜0.06 ＞64.00 0.5 ＞64.00 32
15.03 ＜0.06 ＞64.00 0.25 ＞64.00 8
15.04 ＜0.06 ＞64.00 0.5 ＞64.00 16
15.05 ＜0.06 ＞64.00 0.5 ＞64.00 8
15.06 ＜0.06 ＞64.00 0.5 ＞64.00 32
15.07 ＜0.06 ＞64.00 1 ＞64.00 32
15.08 ＜0.06 ＞64.00 1 ＞6400 2
15.09 ＜0.06 ＞64.00 0.5 ＞64.00 16
15.10 ＜0.06 ＞64.00 8 ＞64.00 4
16.01 0.25 50 25 ＞100.00 1.56
16.02 0.02 3.12 0.78 ＞100.00 0.78
16.03 0.01 1.56 0.5 50 0.5
16.04 0.03 3.12 ＞100.00 ＞100.00 0.5
16.05 0.01 1.56 1.56 3.12 0.5
In some embodiments, the compounds according to the present invention also exhibit advantageous properties with respect to predicted drug-drug interactions (e.g., predicted nystatin DDI), as found by MBI, which in some embodiments of the invention predicts an increase in AUC of the co-administered drug of CYP3a4 order medazolam (midazolam) of about four-fold or less, about three-fold or less, or about two-fold or less. Again, the lung/plasma distribution ratio, according to the present invention, may be greater than about 10, 15 or 20. The muscle/plasma distribution ratio may be about 1 or greater, about 2 or greater, or about 2.4 or greater.
In some embodiments, the compounds of the present invention are useful against macrolide-resistant or multi-resistant species. For example, in some embodiments, the compounds of the invention exhibit advantageous activity against drug-resistant Streptococcus pyogenes species, including methylation-based resistance, such as em1B o and in some embodiments, better than some known ketolides. For example, clarithromycin resistance (e.g., em1B mechanism) in vitro MIC for Streptococcus pyogenes may be about 8 μ g/ml or less, 4 μ g/ml or less, 2 μ g/ml or 1 μ g/ml or less (i.e., generally, the lower the better). Clarithromycin resistance (e.g., efflux mechanism) Streptococcus pneumoniae in vitro MICs can be about 0.5 μ g/ml or less. In some embodiments, the compounds of the invention are useful or effective against Haemophilus influenzae, Staphylococcus aureus, and macrolide-resistant Streptococcus pneumoniae. In at least these aspects, the compounds of the invention may be at least about 8, 16, 32-fold or more cross-cultural more than telithromycin. Thus, the present invention includes the use of these compounds to take advantage of such advantageous properties. Pharmaceutical composition and use
The invention includes methods of treating the human or non-human animal body, for example, to combat or treat (including prevent) bacterial or protozoal infections, which comprise administering to a subject a useful or effective amount of a compound of the invention, including physiologically acceptable salts or solvates thereof, and including compositions.
With respect to systemic administration, when employed for treatment of adult humans, the daily dosage may range from about 2 to 100 mg/kg body weight, preferably about 5 to 60 mg/kg body weight, which may be administered in 1 to 4 daily dosages, depending, for example, on the route of administration, the symptoms of the patient and other factors known to the skilled artisan. When the composition comprises dosage units, each unit may contain from about 200 mg to 1 g of active ingredient. In some embodiments, the dosage may be in the range of about 300 to 430 mg per day. The duration of treatment, in some aspects of the invention, may be guided by the response rate.
The compounds of the present invention may be formulated for administration in any manner for use in human or veterinary medicine, and therefore the present invention includes within its scope pharmaceutical compositions comprising a compound of the present invention suitable for use in human or veterinary medicine. Such compositions may be presented for use in a conventional manner, with or without the aid of one or more suitable carriers or excipients. The compositions of the present invention include those formulated for parenteral, intravenous, oral, buccal, rectal, topical, implant, ocular, nasal, or genitourinary use. In some preferred embodiments, oral administration may be convenient and effective. Dosage forms, such as oral, may include any immediate, modified, extended, controlled or delayed release formulation, including osmotic pumps and the like.
The compounds of the present invention may also be used in combination with other active ingredients as desired to achieve a combination therapy directed to more than one symptom or biological target. For example, these compounds may be used in combination with other agents that prevent infection, or increase the efficacy or other properties of infection prevention agents, such as efflux inhibitors.
General definitions and explanations
It should be understood that any paragraph headings and sub-headings herein are for the convenience of the reader and are not limiting. For example, the subject matter of the summary is not particularly limited, except as a result of its arrangement in this paragraph.
Unless otherwise indicated, the words and terms used in this document are to be given their broadest reasonable constructions as are known to those skilled in the art. Furthermore, in the description and claims, where subject matter (e.g., substitutions at specific molecular positions) is recited as selected from a set of possibilities, the description is expressly intended to include any subset of the recited groups. In the case of multiple variable positions or substituents, any combination of groups or subsets of variables is also intended to be encompassed.
Unless otherwise indicated herein, the erythromycin-based macrocyclic lactone carbon is identified by the numbering convention shown below:
unless otherwise apparent or indicated, the compounds of the present invention and the term "compound" in the claims include any pharmaceutically acceptable salt or solvate, and any amorphous or crystalline form, or tautomer, whether or not the context clearly dictates otherwise. Similarly, a description is open to any substance or composition that contains the recited compound (e.g., compositions containing salts, tautomers, epimers, stereoisomers, impure mixtures of the compounds, etc.).
The term "pharmaceutically acceptable salt" as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compound. Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts. These compounds may form, for example, sulfates, phosphates, citrates, acetates, tosylates, succinates, benzenesulfonates, methanesulfonates, lactates and hydrochlorides. The basic salts may be mono-or di-basic.
The compounds of the invention have asymmetric centers and can therefore exist in different chiral and diastereomeric forms. The present invention includes all optical isomers and stereoisomers, and mixtures thereof in all ratios, and all pharmaceutical compositions and methods of treatment which may employ or contain them. Although the specific compounds exemplified in the present application may be depicted in a specific stereochemical configuration, compounds having any of the opposite stereochemistry at the center of the palm, or mixtures thereof, are also contemplated. The invention further includes all E and Z configurations of the compounds. The foregoing may be present as a mixture, or enriched to any degree in any of the components. Where stereochemistry at one position is not specified, it is intended to encompass any configuration or mixture of proportions.
The compounds of the present invention include pharmaceutically acceptable derivatives or prodrugs thereof. "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester, or other compound derivative that, when administered to a recipient, is capable of providing (directly or indirectly) a compound of the invention or a metabolite or residue thereof. Particularly advantageous derivatives and prodrugs of the invention are those which, when such compounds are administered to a patient, increase the bioavailability of the compound (e.g., by allowing an orally administered compound to be more readily absorbed into the blood), enhance delivery of the parent compound to a particular biological compartment, increase solubility to allow administration by injection, alter metabolism, or alter rate of excretion.
The present invention includes compounds in which one or more hydrogen, carbon or other atoms are replaced by different isotacticities thereof. The compound can be used as a research and diagnosis tool for metabolism pharmacokinetics research and binding detection.
The term "substituted n" and substitutions encompassed by the formulae herein, means that one or more hydrogen groups in a given structure are replaced by the indicated group or, if not indicated, by any chemically feasible group. When more than one position in a particular structure can be substituted with more than one substituent selected from the indicated groups, the substituents at each position can be either the same or different (independently selected), unless otherwise indicated. In some cases, two positions in a particular structure may be substituted with a common substituent. It should be understood that chemically impossible or highly unstable configurations are not desired or intended, as will be apparent to the skilled artisan.
Unless otherwise indicated, substituents, diradicals, or other groups referred to herein can be attached to the subject molecule in question via any suitable position. For example, the term "humming | noise base" includes 1-indolyl, 2-ZI | division base, base from humming | , and the like.
Conventional means for describing the carbon content of certain moieties are n (ca-cb) "or' ° c a-cb", which means that the moiety may contain any number of nan to ub "carbon atoms.
The term "absent n" (e.g., where R-is absent), as used herein to describe a structural variable, means that the diradical R does not have atoms, but merely represents a single bond between adjacent atoms, unless otherwise indicated.
The term "alkyl" as used herein, unless otherwise indicated, means a saturated monovalent hydrocarbon radical having cyclic ("cycloalkyl n at least three ring atoms), straight chain and/or branched moiety groups. The term "Me", as used herein, unless otherwise indicated, refers to methyl. The term "Et" as used herein, unless otherwise indicated, refers to ethyl. The term "prn" as used herein, unless otherwise indicated, refers to propyl, including isopropyl.
The term "alkenyl" as used herein, unless otherwise indicated, means straight chain, cyclic (in the case of four or more ring atoms), or branched chain hydrocarbon radicals containing at least one carbon-carbon double bond. Examples of alkenyl include ethenyl, E ═ and Z-propenyl, isopropenyl, hexylene and ethylbutenyl, E-and Z, isobutenyl, hexylene and ethylpentylene, E-and ethylhexenyl, E, E-, E, Z-, and even Z, Z-hexadienyl and the like.
The term "alkynyl" as used herein, unless otherwise indicated, means straight or branched chain hydrocarbon radicals containing at least one carbon-carbon reference. Examples of alkynyl groups include ethynyl, E-and ethynyl, isopropynyl, E-and butynyl, E-and Z-isobutynyl, E-and Z-pentynyl, E, Z-hexynyl, and the like.
The term "alkoxy" as used herein, unless otherwise indicated, means-O-alkyl, -O-alkenyl or-O-alkynyl.
The term "alkanoyl" as used herein, unless otherwise indicated, means-C (O) -alkyl, -C (O) -alkenyl or (O) -alkynyl.
The term "aromatic" includes a planar ring system containing 4n +2 pi electrons, where n is an integer.
The term "aryl" as used herein, unless otherwise indicated, means a fully aromatic group containing only carbon atoms in its ring system. Non-limiting examples include phenyl, -yl, and allium.
The term n-carbocyclic ring, when used herein, unless otherwise indicated, means a ring system containing only carbon atoms in the ring, regardless of aromaticity. Carbocyclic moiety groups may be aryl or non-aryl, where non-aryl includes saturated and unsaturated rings, and ring systems having aromatic and/or non-aromatic moieties. Examples of carbocycles include phenyl, -yl, cyclohexenyl and the term "n" an-carbonyl-4-10 membered carbocyclic rings means chemically feasible monocyclic and fused bicyclic carbocycles having 4 to 10 ring atoms. Including, for example, cyclopentyl, and the carbocyclic rings indicated above. Similarly, "4-6 membered carbocyclic ring n means a monocyclic carbocyclic ring system having 4 to 6 ring carbons, and" 9-10 membered carbocyclic ring "means a fused bicyclic carbocyclic ring system having 9 to 10 ring carbons.
The term "n-heteroaryl" as used herein, unless otherwise indicated, means a wholly aromatic group containing at least one heteroatom in its ring system. Heteroaryl groups include, for example, 5-and 6-membered monocyclic compounds, such as pyrazinyl and pyridyl, and 9-and 10-membered fused bicyclic ring systems, such as quinolinyl. Other examples of heteroaryl groups include quinolin-4-yl, 7-methoxy-quinolin-4-yl, pyridine -yl, pyridine O-yl, and pyridine-2-yl. Other examples of heteroaryl groups include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazyl, tetrazolyl, pyranyl, thienyl, isoxazolyl, oxazolyl, iso oxazolyl, pyrrolyl, quinolyl, isoquinolyl, | yl, benzimidazolyl, benzofuranyl, cinnolinyl, oxazolyl, ZI | phenanthrenyl, phthalazinyl, pyridazinyl, triphenanthrenyl, iso hum | yl, pteridinyl, purinyl, oxadiazolyl, oxadiazolyl, xanthyl, benzo xanthyl, benzothiophenyl, benzo oxazolyl, benzoxazolyl, quinoxalyl, naphthyridinyl, furopyridyl, and the like. Examples of the 5-to 6-membered heteroaryl group include a thiophenyl group, an isoxazolyl group, a1, 2, 3-triazolyl group, a1, 2, 3-oxadiazolyl group, a1, 2, 3- oxadiazolyl group, a1, 2, 4-triazolyl group, a1, 3, 4-oxadiazolyl group, a1, 3, 4- oxadiazolyl group, a1, 2, 5- oxadiazolyl group, a pyridyl group, a pyridazinyl group, a sigma-mepiridinyl group, a pyrazyl group, a1, 2, 4-oxadiazolyl group, a1, 2, 5-buprenorphinyl group, a1, 3, 5-triazenoyl group and the like.
The term "n-heterocyclic" as used herein, unless otherwise indicated, means any ring system containing at least one N, O or S, and may be heteroaryl or otherwise. Non-aryl heterocyclic groups include both saturated and unsaturated systems, and may include groups having only 4 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems, and ring systems substituted with one or more keto moiety groups. Recitation of ring sulfur is understood to include the sulfide, sulfoxide or sulfone where feasible. Heterocyclic groups also include partially unsaturated or fully saturated 4-10 membered ring systems, such as monocyclic rings of 4 to 8 atoms in size, and bicyclic ring systems, including aromatic 6-membered aryl or heteroaryl rings, fused to a non-aromatic ring. Also included are 4-6 membered ring systems ("4-6 membered heterocyclic n") which include 5-6 membered heteroaryl, and include groups such as azetidinyl and piperidinyl. The heterocyclic ring may be attached via a heteroatom where this is possible. For example, the group derived from pyrrole can be pyrrole-L-horn-linked) or pyrrole-3-yl (c-linked). Other heterocycles include imidazo (4, 5-b) pyridin-3-yl and benzimidazol-L-yl.
Examples of heterocyclic groups include tetrahydropyrrolyl, tetrahydrofuryl, tetrahydro thienyl, tetrahydro cry furyl, tetrahydrothio cry furyl, hexahydropyridyl, morpholinyl, thiomorpholinyl, thiospiroyl, hexahydropyranyl, azetidinyl, oxetanyl, thiiranyl, homopiperidinyl, oxoheptanyl, thiepinyl, diazepinyl, thiepinyl, 1, 2,3, 6-tetrahydropyridinyl, 2-dihydropyrrolyl, 3-hydropyrrolyl, dihydrohum | -yl, 2-twenty cry furyl, 4H cry furyl, dioxolyl, 1, 3-dioxolanyl, dihydropyrazolyl, dithiol, dihydro cry furyl, dihydro thienyl, dihydrofuranyl, tetrahydropyrazolyl, dihydroimidazolyl, tetrahydroimidazolyl, 3-hexahydrobicyclo [ I.1.0.1 3-azabicyclo [4.1.0 ] heptanyl, 3H-ding ] decanyl, cayrazinyl, and the like.
Heterocyclic or carbocyclic substituted rings include, for example, 2-phenyl- oxazol-5-yl, 2-pyridin-3-yl- oxazol-4-yl, 4-phenylimidazol-1-yl, and vehicular pyridino-imidazol-1-yl.
The term "9-10 membered heterocyclic" means a fused 5,6 or 6, 6 bicyclic heterocyclic ring system which may be saturated, unsaturated or aromatic. The term "9-to 10-membered fused bicyclic heterocycle" also refers to a phenyl group fused to a 5-or 6-membered heterocyclic group. Examples include benzofuranyl, benzothiophenyl, hyalo, benzoxazolyl, 3H-imidazo t4, 5-c ] pyridinyl, dihydrophthalazinyl, 1H-imidazo [4, 5-pyrideme-yl, imidazo [4, 5-b ] pyridinyl, 1, 3-benzo [1, 31-dioxolanenyl, 2H-inosyl, iso- -yl, 5-keto-2, 3-dihydro ≡ 5H-I1, 3] -oxazolo [3, 2-pyrimidinyl, 1, 3-benzopupillyl, 1, 4,5, 6-tetrahydroda -yl, 1, 2,3, 4,7, 8-hexahydro-optic-pyrid-yl, ethione-2, 3, 6, 9-tetrahydro-1H-purin-yl, 3, 7-dihydro-1H-purin-8-yl, 3, dihydropyrimidin-L-yl, 2, 3-dihydro-1, 4-benzodioxolenyl, benzo [1, 3I-dioxolenyl, 2H-alkenylyl, 3, 4-dihydrophthalazinyl, 2, 3-dihydro-1H-xylylenyl ,1, 3-hydro-2H-isoquinoyl, 2, 4, 7-trionyl-1, 2,3, 4,7, & hexahydropyrimidyl, thieno [3, 2-d ] pyrimidyl, 4-keto-4, 7-dihydro OH ≡ pyrrolo [2, 3-d ] pyrimidyl, 1, 3-dimethyl-6-keto-2-thione-2, 3, 6, 9 ═ tetrahydro H purinyl, 1, 2-dihydroisoquinolyl, 1, 3-dihydroisoquinolyl, 2H-quinolyl, 2H-oxadiazinyl, 3, 4, 7-trione-1, 2,3, 4, 7-trione-yl, 3, 7, hexahydropyrimidyl, 3, 7, & lt, -acetonyl-1, 3-benzoxazolyl, 2, 3-hydro-5H-1, 3- oxazolo- [3, 2-a ] pyrimidinyl, 5,6, 7, 8-tetrahydro-oxazolixyl, 4-keto pronyl, 1, subfenzo oxazolyl, benzimidazolyl, benzotriazolyl, purinyl, pyranopyridinyl, thiophenyl σ -pyrimidinyl, thiophenylpyridinyl, pyrrolylpyridinyl, oxazolylpyridinyl, pyrazinyl. Pyridyl, 3, 4 ═ hydropyrimidine 4 ξ imidazopyridinyl, quinolyl, isobutryl, quinoxalinyl, oxapyridyl, pyrazolyl I3, 4 octenyl, 1, 2 ═ hydroisoquinolyl, cinnolinyl, 2, 3-dihydro-benzo [1, 4I dioxolen-6-yl, 4,5, 6, 7-tetrahydro ≡ benzo [ bI-thiophen-2-yl, 1, & pyridyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinyl, 1, 7-illness pyridyl, 3, 4, dihydro-2H-1, 4 ═ benzo ,4, 8-dihydroxy ═ quinolyl, 1-diketo, 2-dihydro-isoquinolyl, 4-phenyl- & 1, 2,3 [ oxadiazolyl, and the like.
The size of the ring system can be described using the format "x-y member n" depending on the number of ring atoms, meaning that the ring system in question can have from x to y atoms in the ring system. The ring system may comprise fused rings. For example, the term "9-to 10-membered carbocyclic ring" refers to a 5,6 or 6, 6 fused bicyclic carbocyclic ring system, which may be saturated, unsaturated or aromatic. It also refers to a phenyl group fused to one 5-or 6-membered saturated or unsaturated carbocyclic group. Examples of such groups include, for example, a mesityl group, a1, 2,3, 4-tetrahydro -yl group, an ang-yl group, a h-ang-yl group, etc. Unless stated or indicated otherwise, the ring systems described are unsubstituted.
As used herein, the term "halo" or "halogen" includes fluoro, chloro, bromo, or iodo groups, unless otherwise indicated. Preferably the halogen is fluorine.
The term "protecting group" refers to a suitable chemical group that can be attached to a functional group and removed at a later stage to reveal the functional group as it remains. Examples of suitable protecting groups for various functional groups are described in the works W.Greene and RGM.Wuts, organic synthetic protecting groups, 2 nd edition, JokmWiley & sons (1991 and later), incorporated herein by reference; l. Fieser and m.fieser, organic synthetic Fieser and Fieser reagents, JokmWiley & Sons (1994); and the encyclopedia of reagents for organic synthesis, edited by Paqueue, John wiley & sons (1995). The term "hydroxy-protecting group" as used herein, unless otherwise indicated, includes Ac, CBz and the various hydroxy-protecting groups known to those skilled in the art, including those referred to in Greene.
The terms "treatment," "treating agent," and "treating," as used herein with respect to the use of a compound of the present invention, unless otherwise indicated, mean reversing, alleviating, inhibiting the progression of, or partially or completely preventing the disorder or condition to which such term applies, or one or more signs of such disorder or condition. By "prevention" is meant treatment prior to the occurrence of the infection.
The term "pharmaceutical composition" refers to an active compound in any form suitable for effective administration to a patient, e.g., a mixture of the compound and at least one pharmaceutically acceptable carrier.
The term "pharmaceutically acceptable carrier" refers to a substance that can be administered to a patient in a pharmaceutical composition with a compound. The carrier should not destroy the pharmacological activity of the compound and should be non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound.
Abbreviations: unless otherwise indicated, the following abbreviations apply throughout this document:
ac: acyl radical
AUC: area under the curve
Bn: benzyl radical
Bz: benzoyl radical
Bzh: benzhydryl group
BOC: tert-butyloxycarbonyl radical
CBZ: benzyloxycarbonyl group
CDI: carbonyl diimidazoles
DAST: (diethylamino) sulfur trifluoride
DBU: 1, 8-diazabicyclo [5.4.0] undec-7-ene
DCM: methylene dichloride
DIEA: diisopropylethylamine
DMAP: dimethylaminopyridine
DMF: dimethyl formamide
DMSO, DMSO: dimethyl sulfoxide
EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
eq.: equivalent weight
EtOAc：EtOAc
EtOH: alcohol(s)
HCl: hydrochloric acid
HOBT: n-hydroxybenzotriazoles
HPLC: high performance liquid chromatography
IBX: 1-hydroxy-1, 2-benziodoxowurtzitane-3 (1H) -one L-oxide
IPA: isopropanol (I-propanol)
IPE: diisopropyl ether
KHMDS: hexamethyldisilazide
LCMS: liquid chromatography mass spectrometry
MeCN: acetonitrile
MeOH: methanol
MIC: minimum inhibitory concentration
MS: and (4) mass spectrometry. All samples herein were electrospray by LCMS (using B)
Gradient elution of a mixture of nitrile, water, formic acid) or probe APCI methods.
NaHCO3: sodium bicarbonate
Na2SO4: sodium sulfate
NH4OH: 28-30% concentrated aqueous ammonium hydroxide solution
NMP: n-methyl pyrrolidone
NMR: nuclear magnetic resonance spectroscopy. All samples herein were measured at 400MHz
(Varian apparatus).
And (3) PCR: polymerase chain reaction
RP-HPLC: reversed phase high performance liquid chromatography
RT: at or about room temperature
SGC: silica gel chromatography
TEA: triethylamine
TFA: trifluoroacetic acid
THF: tetrahydrofuran (THF)

Claims (20)

1. A compound of the formula:
wherein:
double base1Is absent, > CH2Or > C (CH)3)H；
Double base2is-C (O) (CH)2)m-、-S(O)2(CH2)m-、-SO2N(R6)-、-C(O)O(CHR20)m-、-(C(R6)(R7))m-or-C (O) N (R)6) -, where m is an integer from 0 to 3;
double base3Is > C (O), > CH (OC (O) R14)、＞CH(OC(O)N(R14)R15)、＞CH(OC(O)OR15)、＞CH(OC(O)CH(N(R14)R15)(CRaRb)n Ar)、＞CH(OC(O)CH(N(R14)R15)R14)、＞CH(OC(O)C(＝NOR14)(CRaRb)n Ar)、＞CH(OC(O)C(＝NOR14)R14)、＞CH(OC(O)(CRaRb)n Ar)、＞CH(OC(O)(CRaRb)nN(R14)(CRaRb)n Ar) Or, alternatively:
wherein n is an integer from 0 to 5;
double base4Is > O or > N (R)10) Provided that when the diradical is3Not > C (O), is diradical4Is > O;
double base5Is > C (O), -C (O) NH-, -N (H), C (O) -, > CH (N (R)8)R9)、＞C(＝NC(O)R19) Or > C (═ NOR)19)；
Double base6Is- (C (R)c)(Rd))x-, where x is an integer from 0 to 5;
double base7Is- (C (R)c)(Re))y-, wherein y is an integer of 0 to 5; provided that the sum of x + y is from 1 to 5;
R1is H, OH, F or (C)1-C6) Alkyl radical with the proviso that1In the absence of R1Is H;
R2is H orAr；
R3Is (C)1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl, any of which may be substitutedArSubstitution;
R4is H or F, with the proviso that when diradical3When not > C (O), R4Is H;
each R5And R20Independently is (C)1-C6) An alkyl group;
each R6And R7Independently H, (C)1-C12) Alkyl, (C)2-C12) Alkenyl or 4-6 membered heterocycle; any of which, other than H, may be substituted with 1 to 3 substituents of group S; and independently wherein (C)1-C12) Alkyl and (C)2-C12) Alkenyl groups may have 1 to2 carbons, independently replaced by a T group diradical; and independently at most one R6/R7Pairs, together with the carbon to which they are attached, may form a 3-to 8-membered carbocyclic ring; with the proviso that not more than a total of two R6And R7The group is not H;
R8independently of each other are H, - (C)1-C6) Alkyl, -C (O) (C)1-C6) Alkyl or-S (O)2)(C1-C6) Alkyl, any of which, other than H, may be substituted with 1 to 3 substituents of group S;
R9is H, or- (C)1-C6) Alkyl, which may be substituted with 1 to 3 substituents of group S;
R10is H or (C)1-C6) An alkyl group;
each R11And R12Independently are (a) H, (C)1-C12) Alkyl, (C)2-C12) Alkenyl, (C)2-C12) Alkynyl, any of which, except H, may have a carbon, is substituted by-NH-, -N (CH)3) -, -N (4-to 10-membered heterocycle), -N (4-to 10-membered carbocycle), -O-, -S-, -S (O) -or-S (O)2-substitution wherein the aforementioned R11And R12And together with the atoms to which they are attached, may form a 3-to 8-membered ring, or (b) a 9-to 10-membered heterocyclic ring, a 9-to 10-membered carbocyclic ring, a 4-to 6-membered heterocyclic ring, or a 4-to 6-membered carbocyclic ring, wherein any of (a) or (b), other than H, may be substituted with 1 to 3 of the following groups: F. cl, OH, (C)1-C3) Alkoxy group, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkyl, halogen substituted (C)1-C3) Alkyl or (C)1-C3) Alkoxy radical- (C1-C3) An alkyl group;
each R13And R16Independently of each other is H, -C (O) (C)1-C6Alkyl), -C (O)Ar-Si (phenyl) (C1-C6Alkyl radical)2or-Si (C)1-C6Alkyl radical)3；
Each R14And R15Independently is H or (C)1-C10) An alkyl group; wherein alkyl may be substituted with 1 to 3 substituents of group S; wherein 1 to2 carbons of the alkyl group may be independently replaced by a T group diradical; and independently, wherein each R14/R15Pairs may, together with the atoms to which they are attached, form a 3-to 8-membered ring;
R17is OR19、-C(O)(C1-C6Alkyl) or-C (O) (4-10 membered carbocyclic or heterocyclic);
R19is H, a 4-to 10-membered carbocyclic or heterocyclic ring, - (C)1-C6) Alkyl or- (C)1-C6) Alkyl- (4-to 10-membered carbocyclic or heterocyclic), in which 1 carbon in any one of the groups may be replaced by-NH-, -N (CH)3) -, -N (4-to 10-membered carbocyclic or heterocyclic), -O-, -S-, -S (O) -or-S (O)2-substitution, wherein any one of the radicals, except H, may be substituted by 1 to 3F, Cl, OH, (C)1-C3) Alkoxy group, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkyl, halogen substituted (C)1-C3) Alkyl or (C)1-C3) Alkoxy radical- (C1-C3) Alkyl) substitution;
each RaAnd RbIndependently is H or (C)1-C6) Alkyl, which may be substituted with 1 to 3 substituents of group S; and wherein 1 to2 carbons of the alkyl group may be replaced by a T group diradical; and independently each Ra/RbPairs, together with the carbons to which they are attached, may form a 3-to 10-membered ring;
each RcThe groups are independently H, F, Cl and (C)1-C3) Alkyl, hydroxy, (C)1-C3) Alkoxy or CN, with the proviso that when diradical6When x is 2 to 5, only one R is presentcMay be other than H;
each RdAnd ReThe radical being H but not more than one RdRadical with an ReTogether, the radicals may form a bridging carbon-carbon single bond, or a bridge (C)1-C3) Alkyl diradicals to make the ringAIs bicyclic;
each one ofArIndependently (a) a 9-to 10-membered heterocycle, (b) a 9-to 10-membered carbocycle, (c) a 4-to 6-membered heterocycle, or (d) a 4-to 6-membered carbocycle, wherein (c) or (d) may be substituted with a 4-to 6-membered heterocycle or a 4-to 6-membered carbocycle; any one of the aboveArThe ring system may be substituted with 1 to 3 substituents of group S;
the substituent of the S group is: nitro, halogen, hydroxy, CF3、OCF3、OCHF2、CHF2、CN、CHO、(C1-C3) Alkoxy radical- (C1-C3) Alkoxy group, (C)1-C3) Alkoxy radical- (C1-C3) Alkyl, oxo, (C)1-C10) Alkanoyl, (C)1-C10) Alkyl, (C)2-C10) Alkenyl, (C)2-C10) Alkynyl, 4-to 10-membered heterocyclic or carbocyclic, hydroxy-substituted (C)1-C6) Alkyl, -C (O) R11C (O) (4-10 membered heterocycle), C (O) (4-10 membered carbocycle), -C (O)2(4-10 membered heterocycle), -C (O)2(4-10 membered carbocycle), -O (4-10 membered heterocycle), -C (O) OR11、-OC(O)R11、-C(O)NR11R12、-OC(O)NR11R12、-NR11R12、-SO2NR11R12and-S (O)pR11Wherein p is 0 to2, and (C) optionally substituted with CN1-C10) Alkoxy, when a substituent of the S group is substituted on a nonaromatic carbon, the substituent of the S group may also be ═ N-NR11R12N- (4-to 10-membered heterocycle), ═ N- (4-to 10-membered carbocycle), ═ N-nhc (o) R11、＝N-NHC(O)NR11R12、-N(R11)SO2R12Or ═ N-R17(ii) a Wherein any heterocyclic and carbocyclic group may be substituted by Cl, F, (C)1-C10) Alkyl, (C)1-C10) Alkoxy, keto, or CN;
the T group bipolymer is: -O-, -S (O)2-、-N((C1-C6) Alkyl) -, -NH-, -C (O) -, -OC (O) -, -C (O) O-, N (O)Ar) and-OC (O) O-.
2. The compound of claim 1, wherein:
double base1Is absent or > CH2；
Double base2is-CH (R)6)-、-C(O)O-、-C(O)N(R6)-、-C(O)(CH2)m-、-S(O)2(CH2)m-, where m is 0 to 2;
double base3Is > C (O);
double base4Is > O;
double base5Is > C (O) or > C (═ NOR)19)；
Double base6Is- (CH)2)x-, wherein x is 0 to 4; double base7Is- (CH)2)y-, wherein y is 0 to 4; provided that the sum of x + y is from 2 to 4;
R1h, OH, or methyl;
each R11And R12Independently H, (C)1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl, wherein, in addition to H, may be substituted with 1-2 of the following groups: cl, F, OH, (C)1-C3) Alkoxy group, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkyl, halogen substituted (C)1-C3) Alkyl or (C)1-C3) Alkoxy radical- (C1-C3) An alkyl group;
R13is H;
R19is H or (C)1-C6) Alkyl which may be interrupted by 1 to 3 oxygen atoms and may independently be taken from a 4-to 10-membered carbocyclic or heterocyclic ringGeneration;
each one ofArIndependently (a) a 9-to 10-membered heterocycle, (b) a 9-to 10-membered carbocycle, (c) a 4-to 6-membered heterocycle, or (d) a 4-to 6-membered carbocycle, wherein (c) or (d) may be substituted with a 4-to 6-membered heterocycle or a 4-to 6-membered carbocycle; wherein any of the above ring systems may be substituted with 1 to2 of the following groups: CF (compact flash)3、OCF3、OCHF2、CHF2Nitro, Cl, F, Br, hydroxyl, (C)1-C6) Alkyl, CN, CHO, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy group, (C)1-C3) Alkoxy radical- (C1-C3) Alkyl, oxo, (C)1-C6) Alkanoyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, hydroxy-substituted (C)1-C6) Alkyl, -C (O) R11、-OC(O)R11、-C(O)OR11、C(O)N(R11)R12、-OC(O)N(R11)R12、-NHC(O)R11、-N(R11)R12、-N(R11)SO2R12、-SO2N(R11)R12and-S (O)pR11Wherein p is 0 to2, or (C) optionally substituted with CN1-C6) An alkoxy group.
3. A compound according to claim 1 or 2, wherein:
double base2is-CH (R)6)-、-C(O)O-、-C(O)N(R6)-、-C(O)(CH2)m-、-S(O)2(CH2)m-, where m is 0 to 2;
double base3Is > CH (OC (O) R14)、＞CH(OC(O)N(R14)R15)、＞CHOC(O)OR15、＞CHOC(O)CH(N(R14)R15)((CRaRb)n Ar)、＞CHOC(O)CH(N(R14)R15)R14、＞CHOC(O)C(＝NOR14)((CRaRb)n-Ar)、＞CHOC(O)C(＝NOR14)R14、＞CHOC(O)((CRaRb)n Ar) Or, alternatively:
double base4Is > O;
double base5Is > C (O) or > C (═ NOR)19)；
Double base6Is- (CH)2)x-, wherein x is 0 to 4; double base7Is- (CH)2)y-, wherein y is 0 to 4; provided that the sum of x + y is from 2 to 4;
R1h, OH, or methyl;
R3is (C)1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl, any of which may be substitutedArSubstitution;
each R11And R12Independently H, (C)1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) An alkynyl group;
R13and R16Are all H;
each R14And R15Independently is H or (C)1-C6) An alkyl group; wherein 1 to 3 methylene units of the alkyl group may be replaced by-O-, -S (O)2-, C (O) -, or-NH-substitution, where each R is14/R15The pairs may independently form a 3-to 8-membered ring together with the atoms to which they are attached, said 3-to 8-membered ring may be substitutedArOr 1-2 substituents of group S;
R19is H or (C)1-C6) Alkyl which may be interrupted by 1 to 3 oxygen atoms and may be independently substituted by a 4-to 10-membered carbocyclic or heterocyclic ring; and
the substituent of the S group is: nitro, Cl, F, Br, CF3、OCF3、OCHF2、CHF2Hydroxy, (C)1-C6) Alkyl, CN, CHO, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy group, (C)1-C3) Alkoxy radical- (C1-C3) Alkyl, oxo, (C)1-C6) Alkanoyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, hydroxy-substituted (C)1-C6) Alkyl, -C (O) R11、-OC(O)R11、-C(O)OR11、C(O)N(R11)R12、-OC(O)N(R11)R12、-NHC(O)R11、-N(R11)R12、-N(R11)SO2R12、-SO2N(R11)R12and-S (O)pR11Wherein p is 0 to2, and (C) optionally substituted with CN1-C6) An alkoxy group.
4. A compound according to claim 1 or 2, wherein:
double base2Is > CH (R)6)；
Double base5Is > C (O);
R3is methyl;
R5is ethyl;
R6is H, or (C)1-C5) Alkyl, optionally substituted by OH or (C)1-C3) Alkoxy substitution.
5. The compound of any one of claims 1, 2 or 4, wherein:
double base1Absent or methylene;
double base6Is- (CH)2)x-, where x is 0 to 3:
double base7Is- (CH)2)y-, wherein y is 0 to 3; and wherein the sum of x + y is from 2 to 3:
R1is H; and is
R6Is H or (C)1-C3) An alkyl group.
6. The compound of any one of claims 1, 2, or 4-5, wherein:
double base1Is absent;
R2is (a)9-10 membersA heterocycle or carbocycle, or (b) a 4-6 membered heterocycle or carbocycle, wherein (b) may be substituted with a 4-6 membered heterocycle or carbocycle, and R2May be substituted with 1 to2 of the following groups: SO (SO)2R11Hydroxy-substituted (C)1-C3) Alkyl, (C)1-C3) Alkyl, CN, CHO, nitro, F, Cl, Br, CF3、OCF3、OCHF2、CHF2Hydroxy, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkanoyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl or optionally substituted with CN (C)1-C3) An alkoxy group; and is
R6Is H or methyl.
7. A compound according to any one of claims 1, 2 or 4 to 6, wherein
Double base6And7are all methylene groups; and is
R2Is (a) a 9-to 10-membered heterocycle, or (b) a 5-to 6-membered heterocycle or carbocycle, wherein (b) may be substituted with a 5-to 6-membered heterocycle or carbocycle, and R2May be substituted with 1 to2 of the following groups: SO (SO)2R11Hydroxy-substituted (C)1-C3) Alkyl, (C)1-C3) Alkyl, CN, CHO, Br, Cl, F, CF3、OCF3、OCHF2、CHF2Nitro, hydroxy, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkanoyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl or optionally substituted with CN (C)1-C3) An alkoxy group.
8. The compound of any one of claims 1, 2, or 4-7, wherein:
R2is a 9-10 membered heteroaryl group containing 1 to 3 heteroatoms, which may be substituted with 1 to2 of the following groups: SO (SO)2R11Hydroxy-substituted (C)1-C3) Alkyl, (C)1-C3) Alkyl, CN, CHO, Cl, F, CF3Nitro, hydroxy, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkanoyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl or optionally substituted with CN (C)1-C3) An alkoxy group.
9. The compound of any one of claims 1, 2, or 4-8, wherein:
R2is quinolyl, isoquinolyl, quinazolinyl, 4H-quinolizinyl, quinoxalinyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinyl, 1, 7-naphthyridinyl, 1, 8-naphthyridinyl, cinnolinyl, phthalazinyl, pyrido [2, 3-b ]]Pyrazinyl, pyrido [3, 4-b ]]Pyrazinyl, pyrido [3, 2-b ]]Pyrazinyl, pyrido [2, 3-d ]]Pyrimidinyl, pyrido [2, 3-c ]]Pyridazinyl, benzimidazolyl, indolyl, indazolyl, 1H-benzotriazolyl, 1H-pyrrolo [3, 2-b ]]Pyridyl, 1H-pyrrolo [3, 2-c]Pyridyl, 1H-pyrrolo [2, 3-c]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl, 1H-imidazo [4, 5-b ]]Pyridyl, 3H-imidazo [4, 5-b ]]Pyridyl, 1H-imidazo [4, 5-c ]]Pyridyl, 1H- [1, 2,3]Triazolo [4, 5-b]Pyridyl, 1H- [1, 2,3]Triazolo [4, 5-c]Pyridyl, pyrazolo [1, 5-a]Pyridyl, imidazo [1, 5-a ]]Pyridyl, imidazo [1, 2-a ]]Pyridyl, pyrrolo [1, 2-a ]]Pyridyl, pyrrolo [1, 2-a ]]Pyrazinyl, pyrrolo [1, 2-c ]]Pyrimidinyl, pyrrolo [1, 2-b ] s]Pyridazinyl, pyrrolo [1, 5-a ]]Pyrimidinyl, imidazo [1, 5-a ]]Pyrimidinyl, imidazo [1, 2-a ] -compounds]Pyrimidinyl, benzo [ d ]][1.3]Dioxolanyl or 1H-indene-2 (3H) -sulfonyl, any of which may be substituted by 1 to2 (C)1-C3) Alkyl, CN, CHO, Cl, F, CF3Nitro, hydroxy, oxo, (C)1-C3) Alkanoyl, (C)2-C3) Alkenyl, (C)2-C3) Alkynyl or (C)1-C3) Alkoxy substitution.
10. A compound according to claim 1 or 2, wherein:
double base2Is > SO2；
Double base5Is > C (O);
R3is methyl; and is
R5Is ethyl.
11. The compound of claim 10, wherein:
double base1Absent or methylene;
double base6Is- (CH)2)x-, wherein x is 0 to 3;
double base7Is- (CH)2)y-, where y is 0 to 3: and wherein the sum of x + y is 2 to 3; and is
R1Is H; and is
R2Is (a) a 9-to 10-membered heterocycle or carbocycle, or (b) a 4-to 6-membered heterocycle or carbocycle, wherein (b) may be substituted with a 4-to 6-membered heterocycle or carbocycle; and R is2May be substituted with 1 to2 of the following groups: SO (SO)2Hydroxy-substituted (C)1-C3) Alkyl, (C)1-C3) Alkyl, CN, CHO, Br, Cl, F, CF3、OCF3、OCHF2、CHF2Nitro, hydroxy, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkanoyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl or optionally substituted with CN (C)1-C3) An alkoxy group.
12. The compound of claim 10 or 11, wherein:
double base1Absence of:
double base6And7are all methylene groups; and is
R2Is (a) a 9-to 10-membered heterocycle, or (b) a 5-to 6-membered heterocycle or carbocycle, wherein (b) may be substituted with a 5-to 6-membered heterocycle or carbocycle, and R2May be substituted with 1 to2 of the following groups: SO (SO)2Hydroxy-substituted (C)1-C3) Alkyl, (C)1-C3) Alkyl, CN, CHO, Br, Cl, F, CF3、OCF3、OCHF2、CHF2Nitro, hydroxy, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkanoyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl or optionally substituted with CN (C)1-C3) An alkoxy group.
13. The compound of any one of claims 10-12, wherein:
R2is a 9-10 membered heteroaryl group containing 1 to 3 heteroatoms, which may be substituted with 1 to2 of the following groups: SO (SO)2R11Hydroxy-substituted (C)1-C3) Alkyl, (C)1-C3) Alkyl, CN, CHO, Cl, F, CF3Nitro, hydroxy, (C)1-C3) Alkoxy radical- (C1-C3) Alkoxy, oxo, (C)1-C3) Alkanoyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl or optionally substituted with CN (C)1-C3) An alkoxy group.
14. The compound of any one of claims 10-12, wherein:
R2is quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, quinazolinyl, 1, 8-naphthyridinyl, 1, 7-naphthyridinyl, 1, 6-naphthyridinyl, 1, 5-naphthyridinyl, phthalazinyl, benzo [ d ] naphthyridinyl]Thiazolyl, 2, 1, 3-benzothiadiazole-2, 2-dioxide, benzo [ c ]][1，2，5]Oxadiazolyl, benzo [ d ]]Isoxazolyl, benzo [ d ]]Oxazolyl, benzo [ d ]]Isothiazolyl, imidazo [2, 1-b ] s]Thiazolyl, 5-phenylthiazolyl, 2-phenyl-1, 3, 4-thiadiazolyl, 4-phenylthiazolyl, 4-phenyl-1, 2, 3-thiadiazolyl, 5-phenyloxazolyl, 2-phenyl-1, 3, 4-oxadiazolyl, 5-phenyl-1, 2, 4-oxadiazolyl, 3-phenyl-1, 2, 4-oxadiazolyl, 1-phenyl-1H-pyranylAzolyl, 4-phenyl-4H-1, 2, 4-triazolyl, 1-phenyl-4H-1, 2, 4-triazolyl, 2- (1H-1, 2, 4-triazol-1-yl) pyridyl, 2- (1H-pyrazol-1-yl) pyridyl, 2- (4H-1, 2, 4-triazol-1-yl) pyridyl, 1H-indazolyl, 1, 3-dihydrobenzo-2, 2-dioxo [ c ] c]Thienyl, 4- (2-oxooxazolidin-3-yl) phenyl or 2H-indazole, any of which may be substituted by 1 to2 (C)1-C3) Alkyl, CN, CHO, Cl, F, CF3Nitro, hydroxy, oxo, (C)1-C3) Alkanoyl, (C)2-C3) Alkenyl, (C)2-C3) Alkynyl or (C)1-C3) Alkoxy substitution.
15. A compound according to claim 1 or 2, wherein:
double base1Absent or methyl:
double base2Is > C (O), -C (O) N (R)6) -or-C (O) O-;
double base5Is > C (O);
double base6Is- (CH)2)x-, wherein x is 0 to 3;
double base7Is- (CH)2)y-, wherein y is 0 to 3; and wherein the sum of x + y is from 2 to 3;
R3is methyl;
R5is ethyl; and is
R6Is H or methyl.
16. A compound according to claim 1 selected from:
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl) - (1- ((quinolin-5-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl) - (1- ((quinolin-4-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- ((1, 8-naphthyridin-4-yl) -methyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- ((1, 5-naphthyridin-4-yl)) -methyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-2-fluoro-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1R- (1, 8-naphthyridin-4-yl) -ethyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1- (quinolin-4-yl) -butyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8-methoxyquinolin-5-methyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-methoxyquinolin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-methoxy-1, 8-naphthyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-bromo-1, 8-naphthyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-chloro-1, 8-naphthyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-ethoxy-1, 8-naphthyridin-4-methyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4- (xazol-5-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (1H-pyrazol-3-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3- (1, 2, 3-thiadiazol-4-yl) benzenesulfonyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (quinoxaline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1, 3-dihydrobenzo-2, 2-dioxo [ c ] thiophene-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8-methoxyquinoline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8-ethoxyquinoline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (3-cyano-4-ethoxybenzene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (4-ethoxy-3-methoxybenzene-1-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a;
3-descladinosyl-11, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (8-methylquinoline-5-sulfonyl) -azetidin-3-yl) -imino) -erythromycin a.
17. The compound of any one of claims 1 to 16, having an in vitro MIC for clarithromycin resistant streptococcus pyogenes (s.
3-Decaclidinosyl-H, 12-dideoxy-6-O-methyl-3-oxo-12, 11- (oxycarbonyl- (1- (1R- (1, 8-naphthyridin-4-yl) -ethyl) -azetidin-3-yl) -imino) -erythromycin A.
19. A method of treating a bacterial infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-18.
20. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for the treatment of a bacterial infection.
HK08103176.2A 2004-12-21 2005-12-12 Macrolides HK1113931A (en)

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US60/638,097 2004-12-21
US60/717,530 2005-09-14

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