阅读说明：本技术 大环内酯及其制备和使用方法 (Macrolides and methods of making and using the same ) 是由 A.G.迈尔斯 I.B.塞普尔 Z.张 于 2014-04-04 设计创作，主要内容包括：本申请提供的是通过以下方式制备大环内酯的方法：使东半部与西半部偶联,然后大环化,得到大环内酯(包括已知的和新型的大环内酯)。本申请还提供在合成大环内酯中的中间体,包括东半部和西半部。本申请还提供药物组合物和使用本发明的大环内酯治疗传染性疾病和炎症性病症的方法。本申请进一步提供在合成西半部中使用的通用非对映立体选择性醛醇方法。(Provided herein are methods of making macrolides by: coupling of the east moiety with the west moiety followed by macrocyclization yields macrolides (including both known and novel macrolides). The present application also provides intermediates in the synthesis of macrolides, including the east and west halves. The present application also provides pharmaceutical compositions and methods of using the macrolides of the invention for treating infectious and inflammatory disorders. The present application further provides a general diastereoselective aldol process for use in the synthesis of the west moiety.)

1. A compound of the formula:

or a salt thereof;

Wherein:

z is a group of the formula:

wherein:

L¹and L²Each independently is a bond or-CH₂–；

z1 and z2 are each independently 0, 1 or 2;

r in each case^1a、R^1b、R^2aAnd R^2bIndependently hydrogen, halogen, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclylAryl, optionally substituted heteroaryl, or wherein R^1aAnd R^1bOr R^2aAnd R^2bCan be formed together

R in each case^Z2Independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, substituted hydroxy, amino, substituted amino, -C (═ O) R^Z8、-C(＝O)OR^Z8、-C(＝O)N(R^Z8)₂Or a nitrogen protecting group, or two R^Z2The groups together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring;

R^Z3is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

R^Z4is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

Or wherein R is^Z3And R^Z4Can be formed together

L³Is a group of the formula:

represents a single bond or a double bond;

R³is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substitutedAlkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -C (═ O) R^Z8、-C(＝O)OR^Z8、-C(＝O)N(R^Z8)₂An oxygen protecting group or a group of the formula:

R⁴is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;

r in each case¹⁸And R¹⁹Independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

r in each case²⁰And R²¹Independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, substituted hydroxy, mercapto, substituted mercapto, amino, substituted amino, halogen, carbonyl, or R ²⁰And R²¹Together form an optionally substituted cyclopropyl or oxetanyl ring;

r in each case^5aAnd R^5bIndependently hydrogen, halogen, silyl, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

R^Y1is-OR¹⁷And R^Y2Is hydrogen, or R^Y1Is halogen and R^Y2Is hydrogen, or R^Y1Is halogen and R^Y2Is halogen, or R^Y1And R^Y2Together form an oxo (═ O) group;

R⁶is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocycleA group, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, hydroxy, substituted hydroxy, mercapto, substituted mercapto, amino, substituted amino, carbonyl, silyl, or halo;

R⁷and R⁸Each independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

R⁹and R¹⁷Each independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -C (═ O) R ^Z8、–C(＝O)OR^Z8、–C(＝O)N(R^Z8)₂An oxygen protecting group or a carbohydrate;

R¹⁰is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, substituted hydroxy, mercapto, substituted mercapto, amino, substituted amino, carbonyl, silyl, and halogen;

G³is-O-, -S-or-N (R)^G1) -, wherein R^G1Is hydrogen, optionally substituted alkyl or a nitrogen protecting group;

G¹is-OR¹²or-NR¹³R¹⁴；

With the proviso that when G¹is-OR¹²When then R is¹¹And R¹²Combined to form a group of formula-C (═ O) -, giving a cyclic carbonate, or R¹¹And R¹²Are not bound together and R¹¹Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or an oxygen protecting group and R¹²Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substitutedAn alkynyl group, an optionally substituted carbocyclyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an oxygen protecting group or a group of the formula:

or provided that when G is ¹is-NR¹³R¹⁴When then R is¹¹And R¹³Combined to form a group of formula-C (═ O) -, giving a cyclic carbamate, or R¹¹And R¹³Are not bound together, R¹¹Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or an oxygen protecting group, R¹³Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or a nitrogen protecting group;

R¹⁴is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, -C (═ O) R^Z8OR-C (═ O) OR^Z8Or a group of the formula:

or R¹³And R¹⁴Together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

l in each case^C1And L^C2Independently a bond or a linker selected from: optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene; optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, and combinations thereof;

A in each case¹Independently is a leaving groupThe radicals (LG), -SH, -OH, -NH₂、–NH–NH₂、–N₃、–O–NH₂、–C(＝O)R^X1、

A is-NH-, -NH-O-, -O-NH-, -S-, -O-,

q is-NH-, -NH-NH-, -O-NH-, -NH-O-, -S-, -O-;

w is O, S or NR^W1；

R^W1Is hydrogen, substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; a substituted or unsubstituted heterocyclic group; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or a nitrogen protecting group;

R^W2is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; optionally substituted heteroaryl, or two R^W2The groups together form an optionally substituted cyclic moiety;

R^X1is hydrogen, halogen OR-OR^X2Wherein R is^X2Is hydrogen; optionally substituted alkyl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; optionally substituted heteroaryl; or an oxygen protecting group;

R²³Is optionally substituted alkyl;optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; or optionally substituted heteroaryl; and

r in each case^Z8Independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, or two R^Z8The groups together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring;

or A is a cyclic moiety selected from: optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

provided that all known macrolides as shown in figure 1 are specifically excluded.

Background

The increasing emergence of resistance to existing antibiotics is rapidly progressing to global crisis, particularly with regard to infection by Staphylococcus aureus (Staphylococcus aureus), Streptococcus pyogenes (Streptococcus pyogenes) and Streptococcus pneumoniae (Streptococcus pneumoniae). Pathogenic bacteria can transmit genes encoding antibiotic resistance both vertically (to their progeny) and horizontally (to adjacent bacteria of different lineages), and thus allow antibiotic resistance to evolve rapidly, particularly in a hospital (hospital) setting. See, e.g., Wright, chem. commun. (2011)47: 4055-. This year, >99,000 deaths in the united states will be attributed to care-related infections, more than the total number of deaths resulting from traffic accidents, HIV and breast cancer, estimated to place a burden of up to $ 450 billion in U.S. care costs. See, e.g., Klevens et al, Public Health Rep (2007)122: 160-. The current crisis is exacerbated by the fact that most important pharmaceutical companies have essentially abandoned research for the development of new antibiotics. See, e.g., Projan curr Opin Microbiol (2003)6: 427-430. At present, the speed of introduction of new antibiotics is not sufficient to solve the growing problem of resistance, and the need for innovation in this field has never been so urgent due to the simplicity of international travel and the increasing population density.

Macrolides are one of several major antibiotics of clinical importance, the only practical way to obtain them is by semi-synthesis or chemical processing of structurally complex fermentation products, a route as long as 16 steps. See, e.g., Paterson, Tetrahedron (1985)41: 3569-3624; omura, Ed., rolling Antibiotics, Chemistry, Biology, and Practice, Second Edition; academic Press, 2002. Since the discovery of erythromycin over 60 years ago, the macrolide antibiotics have proven safe and effective in combating pathogenic bacteria. See, e.g., Wu et al, curr. Med. chem. (2001)8, 1727-1758. Erythromycin exhibits a spectrum of antibacterial activity against gram-positive bacteria that is similar to that of penicillin but has a lesser tendency to induce allergic interactions, and is conventionally prescribed for upper and lower respiratory tract infections and genitourinary infections. See, e.g., Washington et al, Mayo. Clin. Proc. (1985)60: 189-; washington et al, Mayo, Clin, Proc. (1985)60: 271-278. However, erythromycin is known to undergo acid-promoted lactonization in the intestinal tract (the hydroxyl groups of C6 and C12 ring onto C9 ketone), which leads to adverse gastrointestinal events. See, e.g., Kurath et al, Experientia (1971)27: 362. The second generation macrolide antibiotics, clarithromycin and azithromycin, solve the problem of acid instability and are semi-synthesized in 4-6 steps starting from erythromycin, which is readily available by large-scale fermentation. See, e.g., Ma et al, curr.med.chem. (2011)18: 1993-2015; wu et al, Curr.Pharm.Des. (2000)6: 181-223; ma et al, Mini-rev.med.chem. (2010)10: 272-286; asaka et al, curr. Top. Med. chem. (Sharjah, United Arab animals) (2003)3: 961-989; morimoto et al, J.Antibiot. (1990)43: 286-; morimoto et al, J.Antibiot. (1984)37: 187-189; watanabe et al, J.Antibiott, (1993)46: 1163-1167; watanabe et al, J.Antibiott, (1993)46: 647-660; bright et al, J.Antibiot. (1988)41: 1029-1047; djotic et al, J.Antibiott (1987)40: 1006-; mutak et al, J.Antibiott. (2007)60: 85-122; and Retema et al, Antimicrob.Agents Chemother (1987)31: 1939-1947. Azithromycin has been shown to have significantly enhanced efficacy against gram-negative organisms, as well as a longer half-life and higher tissue distribution than other macrolide antibiotics, which are believed to be associated with 15-membered rings containing tertiary amines. See, e.g., Ferwerda et al, J.Antimicrob.Chemother (2001)47: 441-446; girard et al, Antimicrob. Agents Chemother (1987)31: 1948-1954. The natural product tylosin used in veterinary medicine is a 16-membered macrolide which has been shown by X-ray crystallography to occupy the same binding pocket as erythromycin and azithromycin, thus indicating a high tolerance to variations in the ring size and composition of the macrocycle.

Three major causes of macrolide tolerance in bacterial organisms are ribosomal methylation, mutations in ribosomal RNAs or peptides encoded by the erm gene, and cellular efflux mediated by the mef and msr genes. See, e.g., Leclercq et al, Antimicrob. Agents Chemother (1991)35: 1273-; leclercq et al, Antimicrob.AgentsChemother (1991)35: 1267-; weisblum, Antimicrob.Agents Chemother (1995)39: 577-cake 585; vester et al, Antimicrob.Agents Chemother (2001)45: 1-12; pruner et al, Antimicrob. Agents Chemother (2002)46: 3054-3056; li et al, J.Antimicrob.Chemother (2011)66: 1983-1986; sutcliffe et al, Antimicrob. Agents Chemother (1996)40: 1817-1824; wondrack et al, Antimicrob. Agents Chemother (1996)40: 992-. Ketolides such as telithromycin and solithromycin (solithromycin) resist the efflux mechanism of drug resistance by replacing the C3 cladinose (hence the name "ketolide") with a carbonyl group and are believed to exhibit greatly increased binding through favorable interactions between the novel aryl-alkyl side chains and the ribosome. See, e.g., Ma et al, curr.med.chem. (2011)18: 1993-2015; ma et al, Mini-rev.med.chem. (2010)10: 272-286. Despite the great enhancement of binding to ribosomes, ketolides such as telithromycin and solithromycin have not addressed several of the latest forms of macrolide resistance that have evolved in the hospital setting, particularly ribosome methylation and RNA point mutations.

Summary of The Invention

Described herein are processes for the preparation of macrolides, known as well as new and improved macrolides, via a total synthetic route in a practical manner and intermediates thereof. As shown in scheme 1, this practical synthetic method involves coupling two components, namely the west half (a) and the east half (B), to provide a compound of formula (C-1) or a salt thereof:

scheme 1.

Wherein G is¹、R^1a、R^1b、R^2a、R^2b、R^5a、R^5b、R⁷、R⁸、R⁹、R¹¹Z1 and z2 are as defined hereinDefining;

L³is a group of the formula:

whereinR³、R⁴、R¹⁸、R¹⁹、R²⁰And R²¹As defined herein;

G²is a group of the formula:

wherein R is⁶、R¹⁰、R¹⁵、R^16aAnd X^G2As defined herein;

P¹is hydrogen, silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen, nitrogen or thiol protecting group;

G³is-O-, -S-or-N (R)^G1) -, wherein R^G1Is hydrogen, optionally substituted alkyl or a nitrogen protecting group; and

Y¹and Y²One of them is-Z⁴H or-CH₂NO₂And Y is¹And Y²The other is a Leaving Group (LG), -C (═ O) R^Z3、–C(＝O)OR^Z3、–C(＝O)LG、–C(＝O)-CH＝P(R^P1)(R^P2)(R^P3) or-C (═ O) -CH₂-P(O)(OR^P2)(OR^P3) Wherein Z is⁴is-O-, -S-or-NR^Z2-, and wherein the Leaving Group (LG), R ^Z3、R^Z4、R^P1、R^P2And R^P3As defined herein, to yield various linkers of formula Z as defined herein.

For example, in some embodiments, when Y¹is-C (═ O) R^Z3And R^Z3Is hydrogen (i.e. Y)¹is-CHO) and Y²is-C (═ O) -CH ═ P (R)^P1)(R^P2)(R^P3) or-C (═ O) -CH₂-P(O)(OR^P2)(OR^P3) When the eastern and western moieties are coupled by a Wittig or Horner-Emmons reaction to form a-CH-C (═ O) -moiety and to give a compound of formula (C-1) wherein Z is an α, β -unsaturated ketone of formula:

in some embodiments, when Y is²is-C (═ O) R^Z3And R^Z3Is hydrogen (i.e. Y)¹is-CHO) and Y¹is-C (═ O) -CH ═ P (R)^P1)(R^P2)(R^P3) or-C (═ O) -CH₂-P(O)(OR^P2)(OR^P3) When the eastern and western halves are coupled by a Wittig reaction or Horner-Emmons reaction to form a-C (═ O) -CH ═ CH-moiety, a compound of formula (C-1) is obtained, wherein Z is an α β -unsaturated ketone of formula:

the present application also relates to optional synthetic modifications to the-CH-C (═ O) -moiety and the-C (═ O) -CH ═ CH-moiety. For example, a double bond may be reduced to a single bond, and the carbon alpha to the ketone optionally substituted with a non-hydrogen group R^ZaAnd (4) substitution. Nucleophiles can be reacted via non-hydrogen radicals R^ZbWith a double bond, optionally followed by a non-hydrogen radical R^ZaAlpha substitution is performed. Accordingly, various synthetic modifications of the α β -unsaturated ketone structural formulae to which this application is directed are encompassed by the following formulae:

WhereinRepresents a single or double bond, and R^ZaAnd R^ZbEach independently hydrogen or a non-hydrogen group as defined herein.

In some embodiments, when Y is¹is-Z⁴H, and Y²When it is a Leaving Group (LG), or when Y is²is-Z⁴H and Y¹In the case of a Leaving Group (LG), the east moiety is coupled to the west moiety by nucleophilic displacement, optionally in the presence of a base, to give a compound of formula (C-1) wherein Z is an ether, thioether or amine of formula:

wherein Z⁴is-O-, -S-or-NR^Z2-, and wherein R^Z2Is a hydrogen or non-hydrogen group.

In some embodiments, when Y is¹is-Z⁴H, and Y²is-C (═ O) OR^Z3or-C (═ O) LG, the eastern and western moieties are coupled by 1, 2-nucleophilic addition, optionally in the presence of a base, to give a compound of formula (C-1) wherein Z is an ester, thioester or amide of the formula:

wherein Z⁴is-O-, -S-or-NR^Z2-, and wherein R^Z2Is a hydrogen or non-hydrogen group.

Alternatively, in some embodiments, when Y is²is-Z⁴H, and Y¹is-C (═ O) OR^Z3or-C (═ O) LG, the eastern and western moieties are coupled by 1, 2-nucleophilic addition, optionally in the presence of a base, to give a compound of formula (C-1) wherein Z is an ester, thioester or amide of the formula:

wherein Z⁴is-O-, -S-or-NR ^Z2-, and wherein R^Z2Is a hydrogen or non-hydrogen group.

In some embodiments, wherein Y is¹is-NH₂or-NHR^Z2And Y is²is-C (═ O) R^Z3When the east moiety is coupled to the west moiety by reductive amination, optionally followed by a non-hydrogen R^Z2Protecting the amine group to provide a compound of formula (C-1) wherein Z is an amine of the formula:

wherein R is^Z2Is a hydrogen or non-hydrogen group.

In some embodiments, wherein Y is¹is-NH₂And Y is²is-C (═ O) R^Z3When the east and west halves are coupled by imine formation, optionally followed by addition of a group R to the imine double bond^Z4And optionally subsequently by non-hydrogen R^Z2Protecting the amine group to give a compound of formula (C-1) wherein Z is an imine or amine of formula:

wherein R is^Z2Is a hydrogen or non-hydrogen group.

Or, in some embodiments, wherein Y is²is-NH₂or-NHR^Z2And Y¹is-C (═ O) R^Z3When the east and west halves are coupled by reductive amination, optionally followed by a non-hydrogen R^Z2Protecting the amine group to provide a compound of formula (C-1) wherein Z is an amine of the formula:

wherein R is^Z2Is a hydrogen or non-hydrogen group.

In some embodiments, wherein Y is²is-NH₂And Y¹is-C (═ O) R^Z3When the east and west halves are coupled by imine formation, optionally followed by addition of a group R to the imine double bond ^Z4Optionally followed by non-hydrogen R^Z2Protecting the amine group to give a compound of formula (C-1) wherein Z is an imine or amine of formula:

wherein R is^Z2Is a hydrogen or non-hydrogen group.

The invention also relates to nitro-aldol reaction coupling products, and oxidation, reduction and/or addition products formed therefrom.

For example, in some embodiments, wherein Y is¹is-CH₂NO₂And Y is²is-C (═ O) R^Z3Coupling of the east moiety with the west moiety then affords a compound of formula (C-1), wherein Z is a group of the formula:

or, in some embodiments, wherein Y is²is-CH₂NO₂And Y is¹is-C (═ O) R^Z3Coupling of the east moiety with the west moiety then affords a compound of formula (C-1), wherein Z is a group of the formula:

after obtaining the nitro-aldol coupling product, the nitro (-NO) can be synthesized at any stage₂) Processing is carried out, for example, after coupling but before macrocyclization, or after the macrolide has been formed.

For example, reducing the double bond of a nitro-aldol product of the formula:

to give a Z group of the formula:

addition of the group R to a nitro-aldol product of the formula^Z4:

To give a Z group of the formula:

reducing a nitro group provided in the formula:

to obtain a free amine, which is optionally mono-or di-protected, to obtain a Z group of formula:

oxidizing a nitro group provided in the formula:

To give a keto (oxo) product of the formula:

the present application further relates to alternative processes for preparing the ketone (oxo) products described above.

Furthermore, various macrolides (depending on the group G) can be obtained from the coupling products of formula (C-1) by macrocyclization (e.g.via thermally induced macrocyclization)²The nature of (d). For example, as shown in scheme 2, when G²Is a group of the formula:

P¹is hydrogen and R⁶Macrocyclization of compounds of formula (C-1) gives macrolides of formula (C-2) when they are hydrogen or non-hydrogen groups. Enolizing the macrolide of formula (C-2) in the presence of a base, followed by addition of a non-hydrogen radical R¹⁰To give a macrolide of formula (C-3).

Scheme 2.

Alternatively, as shown in scheme 3, when G²Is a group of the formula:

wherein P is¹Is hydrogen, and R⁶And R¹⁰Macrocyclization of compounds of formula (C-1) each independently is hydrogen or a non-hydrogen group gives macrolides of formula (C-3).

Scheme 3.

The application also relates to other functionalisations of macrolides. For example, as shown in schemes 4 and 5, the reduction of C3 ketone of macrolides (C-2) and (C-3) to the hydroxy group, optionally followed by protection, affords macrolides (C-4) and (C-5), respectively, wherein R¹⁷As defined herein. The application also relates to the C3 ketone of the dihalogenated macrolides (C-2) and (C-3) or monohalogenated macrolides (C-4) and (C-5) to yield Substances (C6a/b) and (C7a/b), where X is halogen, for example fluorine.

Scheme 4.

Scheme 5.

The compounds of formula (C-467) and subsets thereof described herein are intended to encompass the compounds of formula (C-2), (C-4), (C6a) and (C7a) and subsets thereof, wherein R is^Y1is-OR¹⁷And R^Y2Is hydrogen, or R^Y1Is halogen and R^Y2Is hydrogen, or R^Y1Is halogen and R^Y2Is halogen. Likewise, compounds of formula (C-567) and subsets thereof are intended to encompass (C-3), (C-5), (C6b) and (C7b), wherein R is^Y1is-OR¹⁷And R^Y2Is hydrogen, or R^Y1Is halogen and R^Y2Is hydrogen, or R^Y1Is halogen and R^Y2Is halogen, or R^Y1And R^Y2Together form an oxo (═ O) group.

The present application also describes the additional functionalization of the coupling products (C-1) and macrolides (C-2), (C-3), (C-4), (C-5), (C-6) and (C-7), for example by additive or synthetic processing of the moieties attached to the east or west part of the molecule, and by the construction of the east and west halves.

It is generally believed that the synthetic methods described herein are useful in both synthesizing known macrolides (such as those depicted in FIG. 1) and in synthesizing and developing the novel macrolides described herein. The novel macrolides synthesized using the innovative approach and their pharmaceutical compositions are contemplated for use in the treatment of various disorders, for example, for the treatment of bacterial and parasitic infections and for the treatment of inflammatory disorders.

Other aspects of the invention are further described herein. In the construction of the west half (a), it was found that pseudoephedrine glycinamide undergoes highly selective addition with aldehydes and ketones, yielding a product with high diastereoselectivity in a single step. See, e.g., scheme 7. Such reactions are considered to be broadly applicable, using other chiral auxiliary agents such as pseudoephedrine glycinamide, in combination with a wide range of aldehydes and ketones.

Scheme 7.

As described below, a detailed description of some embodiments of the invention is set forth in the "detailed description of some embodiments". Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

Drawings

FIG. 1 depicts exemplary 14-, 15-and 16-membered macrolide antibiotics used in the United states.

FIG. 2 depicts the crystal structure of solithromycin bound to E.coli.

The residues in the sphere were generated using MacPyMol from PDB #3 ORB. See, e.g., Llano-Sotelo Anteriometrics Agents Chemother (2010)54: 4961-4970.

FIG. 3 depicts the Ziegler Traxler and Felkin-Ahn models of aldol reactions conducted between pseudoephedrine glycinamide and ketone.

Definition of

Chemical definition

The definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are confirmed to conform to the periodic table of elements (CAS version, Handbook of Chemistry and Physics, 75 th edition, inner cover) and the specific functional groups are generally defined as described therein. Furthermore, the general principles of Organic Chemistry as well as specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausaltio, 1999; smith and March March's Advanced Organic Chemistry, 5 th edition, John Wiley & Sons, Inc., New York, 2001; larock, Comprehensive Organic Transformations, VCHPublishes, Inc., New York, 1989; and Carruther, Some model Methods of organic Synthesis, 3 rd edition, Cambridge University Press, Cambridge, 1987.

The compounds and macrolides described herein may contain one or more asymmetric centers and may therefore exist in stereoisomeric forms such as enantiomers and/or diastereomers. For example, the compounds and macrolides described herein may exist as individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al, eneriomers, Racemates and solutions (Wiley Interscience, New York, 1981); wilen et al, Tetrahedron 33:2725 (1977); eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Table s of Resolving Agents and optical resolution p.268(E.L.Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972). The invention also encompasses compounds and macrolides as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

When a range of values is recited, it is intended to include each value and every subrange within the range. For example, "C_1–6Alkyl "is intended to cover C₁、C₂、C₃、C₄、C₅、C₆、C_1–6、C_1–5、C_1–4、C_1–3、C_1–2、C_2–6、C_2–5、C_2–4、C_2–3、C_3–6、C_3–5、C_3–4、C_4–6、C_4–5And C_5–6An alkyl group.

As used herein, "alkyl" refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 10 carbon atoms ("C)_1–10Alkyl "). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C)_1–9Alkyl "). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C)_1–8Alkyl "). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C)_1–7Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C)_1–6Alkyl "). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C)_1–5Alkyl "). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C)_1–4Alkyl "). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C)_1–3Alkyl "). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C)_1–2Alkyl "). In some embodiments, the alkyl group has 1 carbon atom ("C")₁Alkyl "). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C) _2–6Alkyl "). C_1–6Examples of alkyl groups include methyl (C)₁) Ethyl (C)₂) N-propyl (C)₃) Isopropyl (C)₃) N-butyl (C)₄) Tert-butyl (C)₄) Sec-butyl (C)₄) Isobutyl (C)₄) N-pentyl group (C)₅) 3-pentyl (C)₅) Pentyl group (C)₅) Neopentyl (C)₅) 3-methyl-2-butylalkyl (C)₅) Tert-amyl (C)₅) And n-hexyl (C)₆). Other examples of alkyl groups include n-heptyl (C)₇) N-octyl (C)₈) And the like. Unless otherwise specified, an alkyl group in each instance is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In some embodiments, the alkyl group is unsubstituted C_1–10Alkyl (e.g., -CH)₃). In some embodiments, the alkyl is substituted C_1–10An alkyl group.

As used herein, "haloalkyl" is a substituted alkyl group as defined herein, wherein one or more hydrogen atoms are independently replaced by a halogen, e.g., fluorine, bromine, chlorine or iodine. "perhaloalkyl" is a subset of haloalkyl and refers to an alkyl in which all hydrogen atoms are independently replaced by a halogen, e.g., fluorine, bromine, chlorine, or iodine. In some embodiments, the haloalkyl moiety has from 1 to 8 carbon atoms ("C) _1–8Haloalkyl "). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C)_1–6Haloalkyl "). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C)_1–4Haloalkyl "). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C_1–3Haloalkyl "). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C)_1–2Haloalkyl "). In some embodiments, all hydrogen atoms of a haloalkyl are replaced with fluorine to provide a perfluoroalkyl group. In some embodiments, all hydrogen atoms of a haloalkyl are replaced with chlorine to provide a "perchloroalkyl" group. Examples of haloalkyl groups include-CF₃,–CF₂CF₃,–CF₂CF₂CF₃,–CCl₃,–CFCl₂,–CF₂Cl, and the like.

As used herein, "heteroalkyl" refers to an alkyl group, as defined herein, that further includes at least one heteroatom (e.g., 1,2,3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, either within the parent chain (i.e., interposed between adjacent carbon atoms) and/or placed in one or more terminal positions of the parent chain. In some embodiments, heteroalkyl refers to a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroc _1–10Alkyl "). In some embodiments, heteroalkyl is a saturated group having from 1 to 9 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroc_1–9Alkyl "). In some embodiments, heteroalkyl is a saturated group having from 1 to 8 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroc_1–8Alkyl "). In some embodiments of the present invention, the substrate is,heteroalkyl is a saturated radical having 1 to 7 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC_1–7Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroc_1–6Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroc_1–5Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroc_1–4Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroc_1–3Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroc _1–2Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 carbon atom and 1 heteroatom ("heteroc₁Alkyl "). In some embodiments, heteroalkyl is a saturated group having from 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroc_2–6Alkyl "). Unless otherwise specified, heteroalkyl groups in each instance are independently unsubstituted (unsubstituted heteroalkyl groups) or substituted with one or more substituents (substituted heteroalkyl groups). In some embodiments, the heteroalkyl is unsubstituted heteroc_1–10An alkyl group. In some embodiments, the heteroalkyl is a substituted heteroc_1–10An alkyl group.

"alkenyl" as used herein refers to a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1,2,3, or 4 double bonds). In some embodiments, alkenyl groups have 2 to 9 carbon atoms ("C)_2–9Alkenyl "). In some embodiments, alkenyl groups have 2 to 8 carbon atoms ("C)_2–8Alkenyl "). In some embodiments, alkenyl groups have 2 to 7 carbon atoms ("C)_2–7Alkenyl "). In some embodiments, alkenyl groups have 2 to 6 carbon atoms ("C)_2–6Alkenyl "). In some embodiments, alkenyl groups have 2 to 5 carbon atoms (“C_2–5Alkenyl "). In some embodiments, alkenyl groups have 2 to 4 carbon atoms ("C)_2–4Alkenyl "). In some embodiments, alkenyl groups have 2 to 3 carbon atoms ("C)_2–3Alkenyl "). In some embodiments, alkenyl has 2 carbon atoms ("C)_{2 ene}Base "). The one or more carbon-carbon double bonds may be internal (e.g., in 2-butene) or terminal (e.g., in 1-butene). C_2–4Examples of the alkenyl group include vinyl (C)₂) 1-propenyl (C)₃) 2-propenyl (C)₃) 1-butenyl (C)₄) 2-butenyl (C)₄) Butadienyl radical (C)₄) And the like. C_2–6Examples of the alkenyl group include the foregoing C_2–4Alkenyl and pentenyl (C)₅) Pentadienyl (C)₅) Hexenyl (C)₆) And the like. Other examples of alkenyl groups include heptenyl (C)₇) Octenyl (C)₈) Octrienyl (C)₈) And the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In some embodiments, the alkenyl group is unsubstituted C_2–10An alkenyl group. In some embodiments, the alkenyl is substituted C_2–10An alkenyl group.

As used herein, "heteroalkenyl" refers to an alkenyl group as defined herein that further includes at least one heteroatom (e.g., 1,2,3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, which heteroatom is internal to the parent chain (i.e., interposed between adjacent carbon atoms) and/or placed in one or more terminal positions of the parent chain. In some embodiments, heteroalkenyl refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroc _2–10Alkenyl "). In some embodiments, heteroalkenyl has 2 to 9 carbon atoms, at least one double bond, and 1 or more heteroatoms ("heteroc") within the parent chain_2–9Alkenyl "). In some embodiments, heteroalkenyl has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms ("heteroc") within the parent chain_2–8Alkenyl "). In some embodiments, the heteroalkenyl group is in the parentHaving 2 to 7 carbon atoms in the chain, at least one double bond and 1 or more heteroatoms ("hetero C)_2–7Alkenyl "). In some embodiments, heteroalkenyl has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms ("heteroc") within the parent chain_2–6Alkenyl "). In some embodiments, heteroalkenyl has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroc") in the parent chain_2–5Alkenyl "). In some embodiments, heteroalkenyl has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroc") in the parent chain_2–4Alkenyl "). In some embodiments, heteroalkenyl has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom ("heteroc") in the parent chain_2–3Alkenyl "). In some embodiments, heteroalkenyl has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroc") in the parent chain _{2-6 ene}Base "). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In some embodiments, the heteroalkenyl is unsubstituted heteroc_2–10An alkenyl group. In some embodiments, the heteroalkenyl is substituted heteroac_2–10An alkenyl group.

As used herein, "alkynyl" refers to a straight or branched chain hydrocarbon group ("C") having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1,2,3, or 4 triple bonds)_2–10Alkynyl "). In some embodiments, alkynyl has 2 to 9 carbon atoms ("C)_2–9Alkynyl "). In some embodiments, alkynyl groups have 2 to 8 carbon atoms ("C)_2–8Alkynyl "). In some embodiments, alkynyl has 2 to 7 carbon atoms ("C)_2–7Alkynyl "). In some embodiments, alkynyl has 2 to 6 carbon atoms ("C)_2–6Alkynyl "). In some embodiments, alkynyl has 2 to 5 carbon atoms ("C)_2–5Alkynyl "). In some embodiments, alkynyl groups have 2 to 4 carbon atoms ("C)_2–4Alkynyl "). In some embodiments, alkynyl groups have 2 to 3 carbon atoms ("C)_2–3Alkynyl "). At one endIn some embodiments, alkynyl has 2 carbon atoms ("C) ₂Alkynyl "). The one or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C_2–4Examples of alkynyl groups include, but are not limited to, ethynyl (C)₂) 1-propynyl (C)₃) 2-propynyl (C)₃) 1-butynyl (C)₄) 2-butynyl (C)₄) And the like. C_2–6Examples of alkynyl groups include the aforementioned C_2–4Alkynyl and pentynyl (C)₅) Hexynyl (C)₆) And the like. Other examples of alkynyl groups include heptynyl (C)₇) (C) octynyl group₈) And the like. Unless otherwise specified, alkynyl groups in each instance are independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In some embodiments, the alkynyl group is unsubstituted C_2–10Alkynyl. In some embodiments, the alkynyl is substituted C_2–10Alkynyl.

As used herein, "heteroalkynyl" refers to an alkynyl group as defined herein that further includes at least one heteroatom (e.g., 1,2,3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, which heteroatom is internal to the parent chain (i.e., inserted between adjacent carbon atoms) and/or disposed in one or more terminal positions of the parent chain. In some embodiments, heteroalkynyl refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroc _2–10Alkynyl "). In some embodiments, heteroalkynyl has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroc") in the parent chain_2–9Alkynyl "). In some embodiments, heteroalkynyl has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroc") in the parent chain_2–8Alkynyl "). In some embodiments, heteroalkynyl has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroc") in the parent chain_2–7Alkynyl "). In some embodiments, heteroalkynyl has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroc") in the parent chain_2–6Alkynyl "). In some embodiments, the heteroalkynyl is within the parent chainHaving 2 to 5 carbon atoms, at least one triple bond and 1 or 2 heteroatoms ('hetero C')_2–5Alkynyl "). In some embodiments, heteroalkynyl has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroc") in the parent chain_2–4Alkynyl "). In some embodiments, heteroalkynyl has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom ("heteroc") in the parent chain_2–3Alkynyl "). In some embodiments, heteroalkynyl has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroc") in the parent chain _2–6Alkynyl "). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In some embodiments, the heteroalkynyl is unsubstituted heteroc_2–10Alkynyl. In some embodiments, the heteroalkynyl is substituted heteroc_2–10Alkynyl.

"carbocyclyl" or "carbocyclic" as used herein, means having from 3 to 14 ring carbon atoms ("C") in a non-aromatic ring system_3–14Carbocyclyl ") and 0 heteroatom non-aromatic cyclic hydrocarbyl groups. In some embodiments, carbocyclyl has 3 to 10 ring carbon atoms ("C)_3–10Carbocyclyl "). In some embodiments, carbocyclyl has 3 to 9 ring carbon atoms ("C)_3–9Carbocyclyl "). In some embodiments, carbocyclyl has 3 to 8 ring carbon atoms ("C)_3–8Carbocyclyl "). In some embodiments, carbocyclyl has 3 to 7 ring carbon atoms ("C)_3–7Carbocyclyl "). In some embodiments, carbocyclyl has 3 to 6 ring carbon atoms ("C)_3–6Carbocyclyl "). In some embodiments, carbocyclyl has 4 to 6 ring carbon atoms ("C)_4–6Carbocyclyl "). In some embodiments, carbocyclyl has 5 to 6 ring carbon atoms ("C) _5–6Carbocyclyl "). In some embodiments, carbocyclyl has 5 to 10 ring carbon atoms ("C)_5–10Carbocyclyl "). Exemplary C_3–6Carbocyclyl includes, but is not limited to, cyclopropyl (C)₃) Cyclopropenyl group (C)₃) Cyclobutyl (C)₄) Cyclobutenyl radical (C)₄) Cyclopentyl (C)₅) Cyclopentenyl group (C)₅) Cyclohexyl (C)₆) Cyclohexenyl (C)₆) Cyclohexadienyl (C)₆) And the like. Exemplary C_3–8Carbocyclyl includes, but is not limited to, C as described above_3–6Carbocyclyl and cycloheptyl (C)₇) Cycloheptenyl (C)₇) Cycloheptadienyl (C)₇) Cycloheptatrienyl (C)₇) Cyclooctyl (C)₈) Cyclooctenyl (C)₈) Bicyclo [2.2.1]Heptylalkyl radical (C)₇) Bicyclo [2.2.2]Octyl radical (C)₈) And the like. Exemplary C_3–10Carbocyclyl includes, but is not limited to, C as described above_3–8Carbocyclyl and cyclononyl (C)₉) Cyclononenyl (C)₉) Cyclodecyl (C)₁₀) Cyclodecenyl (C)₁₀) octahydro-1H-indenyl (C)₉) Decahydronaphthyl (C)₁₀) Spiro [4.5 ]]Decyl (C)₁₀) And the like. As set forth in the foregoing examples, in some embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing fused, bridged, or spiro ring systems such as bicyclic systems ("bicyclic carbocyclyl") or tricyclic systems ("tricyclic carbocyclyl")) and may be saturated or may contain one or more carbon-carbon double or triple bonds. "carbocyclyl" also includes where a ring system as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on said carbocyclyl ring, and in that case, the number of carbons still refers to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, carbocyclyl groups in each instance are independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In some embodiments, the carbocyclyl is unsubstituted C _3–14A carbocyclic group. In some embodiments, the carbocyclyl is substituted C_3–14A carbocyclic group.

In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl ("C") having 3 to 14 ring carbon atoms_3–14Cycloalkyl "). In some embodiments, cycloalkyl groups have from 3 to 10 ring carbon atoms ("C)_3–10Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 9 ring carbon atoms ("C)_3–9Cycloalkyl radicals "). In some embodiments, cycloalkyl groups have 3 to 8 ring carbon atoms ("C)_3–8Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 7 ring carbon atoms ("C)_3–7Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 6 ring carbon atoms ("C)_3–6Cycloalkyl "). In some embodiments, cycloalkyl groups have 4 to 6 ring carbon atoms ("C)_4–6Cycloalkyl "). In some embodiments, cycloalkyl groups have 5 to 6 ring carbon atoms ("C)_5–6Cycloalkyl "). In some embodiments, cycloalkyl groups have from 5 to 10 ring carbon atoms ("C)_5–10Cycloalkyl "). C_5–6Examples of cycloalkyl include cyclopentyl (C)₅) And cyclohexyl (C)₅)。C_3–6Examples of the cycloalkyl group include the aforementioned C_5–6Cycloalkyl and cyclopropyl (C)₃) And cyclobutyl (C)₄)。C_3–8Examples of the cycloalkyl group include the aforementioned C_3–6Cycloalkyl and cycloheptyl (C) ₇) And cyclooctyl (C)₈). Unless otherwise specified, a cycloalkyl group in each instance is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In some embodiments, the cycloalkyl is unsubstituted C_3–14A cycloalkyl group. In some embodiments, the cycloalkyl is substituted C_3–14A cycloalkyl group.

"heterocyclyl" or "heterocyclic" as used herein refers to a 3-to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, as valency permits. A heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclic polycyclic ring systems may include one or more heteroatoms in one or both rings. "heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclic groups, where the point of attachment is on a carbocyclic ring or on a heterocyclyl ring, or ring systems in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on a heterocyclyl ring, and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, a heterocyclyl group in each instance is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In some embodiments, a heterocyclyl is an unsubstituted 3-14 membered heterocyclyl. In some embodiments, heterocyclyl is a substituted 3-14 membered heterocyclyl.

In some embodiments, heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary groups of 3-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, aziridinyl, oxacyclopropaneyl, and thiepinyl. Exemplary groups of 4-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl and thietanyl. 5-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2, 5-diketonyl. Containing 2 hetero atoms A5-membered heterocyclic group includes, but is not limited to, dioxolanyl, oxathiacyclopentane and dithiolane. Exemplary 5-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary groups of 6-membered heterocyclyl containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiacyclohexanyl. Exemplary groups of 6-membered heterocyclyl containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazacyclohexanyl. Exemplary groups of 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepinyl, and thiacycloheptyl. Exemplary groups of 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azacyclooctyl (azocanyl), oxocyclooctyl (oxocanyl), and thiacyclooctyl (thiocanyl). Exemplary bicyclic heterocyclic groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydro-benzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1, 8-naphthyridinyl, octahydropyrrolo [3,2-b ] phenyl ]Pyrrole, indolinyl, phthalimidyl, naphthalimide, chromanyl, chromenyl, 1H-benzo [ e ]][1,4]Diaza derivatives1,4,5, 7-tetrahydropyrano [3,4-b ]]Pyrrolyl, 5, 6-dihydro-4H-furo [3,2-b]Pyrrolyl, 6, 7-dihydro-5H-furo [3,2-b]Pyranyl, 5, 7-dihydro-4H-thieno [2,3-c]Pyranyl, 2, 3-dihydro-1H-pyrrolo [2,3-b ]]Pyridyl, 2, 3-dihydrofuro [2,3-b ]]Pyridyl, 4,5,6, 7-tetrahydro-1H-pyrrolo [2,3-b ]]Pyridyl, 4,5,6, 7-tetrahydrofuro [3,2-c ]]Pyridyl, 4,5,6, 7-tetrahydrothieno [3,2-b ]]Pyridyl, 1,2,3, 4-tetrahydro-1, 6-naphthyridinyl, and the like.

As used herein, "aryl" is meant to be inA group of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n +2 aromatic ring system (e.g., having 6, 10, or 14 shared pi electrons in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms in the aromatic ring system ("C_6-14Aryl "). In some embodiments, an aryl group has 6 ring carbon atoms ("C)₆Aryl "; for example, phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C)₁₀Aryl "; for example, naphthyl groups such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C) ₁₄Aryl "; for example, an anthracene group). "aryl" also includes ring systems in which the aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups in which the linking group or point is on the aryl ring, and in which case the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system. Unless otherwise indicated, each aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In some embodiments, the aryl group is unsubstituted C_6-14And (4) an aryl group. In some embodiments, the aryl group is substituted C_6-14And (4) an aryl group.

"aralkyl" is a subset of "alkyl" and refers to an alkyl group, as defined herein, substituted with an aryl group, as defined herein, wherein the point of attachment is on the alkyl moiety. An exemplary aralkyl is-CH₂-phenyl (benzyl, Bz), wherein the phenyl moiety may be substituted or unsubstituted.

As used herein, "heteroaryl" refers to a group of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n +2 aromatic ring system (e.g., having 6, 10, or 14 shared pi electrons in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems may include one or more heteroatoms in one or both rings. "heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups in which the point of attachment is on the heteroaryl ring, and in this case the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "heteroaryl" also includes ring systems in which the heteroaryl ring as defined above is fused with one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in this case the number of ring members continues to refer to the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment may be on either ring, i.e., on the ring carrying the heteroatom (e.g., 2-indolyl) or on the ring that does not contain the heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, heteroaryl groups in each instance are independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In some embodiments, the heteroaryl is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl is a substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, azaOxygen radical and oxygen radicalRadicals and sulfur hetero

And (4) a base. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzoisothiofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

"heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein, wherein the point of attachment is on the alkyl moiety.

As used herein, the term "partially unsaturated" refers to a cyclic moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to include rings having multiple sites of unsaturation, but not aromatic groups (e.g., aryl or heteroaryl moieties) as defined herein.

As used herein, the term "saturated" refers to a cyclic moiety that does not contain double or triple bonds, i.e., the ring contains all single bonds.

The addition of the prefix/suffix "-ene" to a group indicates that the group is a divalent group, e.g., alkylene is a divalent group of alkyl, alkenylene is a divalent group of alkenyl, alkynylene is a divalent group of alkynyl, heteroalkylene is a divalent group of heteroalkyl, heteroalkenylene is a divalent group of heteroalkenyl, heteroalkynylene is a divalent group of heteroalkynyl, carbocyclylene is a divalent group of carbocyclyl, heterocyclylene is a divalent group of heterocyclyl, arylene is a divalent group of aryl, and heteroarylene is a divalent group of heteroaryl.

As will be appreciated from the above, the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups defined herein, in some embodiments, are optionally substituted. Optionally substituted means that the group may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Generally, the term "substituted" means that at least one hydrogen on the group is replaced with an allowable substituent, e.g., a substituent that results in a stable compound upon substitution, e.g., a compound that does not spontaneously undergo transformation (e.g., rearrangement, cyclization, elimination or other reaction). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when substituted at more than one position of a given structure, the substituents at each position may be the same or different. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that form stable compounds. The present invention is intended to include any and all such combinations that result in stable compounds. For purposes of the present invention, a heteroatom (e.g., nitrogen) may have a hydrogen substituent and/or any suitable substituent described herein, so long as the heteroatom's valence is satisfied and a stable moiety is formed.

Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO₂、–N₃、–SO₂H、–SO₃H、–OH、–OR^aa、–ON(R^bb)₂、–N(R^bb)₂、–N(R^bb)₃ ⁺X^–、–N(OR^cc)R^bb、–SH、–SR^aa、–SSR^cc、–C(＝O)R^aa、–CO₂H、–CHO、–C(OR^cc)₂、–CO₂R^aa、–OC(＝O)R^aa、–OCO₂R^aa、–C(＝O)N(R^bb)₂、–OC(＝O)N(R^bb)₂、–NR^bbC(＝O)R^aa、–NR^bbCO₂R^aa、–NR^bbC(＝O)N(R^bb)₂、–C(＝NR^bb)R^aa、–C(＝NR^bb)OR^aa、–OC(＝NR^bb)R^aa、–OC(＝NR^bb)OR^aa、–C(＝NR^bb)N(R^bb)₂、–OC(＝NR^bb)N(R^bb)₂、–NR^bbC(＝NR^bb)N(R^bb)₂、–C(＝O)NR^bbSO₂R^aa、–NR^bbSO₂R^aa、–SO₂N(R^bb)₂、–SO₂R^aa、–SO₂OR^aa、–OSO₂R^aa、–S(＝O)R^aa、–OS(＝O)R^aa、–Si(R^aa)₃、–OSi(R^aa)₃–C(＝S)N(R^bb)₂、–C(＝O)SR^aa、–C(＝S)SR^aa、–SC(＝S)SR^aa、–SC(＝O)SR^aa、–OC(＝O)SR^aa、–SC(＝O)OR^aa、–SC(＝O)R^aa、–P(＝O)₂R^aa、–OP(＝O)₂R^aa、–P(＝O)(R^aa)₂、–OP(＝O)(R^aa)₂、–OP(＝O)(OR^cc)₂、–P(＝O)₂N(R^bb)₂、–OP(＝O)₂N(R^bb)₂、–P(＝O)(NR^bb)₂、–OP(＝O)(NR^bb)₂、–NR^bbP(＝O)(OR^cc)₂、–NR^bbP(＝O)(NR^bb)₂、–P(R^cc)₂、–P(R^cc)₃、–OP(R^cc)₂、–OP(R^cc)₃、–B(R^aa)₂、–B(OR^cc)₂、–BR^aa(OR^cc)、C_1–10Alkyl radical, C_1–10Perhaloalkyl, C_2–10Alkenyl radical, C_2–10Alkynyl, hetero C_1–10Alkyl, hetero C_2–10Alkenyl, hetero C_2–10Alkynyl, C_3–14Carbocyclyl, 3-14 membered heterocyclyl, C_6–14Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups;

or two twin hydrogens on a carbon atom are replaced by: o, S, NN (R)^bb)₂、＝NNR^bbC(＝O)R^aa、＝NNR^bbC(＝O)OR^aa、＝NNR^bbS(＝O)₂R^aa、＝NR^bbOr as NOR^cc；

R in each case^aaIndependently selected from C_1–10Alkyl radical, C_1–10Perhaloalkyl, C_2–10Alkenyl radical, C_2–10Alkynyl, hetero C_1–10Alkyl, hetero C_2–10Alkenyl, hetero C_2–10Alkynyl, C_3–10Carbocyclyl, 3-14 membered heterocyclyl, C_6–14Aryl and 5-14 membered heteroaryl, or two R^aaThe groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups;

r in each case^bbIndependently selected from hydrogen, -OH, -OR^aa、–N(R^cc)₂、–CN、–C(＝O)R^aa、–C(＝O)N(R^cc)₂、–CO₂R^aa、–SO₂R^aa、–C(＝NR^cc)OR^aa、–C(＝NR^cc)N(R^cc)₂、–SO₂N(R^cc)₂、–SO₂R^cc、–SO₂OR^cc、–SOR^aa、–C(＝S)N(R^cc)₂、–C(＝O)SR^cc、–C(＝S)SR^cc、–P(＝O)₂R^aa、–P(＝O)(R^aa)₂、–P(＝O)₂N(R^cc)₂、–P(＝O)(NR^cc)₂、C_1–10Alkyl radical, C_1–10Perhaloalkyl, C_2–10Alkenyl radical, C_2–10Alkynyl, hetero C _1–10Alkyl, hetero C_2–10Alkenyl, hetero C_2–10Alkynyl, C_3–10Carbocyclyl, 3-14 membered heterocyclyl, C_6–14Aryl and 5-14 membered heteroaryl, or two R^bbThe groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5R^ddSubstituted by groups;

r in each case^ccIndependently selected from hydrogen, C_1–10Alkyl radical, C_1–10Perhaloalkyl, C_2–10Alkenyl radical, C_2–10Alkynyl, hetero C_1–10Alkyl, hetero C_2–10Alkenyl, hetero C_2–10Alkynyl, C_3–10Carbocyclyl, 3-14 membered heterocyclyl, C_6–14Aryl and 5-14 membered heteroaryl, or two R^ccThe groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddSubstituted by groups;

r in each case^ddIndependently selected from halogen, -CN, -NO₂、–N₃、–SO₂H、–SO₃H、–OH、–OR^ee、–ON(R^ff)₂、–N(R^ff)₂、–N(R^ff)₃ ⁺X^–、–N(OR^ee)R^ff、–SH、–SR^ee、–SSR^ee、–C(＝O)R^ee、–CO₂H、–CO₂R^ee、–OC(＝O)R^ee、–OCO₂R^ee、–C(＝O)N(R^ff)₂、–OC(＝O)N(R^ff)₂、–NR^ffC(＝O)R^ee、–NR^ffCO₂R^ee、–NR^ffC(＝O)N(R^ff)₂、–C(＝NR^ff)OR^ee、–OC(＝NR^ff)R^ee、–OC(＝NR^ff)OR^ee、–C(＝NR^ff)N(R^ff)₂、–OC(＝NR^ff)N(R^ff)₂、–NR^ffC(＝NR^ff)N(R^ff)₂、–NR^ffSO₂R^ee、–SO₂N(R^ff)₂、–SO₂R^ee、–SO₂OR^ee、–OSO₂R^ee、–S(＝O)R^ee、–Si(R^ee)₃、–OSi(R^ee)₃、–C(＝S)N(R^ff)₂、–C(＝O)SR^ee、–C(＝S)SR^ee、–SC(＝S)SR^ee、–P(＝O)₂R^ee、–P(＝O)(R^ee)₂、–OP(＝O)(R^ee)₂、–OP(＝O)(OR^ee)₂、C_1–6Alkyl radical, C_1–6Perhaloalkyl, C_2–6Alkenyl radical, C_2–6Alkynyl, hetero C_1–6Alkyl, hetero C_2–6Alkenyl, hetero C_2–6Alkynyl, C_3–10Carbocyclyl, 3-10 membered heterocyclyl, C_6–10Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R ^ggSubstituted by radicals, or two geminal R^ddSubstituents may combine to form ═ O or ═ S;

r in each case^eeIndependently selected from C_1–6Alkyl radical, C_1–6Perhaloalkyl, C_2–6Alkenyl radical, C_2–6Alkynyl, hetero C_1–6Alkyl, hetero C_2–6Alkenyl, hetero C_2–6Alkynyl, C_3–10Carbocyclyl, C_6–10Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ggSubstituted by groups;

r in each case^ffIndependently selected from hydrogen, C_1–6Alkyl radical, C_1–6Perhaloalkyl, C_2–6Alkenyl radical, C_2–6Alkynyl, hetero C_1–6Alkyl, hetero C_2–6Alkenyl, hetero C_2–6Alkynyl, C_3–10Carbocyclyl, 3-10 membered heterocyclyl, C_6–10Aryl and 5-10 membered heteroaryl, or two R^ffThe groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, each of which isAlkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5R^ggSubstituted by groups; and

r in each case^ggIndependently halogen, -CN, -NO₂、–N₃、–SO₂H、–SO₃H、–OH、–OC_1–6Alkyl, -ON (C)_1–6Alkyl radical)₂、–N(C_1–6Alkyl radical)₂、–N(C_1–6Alkyl radical)₃ ⁺X^–、–NH(C_1–6Alkyl radical)₂ ⁺X^–、–NH₂(C_1–6Alkyl radical)⁺X^–、–NH₃ ⁺X^–、–N(OC_1–6Alkyl) (C_1–6Alkyl), -N (OH) (C) _1–6Alkyl), -NH (OH), -SH, -SC_1–6Alkyl, -SS (C)_1–6Alkyl), -C (═ O) (C)_1–6Alkyl), -CO₂H、–CO₂(C_1–6Alkyl), -OC (═ O) (C)_1–6Alkyl), -OCO₂(C_1–6Alkyl), -C (═ O) NH₂、–C(＝O)N(C_1–6Alkyl radical)₂、–OC(＝O)NH(C_1–6Alkyl), -NHC (═ O) (C)_1–6Alkyl), -N (C)_1–6Alkyl) C (═ O) (C)_1–6Alkyl), -NHCO₂(C_1–6Alkyl), -NHC (═ O) N (C)_1–6Alkyl radical)₂、–NHC(＝O)NH(C_1–6Alkyl), -NHC (═ O) NH₂、–C(＝NH)O(C_1–6Alkyl), -OC (═ NH) (C)_1–6Alkyl), -OC (═ NH) OC_1–6Alkyl, -C (═ NH) N (C)_1–6Alkyl radical)₂、–C(＝NH)NH(C_1–6Alkyl), -C (═ NH) NH₂、–OC(＝NH)N(C_1–6Alkyl radical)₂、–OC(NH)NH(C_1–6Alkyl), -OC (NH) NH₂、–NHC(NH)N(C_1–6Alkyl radical)₂、–NHC(＝NH)NH₂、–NHSO₂(C_1–6Alkyl), -SO₂N(C_1–6Alkyl radical)₂、–SO₂NH(C_1–6Alkyl), -SO₂NH₂、–SO₂C_1–6Alkyl, -SO₂OC_1–6Alkyl, -OSO₂C_1–6Alkyl, -SOC_1–6Alkyl, -Si (C)_1–6Alkyl radical)₃、–OSi(C_1–6Alkyl radical)₃、–C(＝S)N(C_1–6Alkyl radical)₂、-C(＝S)NH(C_1–6Alkyl), -C (═ S) NH₂、–C(＝O)S(C_1–6Alkyl), -C (═ S) SC_1–6Alkyl, -SC (═ S) SC_1–6Alkyl, -P (═ O)₂(C_1–6Alkyl), -P (═ O) (C)_1–6Alkyl radical)₂、–OP(＝O)(C_1–6Alkyl radical)₂、–OP(＝O)(OC_1–6Alkyl radical)₂、C_1–6Alkyl radical, C_1–6Perhaloalkyl, C_2–6Alkenyl radical, C_2–6Alkynyl, hetero C_1–6Alkyl, hetero C_2–6Alkenyl, hetero C_2–6Alkynyl, C_3–10Carbocyclyl, C_6–10Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two twinned R^ggSubstituents may combine to form ═ O or ═ S; wherein X^–Are counter ions.

In some embodiments, the carbon substituent is selected from the group consisting of halogen, -CN, -NO ₂、–OH、–OR^aa、–N(R^bb)₂、–SH、–SR^aa、–C(＝O)R^aa、–CO₂H、–CHO、–CO₂R^aa、–OC(＝O)R^aa、–C(＝O)N(R^bb)₂、–OC(＝O)N(R^bb)₂、–NR^bbC(＝O)R^aa、–SO₂N(R^bb)₂、–SO₂R^aa、C_1–6Alkyl radical, C_1–6Perhaloalkyl, C_2–6Alkenyl radical, C_2–6Alkynyl, C_3–6Carbocyclyl, 3-6 membered heterocyclyl, C_{6 aromatic hydrocarbon}And 5-6 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0,1. 2, 3, 4 or 5R^ddAnd (4) substituting the group.

The term "halo" or "halogen" as used herein refers to fluoro (fluoro, -F), chloro (chloro, -Cl), bromo (bromo, -Br), or iodo (iodo, -I).

As used herein, a "counterion" is a negatively charged group associated with a positively charged quaternary ammonium to maintain charge neutrality. Exemplary counterions include halide ions (e.g., F)^–、Cl^–、Br^–、I^–)、NO₃ ^–、ClO₄ ^–、OH^–、H₂PO₄ ^–、HSO₄ ^–Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

The term "hydroxy" as used herein refers to the group-OH. The expanded term "substituted hydroxyl" refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule is substituted with a non-hydrogen group and includes groups selected from: -OR ^aa、–ON(R^bb)₂、–OC(＝O)SR^aa、–OC(＝O)R^aa、–OCO₂R^aa、–OC(＝O)N(R^bb)₂、–OC(＝NR^bb)R^aa、–OC(＝NR^bb)OR^aa、–OC(＝NR^bb)N(R^bb)₂、–OS(＝O)R^aa、–OSO₂R^aa、–OSi(R^aa)_3、–OP(R^cc)₂、–OP(R^cc)₃、–OP(＝O)₂R^aa、–OP(＝O)(R^aa)₂、–OP(＝O)(OR^cc)₂、–OP(＝O)₂N(R^bb)₂and-OP (═ O) (NR)^bb)₂Wherein R is^aa、R^bbAnd R^ccAs defined herein.

The term "mercapto" or "thio" as used herein refers to the group-SH. The expanded term "substituted thio" refers to a mercapto group in which the sulfur atom directly attached to the parent molecule is substituted with a non-hydrogen group and includes groups selected from: -SR^aa、–S＝SR^cc、–SC(＝S)SR^aa、–SC(＝O)SR^aa、–SC(＝O)OR^aaand-SC (═ O) R^aaWherein R is^aaAnd R^ccAs defined herein.

The term "amino" as used herein refers to the group-NH₂. The expanded term "substituted amino" refers to a mono-, di-, or tri-substituted amino group as defined herein. In some embodiments, the "substituted amino" is a mono-substituted amino or di-substituted amino group.

The term "monosubstituted amino" as used herein refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one non-hydrogen group, and includes groups selected from: -NH (R)^bb)、–NHC(＝O)R^aa、–NHCO₂R^aa、–NHC(＝O)N(R^bb)₂、–NHC(＝NR^bb)N(R^bb)₂、–NHSO₂R^aa、–NHP(＝O)(OR^cc)₂and-NHP (═ O) (NR)^bb)₂Wherein R is^aa、R^bbAnd R^ccAs defined herein, and wherein the group-NH (R)^bb) R in (1)^bbIs not hydrogen.

The term "disubstituted amino" as used herein refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two non-hydrogen groups and includes groups selected from: -N (R) ^bb)₂、–NR^bbC(＝O)R^aa、–NR^bbCO₂R^aa、–NR^bbC(＝O)N(R^bb)₂、–NR^bbC(＝NR^bb)N(R^bb)₂、–NR^bbSO₂R^aa、–NR^bbP(＝O)(OR^cc)₂and-NR^bbP(＝O)(NR^bb)₂Wherein R is^aa、R^bbAnd R^ccAs defined herein, provided that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

The term "trisubstituted amino" as used herein refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups and includes groups selected from: -N (R)^bb)₃and-N (R)^bb)₃ ⁺X^–Wherein R is^bbAnd X^–As defined herein.

The term "alkoxyalkyl" as used herein refers to a compound represented by the formula-OR^aaAlkyl groups as defined herein substituted by radicals in which R is^aaAs defined herein, wherein the point of attachment is on the alkyl group.

The term "aminoalkyl" as used herein, refers to an alkyl group, as defined herein, substituted with an amino or substituted amino group, wherein the point of attachment is on the alkyl group.

The term "sulfonyl", as used herein, refers to a group selected from: -SO₂N(R^bb)₂,–SO₂R^aaand-SO₂OR^aaWherein R is^aaAnd R^bbAs defined herein.

The term "sulfinyl" as used herein refers to the group-S (═ O) R^aaWherein R is^aaAs defined herein.

The term "carbonyl" as used herein refers to a group wherein the carbon directly attached to the parent molecule is sp2 hybridized and is substituted with an oxygen, nitrogen or sulfur atom, for example, selected from: ketone (-C (═ O) R ^aa) Carboxylic acid (-CO)₂H) Aldehyde (-CHO), ester (-CO)₂R^aa、–C(＝O)SR^aa、–C(＝S)SR^aa) Amide (-C (═ O) N (R)^bb)₂、–C(＝O)NR^bbSO₂R^aa、–C(＝S)N(R^bb)₂) And imines (-C (═ NR)^bb)R^aa、–C(＝NR^bb)OR^aa)、–C(＝NR^bb)N(R^bb)₂) Wherein R is^aaAnd R^bbAs defined herein.

The term "silyl" as used herein refers to the group-Si (R)^aa)₃Wherein R is^aaAs defined herein.

As used herein, the term "oxo" refers to the group ═ O, and the term "thio" refers to the group ═ S.

The nitrogen atoms may be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR^aa、–N(R^cc)₂、–CN、–C(＝O)R^aa、–C(＝O)N(R^cc)₂、–CO₂R^aa、–SO₂R^aa、–C(＝NR^bb)R^aa、–C(＝NR^cc)OR^aa、–C(＝NR^cc)N(R^cc)₂、–SO₂N(R^cc)₂、–SO₂R^cc、–SO₂OR^cc、–SOR^aa、–C(＝S)N(R^cc)₂、–C(＝O)SR^cc、–C(＝S)SR^cc、–P(＝O)₂R^aa、–P(＝O)(R^aa)₂、–P(＝O)₂N(R^cc)₂、–P(＝O)(NR^cc)₂、C_1–10Alkyl radical, C_1–10Perhaloalkyl, C_2–10Alkenyl radical, C_2–10Alkynyl, hetero C_1–10Alkyl, hetero C_2–10Alkenyl, hetero C_2–10Alkynyl, C_3–10Carbocyclyl, 3-14 membered heterocyclyl, C_6–14Aryl and 5-14 membered heteroaryl, or two R attached to the N atom^ccThe groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddIs substituted by radicals, and wherein R^aa、R^bb、R^ccAnd R^ddAs defined above.

In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -OR ^aa、–N(R^cc)₂、–C(＝O)R^aa、–C(＝O)N(R^cc)₂、–CO₂R^aa、–SO₂R^aa、–C(＝NR^cc)R^aa、–C(＝NR^cc)OR^aa、–C(＝NR^cc)N(R^cc)₂、–SO₂N(R^cc)₂、–SO₂R^cc、–SO₂OR^cc、–SOR^aa、–C(＝S)N(R^cc)₂、–C(＝O)SR^cc、–C(＝S)SR^cc、C_1–10Alkyl (e.g., aralkyl, heteroaralkyl), C_2–10Alkenyl radical, C_2–10Alkynyl, hetero C_1–10Alkyl, hetero C_2–10Alkenyl, hetero C_2–10Alkynyl, C_3–10Carbocyclyl, 3-14 membered heterocyclyl, C_6–14Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R^ddIs substituted by radicals, and wherein R^aa、R^bb、R^ccAnd R^ddAs defined herein. Nitrogen Protecting Groups are well known in the art and are included in Protecting Groups in organic Synthesis, T.W.Greene and P.G.M.Wuts,3^rdedition,John Wiley&Sons,1999, which is incorporated herein by reference.

For example, a nitrogen protecting group such as an amide group (e.g., -C (═ O) R^aa) Including, but not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridine-2-carboxamide, pyridine-3-carboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-substituted ketonesNitrophenoxyacetamide, acetoacetamide, (N' -dithiobenzyloxyacylamino) acetamide, 3- (p-hydroxyphenyl) propionamide, 3- (o-nitrophenyl) propionamide, 2-methyl-2- (o-nitrophenoxy) propionamide, 2-methyl-2- (o-phenylazophenoxy) propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine derivative, o-nitrobenzamide, and o- (benzoyloxymethyl) benzamide.

Nitrogen protecting groups such as carbamate groups (e.g., -C (═ O) OR^aa) Including, but not limited to, methylcarbamate, ethylcarbamate, 9-fluorenylmethylcarbamate (Fmoc), 9- (2-sulfo) fluorenylmethylcarbamate, 9- (2, 7-dibromo) fluorenylmethylcarbamate, 2, 7-di-tert-butyl- [9- (10, 10-dioxo-10, 10,10, 10-tetrahydrothioxanthyl)]Methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl carbamate (Phenoc), 2,2, 2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (1-adamantyl) -1-methylethyl carbamate (Adpoc), 1-dimethyl-2-haloethylcarbamate, 1-dimethyl-2, 2-dibromoethylcarbamate (DB-t-BOC), 1-dimethyl-2, 2, 2-Trichloroethylcarbamate (TCBOC), 1-methyl-1- (4-biphenylyl) ethylcarbamate (Bpoc), 1- (3, 5-di-tert-butylphenyl) -1-methylethylcarbamate (t-Bumeoc), 2- (2 '-and 4' -pyridyl) ethylcarbamate (Pyoc), 2- (N, N-dicyclohexylcarboxamido) ethylcarbamate, tert-Butylcarbamate (BOC), 1-adamantylcarbamate (Adoc), vinylcarbamate (Voc), allylcarbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamoylcarbamate (Coc), 4-nitrocinnamoylcarbamate (Noc), 8-quinolinylcarbamate, N-hydroxypiperidinylcarbamate, alkyldithiocarbamates, benzylcarbamate (Cbz), P-methoxybenzylcarbamate (Moz), p-nitrobenzylcarbamate, p-bromobenzylcarbamate, p-chlorobenzylcarbamate, 2, 4-dichlorobenzylcarbamate, 4-methylsulfinylbenzylamino Carbamates (Msz), 9-anthrylmethylcarbamates, diphenylmethylcarbamates, 2-methylthioethylcarbamates, 2-methylsulfonylethylcarbamates, 2- (p-toluenesulfonyl) ethylcarbamates, [2- (1, 3-dithianyl)]Methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2, 4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonium ethyl carbamate (Peoc), 2-triphenylphosphonium isopropyl carbamate (Ppoc), 1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzylcarbamate, p- (dihydroxyboryl) benzyl carbamate, 5-benzisoxazolyl methyl carbamate, 2- (trifluoromethyl) -6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3, 5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3, 4-dimethoxy-6-nitrobenzyl carbamate, methyl carbamate, Phenyl (o-nitrophenyl) methylcarbamate, t-pentylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2-dimethoxyacylvinylcarbamate, o- (N, N-dimethylcarboxamido) benzylcarbamate, 1-dimethyl-3- (N, N-dimethylcarboxamido) propylcarbamate, 1-dimethylpropynylcarbamate, bis (2-pyridyl) methylcarbamate, 2-furylmethyl carbamate, 2-iodoethylcarbamate, N-cyclohexylcarbamate, N-dimethylcarbamoylcarbamate, N-decyloxybenzylcarbamate, N-ethylcarbamoylcarbamate, N-, Isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p- (p' -methoxybenzazo) benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1- (3, 5-dimethoxyphenyl) ethyl carbamate, 1-methyl-1- (p-phenylazophenyl) ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1- (4-pyridyl) ethyl carbamate, phenyl carbamate, p- (phenylazo) benzyl carbamate, 2,4, 6-tri-tert-butylphenyl carbamate, 4- (trimethylammonium) benzyl Carbamate and 2,4, 6-trimethylbenzylcarbamate.

A nitrogen protecting group such as a sulfonamide group (e.g., -S (═ O)₂R^aa) Including, but not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3, 6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4, 6-trimethoxybenzenesulfonamide (Mtb), 2, 6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5, 6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4, 6-trimethylbenzenesulfonamide (Mts), 2, 6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,5,7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β -trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4 ', 8' -dimethoxynaphthylmethyl) benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide and benzoylsulfonamide.

Other nitrogen protecting groups include, but are not limited to, phenothiazinyl- (10) -acyl derivatives, N ' -p-toluenesulfonylaminoacyl derivatives, N ' -phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4, 5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2, 3-diphenylmaleimide, N-2, 5-dimethylpyrrole, N-1,1,4, 4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1, 3-dimethyl-1, 3, 5-triazacyclohexan-2-one, N-p-toluenesulfonylaminoyl derivatives, N ' -phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4, 5-diphenyl-3-oxazolin-2-one, N, 5-substituted 1, 3-dibenzyl-1, 3, 5-triazacyclohex-2-ones, 1-substituted 3, 5-dinitro-4-pyridone, N-methylamine, N-allylamine, N- [2- (trimethylsilyl) ethoxy ] methylamine (SEM), N-3-acetoxypropylamine, N- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl) amine, quaternary ammonium salts, N-benzylamine, N-bis (4-methoxyphenyl) methylamine, N-5-dibenzocycloheptylamine, N-triphenylmethylamine (Tr), N- [ (4-methoxyphenyl) diphenylmethyl ] amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2, 7-dichloro-9-fluorenylmethylidene amine, N-ferrocenylmethylamino (Fcm), N-pyridine-2-methylamino N '-oxide, N-1, 1-dimethylthiomethylidene amine, N-benzylidene amine, N-p-methoxybenzylideneamine, N-diphenylmethylidene amine, N- [ (2-pyridyl) mesityl ] methylidene amine, N- (N', N '-dimethylaminomethylene) amine, N' -isopropylidene diamine, N-p-nitrobenzylideneamine, N-salicylidene amine, N-5-chlorosalicylidene amine, N- (5-chloro-2-hydroxyphenyl) phenylmethylidene amine, N-cyclohexylidene amine, N- (5, 5-dimethyl-3-oxo-1-cyclohexenyl) amine, N-borane derivatives, N-diphenylboronic acid derivatives, N- [ phenyl (pentaacylchromium-or tungsten) acyl ] amines, N-copper chelates, N-zinc chelates, N-nitramines, N-nitrosamines, amine N-oxides, diphenylphosphoramide (Dpp), dimethylthiophosphoryl-amide (Mpt), diphenylthiophosphoryl-amide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfinamides (Nps), 2, 4-dinitrobenzenesulfenamides, pentachlorobenzenesulfinamides, 2-nitro-4-methoxybenzenesulfinamides, N-nitrobenzenesulfinamides, N-nitrobenzenesulfonamides, N-nitrobenzenesulfinamides, N-nitrobenzenesulfi, Triphenylmethylsulfinamide and 3-nitropyridine sulfinamide (Npys).

In some embodiments, the substituents present on the oxygen atom are oxygen protecting groups (also referred to as "hydroxyl protecting groups"). Oxygen protecting groups include, but are not limited to, -R^aa、–N(R^bb)₂、–C(＝O)SR^aa、–C(＝O)R^aa、–CO₂R^aa、–C(＝O)N(R^bb)₂、–C(＝NR^bb)R^aa、–C(＝NR^bb)OR^aa、–C(＝NR^bb)N(R^bb)₂、–S(＝O)R^aa、–SO₂R^aa、–Si(R^aa)_3、–P(R^cc)₂、–P(R^cc)₃、–P(＝O)₂R^aa、–P(＝O)(R^aa)₂、–P(＝O)(OR^cc)₂、–P(＝O)₂N(R^bb)₂and-P (═ O) (NR)^bb)₂Wherein R is^aa、R^bbAnd R^ccAs defined herein. Oxygen protecting groups are well known in the art and are included in protecting groups in Organic Synthesis, t.w.greene and p.g.m.wuts,3^rdedition,John Wiley&Sons,1999, which is incorporated herein by reference.

Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM), Benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy) methyl (p-AOM), methyl Guaiacol (GUM), t-butoxymethyl, 4-Pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2, 2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl (SEMOR), Tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-Methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl S, S-dioxide, 1- [ (2-chloro-4-methyl) phenyl ] -4-methoxypiperidin-4-yl (CTMP), 1, 4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothienyl, 2,3,3a,4,5,6,7,7 a-octahydro-7, 8, 8-trimethyl-4, 7-methylenebenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2, 2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2, 4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-halobenzyl, 2, 6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-methylpyridyl, 4-methylpyridyl, 3-methyl-2-methylpyridyl N-oxide, diphenylmethyl, p '-dinitrobenzhydryl, p-tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2, 4-dinitrophenyl, benzyl, p-phenylbenzyl, diphenylmethyl, p' -dinitrobenzhydryl, N-oxide, 5-dibenzosuberyl, triphenylmethyl, α -naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4 '-bromophenoyloxyphenyl) diphenylmethyl, 4', 4 "-tris (4, 5-dichlorophthalimidophenyl) methyl, 4 ', 4" -tris (levulinoyl) oxyphenyl) methyl, 4', 4 "-tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-yl) bis (4 ', 4" -dimethoxyphenyl) methyl, 1-bis (4-methoxyphenyl) -1' -pyrenylmethyl, 9-anthryl, and the like, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthracenyl, 1, 3-benzodithiolan-2-yl, benzisothiazolyl S, S-dioxide, Trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), dimethyltert-hexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, Diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (MPS), formate, benzoylformate, TBacetate, chloroacetate, di-tert-butylmethoxyphenylsilyl (MPS), di-n-butyldimethylsilyl (TBDMS), di-tert-butyldimethylsilyl (TBDMS), tri-p-xylylsilyl, tri-p-xyl, Dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4- (ethylenedithio) pentanoate (levulinyl dithioacetal), pivalate (pivaloate), adamantanate (adamantoate), crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4, 6-trimethylbenzoate (mesitylbenzoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2, 2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl) ethyl carbonate (TMSEC), 2- (phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonium) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3, 4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethyl, 4- (methylthiomethoxy) butyrate, methyl ethyl acetate, methyl acetate, ethyl acetate, methyl acetate, ethyl acetate, 2- (methylthiomethoxymethyl) benzoate, 2, 6-dichloro-4-methylphenoxyacetate, 2, 6-dichloro-4- (1,1,3, 3-tetramethylbutyl) phenoxyacetate, 2, 4-bis (1, 1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E) -2-methyl-2-butenoate, o- (methoxyacyl) benzoate, α -naphthoate, nitrate, alkyl N, N, N ', N' -tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinylsulfinyl, alkyl 2, 4-dinitrophenylsulfenate, sulfate, methanesulfonate (methanesulfonate), Benzylsulfonate and tosylate (Ts).

In some embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "mercapto protecting group"). Sulfur protecting groups include, but are not limited to, -R^aa、-N(R^bb)₂、-C(＝O)SR^aa、-C(＝O)R^aa、-CO₂R^aa、-C(＝O)N(R^bb)₂、-C(＝NR^bb)R^aa、-C(＝NR^bb)OR^aa、-C(＝NR^bb)N(R^bb)₂、-S(＝O)R^aa、-SO₂R^aa、-Si(R^aa)₃、-P(R^cc)₂、-P(R^cc)₃、-P(＝O)₂R^aa、-P(＝O)(R^aa)₂、-P(＝O)(OR^cc)₂、-P(＝O)₂N(R^bb)₂and-P (═ O) (NR)^bb)₂Wherein R is^aa、R^bbAnd R^ccAs defined herein. Sulfur protecting groups are well known in the art and include those described in protecting groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts,3^rdedition,John Wiley&Sons,1999, which is incorporated herein by reference.

As used herein, "leaving group" (LG) is a term of art and refers to a molecular fragment that carries a pair of electron-leaving groups in heterolytic bond cleavage, wherein the molecular fragment is an anionic or neutral molecule. See, for example, Smith, MarchAdvanced organic Chemistry 6th ed (501-502). Exemplary leaving groups include, but are not limited to, halide ions (e.g., chloride, bromide, iodide), -OR^aa(wherein R when attached to the carbonyl group^aaAs defined herein), -O (C ═ O) R^LGor-O (SO)₂R^LG(e.g., tosyl, mesyl, phenylsulfonyl), wherein R^LGIs optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.

The phrase "at least one occurrence" as used herein refers to 1, 2, 3, 4 or more occurrences, and includes ranges, for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 occurrences.

"non-hydrogen radical" refers to any radical defined for a particular variable that is not hydrogen.

"carbohydrate group" or "carbohydrate" refers to a monosaccharide or polysaccharide (e.g., a disaccharide or oligosaccharide). Exemplary monosaccharides include, but are not limited to, natural sugars such as allose, altrose, glucose, mannose, gulose, idose, galactose, talose, ribose, arabinose, xylose, and lyxose. Disaccharides are two monosaccharides that are bound together. Exemplary disaccharides include, but are not limited to, sucrose, maltose, cellobiose, and lactose. Commonly, oligosaccharides comprise 3 to 10 monosaccharide units (e.g., raffinose, stachyose). The carbohydrate group may be a natural sugar or a modified sugar. Exemplary modified sugars include, but are not limited to, sugars with the hydroxyl group replaced with an amino group and/or an alkyl group (e.g., deoxyglycosylamine sugars), 2 ' -deoxyribose with the hydroxyl group removed, 2 ' -fluororibose with the hydroxyl group replaced with fluorine, or N-acetylglucosamine or nitrogen-containing forms of sugars (e.g., 2 ' -fluororibose, deoxyribose, and hexose), and the like. Various carbohydrates are described further below and herein. Carbohydrates can exist in a number of different forms, for example, conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers.

These and other exemplary substituents are described in more detail in the "detailed description," "examples," and "claims" sections. The invention is not in any way restricted to the substituents listed above as examples.

Other definitions

The term "salt" as used herein refers to any or all salts and encompasses pharmaceutically acceptable salts.

As used herein, the term "pharmaceutically acceptable salt" means a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals and that does not possess excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, by Berge et al in j.pharmaceutical sciences,1977,66,1-19 (which is incorporated herein by reference). Pharmaceutically acceptable salts of the macrolides of the invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods known in the art (e.g. ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, dodecylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, Picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N ⁺(C_1-4Alkyl radical)₄And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, sodium, potassium,potassium salts, calcium salts, magnesium salts, and the like. Where appropriate, other pharmaceutically acceptable salts include salts formed using counterions (e.g., halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate) with non-toxic ammonium, quaternary ammonium and amine cations.

"subjects" to which administration is made include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle aged, or elderly)) and/or other non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rowsus; commercially available mammals such as cows, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially available birds such as chickens, ducks, geese, and/or turkeys), reptiles, amphibians, and fish. In some embodiments, the non-human animal is a mammal. The non-human animal may be male or female at any developmental stage. The non-human animal can be a transgenic animal.

"disease," "disorder," and "condition" are used interchangeably.

As used herein, unless otherwise indicated, the term "treatment" refers to an action that occurs when a subject suffers from a particular infectious disease or inflammatory disorder, which reduces the severity of the infectious disease or inflammatory disorder, or blocks or slows the progression of the infectious disease or inflammatory disorder ("therapeutic treatment"), and also refers to an action that occurs before the subject begins to suffer from the particular infectious disease or inflammatory disorder ("prophylactic treatment").

In general, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. One skilled in the art will appreciate that the effective amount of a compound of the present invention may vary depending on the following factors: the desired biological endpoint, the pharmacokinetics of the compound, the condition to be treated, the mode of administration, and the age, health, and condition of the subject. An effective amount includes both therapeutic and prophylactic treatment.

As used herein, unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount of the compound sufficient to provide a therapeutic benefit in treating an infectious disease or inflammatory condition, or to delay or minimize one or more symptoms associated with an infectious disease or inflammatory condition. A therapeutically effective amount of a compound means the amount of a therapeutic agent, alone or in combination with other therapeutic agents, that provides a therapeutic benefit in treating an infectious disease or inflammatory disorder. The term "therapeutically effective amount" can include an amount that increases the overall treatment, reduces or avoids the symptoms or causes of an infectious disease or inflammatory disorder, or enhances the therapeutic efficacy of another therapeutic agent.

As used herein and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent an infectious disease or inflammatory disorder, or one or more symptoms associated with an infectious disease or inflammatory disorder, or to prevent recurrence thereof. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapeutic agents, that provides a prophylactic benefit in the prevention of an infectious disease or inflammatory disorder. The term "prophylactically effective amount" can include an amount that increases the overall prophylactic or enhancing prophylactic efficacy of another prophylactic agent.

Detailed description of some embodiments of the invention

As will be generally understood from the disclosure of the present application, the present invention relates in part to macrolides of the formula and salts thereof, which are constructed by coupling of the east and west halves followed by macrocyclization, followed by further synthetic processing:

wherein:

z is:

[1] an ether, thioether, or amine of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and Z2 are each independently 0, 1 or 2 and Z⁴is-O-, -S-or-NR^Z2-, for example, to give a 13-, 14-, 15-or 16-membered ring system, for example, a compound of the formula:

wherein the macrolide is prepared by macrocyclization (e.g., heat-induced macrocyclization) of a coupled precursor of one of the following formulae, optionally followed by further synthetic processing, as described herein:

[2] An ester, thioester or amide of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and Z2 are each independently 0, 1 or 2, and Z⁴is-O-, -S-or-NR^Z2-, for example, to provide a 13-, 14-, 15-or 16-membered ring system of the formula:

wherein, in some embodiments, wherein the macrolide is prepared by macrocyclization (e.g., heat-induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[3] an ester, thioester or amide of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and Z2 are each independently 0, 1 or 2, and Z⁴is-O-, -S-or-NR^Z2-, for example, to provide a 13-, 14-, 15-or 16-membered ring system of the formula:

wherein, in some embodiments, wherein the macrolide is prepared by macrocyclization (e.g., heat-induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[4] an amine of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are 0, 1 or 2, for example, to give a 13-, 14-, 15-or 16-membered ring system, for example of the formulae:

Wherein the macrolide is prepared by macrocyclization (e.g., thermally induced macrocyclization) of a coupled precursor of the formula, optionally followed by further synthetic processing, as described herein:

[5] an amine of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are each independently 0, 1 or 2, for example, to give a 13-, 14-, 15-or 16-membered ring system, for example of the formula:

wherein, in some embodiments, a portion of the macrolide is prepared by macrocyclization (e.g., thermally-induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[6] and an amine of the formula:

wherein L is¹And L²Each independently a bond, and z1 and z2 are 1 or 2, for example, to give a ring system of the formula:

wherein the macrolide is prepared by macrocyclization (e.g., thermally induced macrocyclization) of a coupled precursor of the formula, optionally followed by further synthetic processing, as described herein:

[7] and an amine of the formula:

wherein L is¹And L²Each independently a bond, and z1 and z2 each independently 1 or 2, to give a ring system of the formula:

wherein, in some embodiments, the macrolide is prepared in part by macrocyclization (e.g., thermally induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[8] And an amine of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are each independently 0, 1 or 2, for example, to give a ring system of any of the following formulae:

wherein, in some embodiments, the macrolide is prepared in part by macrocyclization (e.g., thermally induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[9] and for example imines of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are each independently 0, 1 or 2, giving, for example, a 13-, 14-, 15-or 16-membered ring system of the formula:

wherein, in some embodiments, wherein the macrolide is prepared by macrocyclization (e.g., heat-induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[10] for example, nitroolefins of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are 0, 1 or 2, giving, for example, a 13-, 14-, 15-or 16-membered ring system of the formula:

wherein, in some embodiments, wherein the macrolide is prepared by macrocyclization (e.g., heat-induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[11] For example nitro compounds of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are 0, 1 or 2, giving, for example, a 13-, 14-, 15-or 16-membered ring system of the formula:

wherein, in some embodiments, wherein the moiety of the macrolide is prepared by macrocyclization (e.g., thermally induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[12] for example nitro compounds of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are 0, 1 or 2, giving, for example, a 13-, 14-, 15-or 16-membered ring system of the formula:

wherein, in some embodiments, a portion of the macrolide is prepared by macrocyclization (e.g., thermally-induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[13] for example, a group of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are 0, 1 or 2, giving, for example, a 13-, 14-, 15-or 16-membered ring system of the formula:

wherein, in some embodiments, a portion of the macrolide is prepared by macrocyclization (e.g., thermally-induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[14] A group of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are 0, 1 or 2, giving, for example, a 13-, 14-, 15-or 16-membered ring system of the formula:

wherein, in some embodiments, a portion of the macrolide is prepared by macrocyclization (e.g., thermally-induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[15] for example an amino group of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are 0, 1 or 2, giving, for example, a 13-, 14-, 15-or 16-membered ring system of the formula:

wherein, in some embodiments, wherein the macrolide is prepared by macrocyclization (e.g., heat-induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[16] for example, ketone compounds of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are 0, 1 or 2, giving, for example, a 13-, 14-, 15-or 16-membered ring system of the formula:

wherein, in some embodiments, a portion of the macrolide is prepared by macrocyclization (e.g., thermally-induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[17] Such as a ketone group of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 is 0, 1 or 2, to give, for example, a 13-, 14-, 15-or 16-membered ring system of the formula:

wherein, in some embodiments, wherein the macrolide is prepared by macrocyclization (e.g., heat-induced macrocyclization) of a coupled precursor compound of the formula, optionally followed by further synthetic processing, as described herein:

[18] a ketone of the formula:

wherein L is¹And L²Each independently is a bond or-CH₂-; z1 and z2 are each independently 0, 1 or 2, giving, for example, a 14-, 15-or 16-membered ring system of the formula:

wherein the macrolide is prepared by macrocyclization (e.g., heat-induced macrocyclization) of a coupled precursor of one of the following formulae, optionally followed by further synthetic processing, as described herein:

wherein:

R^Y1is-OR¹⁷And R^Y2Is hydrogen, or R^Y1Is halogen and R^Y2Is hydrogen, or R^Y1Is halogen and R^Y2Is halogen, or R^Y1And R^Y2Together form an oxo (═ O) group;

r in each case^1a、R^1b、R^2aAnd R^2bIndependently hydrogen, halogen, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl Optionally substituted aryl, optionally substituted heteroaryl, or wherein R is^1aAnd R^1bOr R^2aAnd R^2bCan be formed together

R^ZaAnd R^ZbEach independently is hydrogen, halogen, hydroxy, substituted hydroxy, amino, substituted amino, mercapto, substituted mercapto, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

r in each case^Z2Independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, substituted hydroxy, amino, substituted amino, -C (═ O) R^Z8、-C(＝O)OR^Z8、-C(＝O)N(R^Z8)₂Or a nitrogen protecting group, or two R^Z2The groups together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring;

R^Z3is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

R^Z4is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

Or wherein R is^Z3And R^Z4Can be formed together

L³Is a group of the formula:

represents a single bond or a double bond;

R³is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -C (═ O) R^Z8、-C(＝O)OR^Z8、-C(＝O)N(R^Z8)₂An oxygen protecting group or a group of the formula:

R⁴is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

r in each case¹⁸And R¹⁹Independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

r in each case²⁰And R²¹Independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, substituted hydroxy, mercapto, substituted mercapto, amino, substituted amino, halogen, carbonyl or R ²⁰And R²¹Together form an optionally substituted cyclopropyl or oxetanyl ring;

r in each case^5aAnd R^5bIndependently hydrogen, halogen, silyl, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

R⁶is hydrogen, optionally substituted alkyl, optionally substitutedSubstituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, hydroxy, substituted hydroxy, mercapto, substituted mercapto, amino, substituted amino, carbonyl, silyl, or halo;

R⁷and R⁸Each independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

R⁹and R¹⁷Each independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -C (═ O) R^Z8、–C(＝O)OR^Z8、–C(＝O)N(R^Z8)₂An oxygen protecting group or a carbohydrate;

R¹⁰Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, substituted hydroxy, mercapto, substituted mercapto, amino, substituted amino, carbonyl, silyl, and halogen;

G³is-O-, -S-or-N (R)^G1) -, wherein R^G1Is hydrogen, optionally substituted alkyl or a nitrogen protecting group;

P¹is hydrogen, silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen, nitrogen or thiol protecting group;

G¹is-OR¹²or-NR¹³R¹⁴；

With the proviso that when G¹is-OR¹²Then:

R¹¹and R¹²Combination ofTo form a group of the formula-C (═ O) -, to give a cyclic carbonate, or

R¹¹And R¹²Are not combined, and R¹¹Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or an oxygen protecting group, and R¹²Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group or a group of the formula:

Or provided that when G is¹is-NR¹³R¹⁴Then:

R¹¹and R¹³Combine to form a group of formula-C (═ O) -, thereby giving a cyclic carbamate, or

R¹¹And R¹³Not in combination, R¹¹Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or an oxygen protecting group, R¹³Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or a nitrogen protecting group;

R¹⁴is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, -C (═ O) R^Z8OR-C (═ O) OR^Z8Or a group of the formula:

or R¹³And R¹⁴Together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

G²is a group of the formula:

x in each case^G2is-OR¹⁵、–SR¹⁵or-N (R)¹⁵)₂；

R in each case¹⁵Independently is silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or two R ¹⁵The groups may together form an optionally substituted heteroaryl or heterocyclic ring;

r in each case^16aIndependently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

l in each case^C1And L^C2Independently a bond or a linker selected from: optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene; optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, and combinations thereof;

leaving Group (LG) is-Br, -I, -Cl, -O (C ═ O) R^LGor-O (SO)₂R^LGWherein R is^LGIs optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl;

a in each case¹And A²Independently a Leaving Group (LG), -SH, -OH, -NH₂、–NH–NH₂、–N₃、–O–NH₂、–C(＝O)R^X1、

A is-NH-, -NH-O-, -O-NH-, -S-, -O-,

q is-NH-, -NH-NH-, -O-NH-, -NH-O-, -S-or-O-;

w is O, S or NR^W1；

R^W1Is hydrogen, substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; a substituted or unsubstituted heterocyclic group; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or a nitrogen protecting group;

R^W2Is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; or optionally substituted heteroaryl, or two R^W2The groups together form an optionally substituted cyclic moiety;

R^X1is hydrogen, halogen OR-OR^X2Wherein R is^X2Is hydrogen; optionally substituted alkyl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; optionally substituted heteroaryl; or an oxygen protecting group;

R²³is optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; or optionally substituted heteroaryl; and

r in each case^Z8Independently hydrogen, optionally substituted alkyl, optionally substituted alkenylSubstituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, or two R^Z8The groups together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring;

or A is a cyclic moiety selected from: optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

Coupling and macrocyclization

As generally described herein, the macrolides of the invention are prepared by coupling the west moiety (A) with the east moiety (B) to give a compound of formula (C-1), or a salt thereof, as shown in scheme 8:

scheme 8.

Wherein L is¹、L²、L³、G¹、G³、R^1a、R^1b、R^2a、R^2b、R^5a、R^5b、R⁷、R⁸、R⁹、R¹¹Z1 and z2 are as defined herein;

P¹is hydrogen, silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen, nitrogen or thiol protecting group;

G²is a group of the formula:

wherein R is⁶And R¹⁰As defined herein;

x in each case^G2is-OR¹⁵、–SR¹⁵or-N (R)¹⁵)₂；

R in each case¹⁵Independently is silyl, optionallySubstituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or two R¹⁵The groups may together form an optionally substituted heteroaryl or heterocyclic ring;

r in each case^16aIndependently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and

Y¹And Y²One of them is-Z⁴H or-CH₂NO₂And Y is¹And Y²The other is a Leaving Group (LG), -C (═ O) R^Z3、–C(＝O)OR^Z3、–C(＝O)LG、–C(＝O)-CH＝P(R^P1)(R^P2)(R^P3) or-C (═ O) -CH₂-P(O)(OR^P2)(OR^P3) Wherein Z is⁴is-O-, -S-or-NR^Z2-, and wherein the Leaving Group (LG), R^Z3、R^Z4、R^P1、R^P2And R^P3As defined herein, thereby yielding various linker formulae Z.

For example, in some embodiments, when Y¹is-C (═ O) R^Z3And R^Z3Is hydrogen (i.e. Y)¹is-CHO) and Y²is-C (═ O) -CH ═ P (R)^P1)(R^P2)(R^P3) or-C (═ O) -CH₂-P(O)(OR^P2)(OR^P3) When the eastern and western halves are coupled by a Wittig or Horner-Emmons reaction to form a-CH-C (═ O) -moiety and to give a compound of formula (C-1) wherein Z is an-unsaturated ketone of formula:

in some embodiments, the double bond of the above formula is provided in the cis configuration. In some embodiments, the double bond of the above formula is provided in the trans configuration.

At one endIn some embodiments, when Y is²is-C (═ O) R^Z3And R^Z3Is hydrogen (i.e. Y)¹is-CHO), and Y¹is-C (═ O) -CH ═ P (R)^P1)(R^P2)(R^P3) or-C (═ O) -CH₂-P(O)(OR^P2)(OR^P3) When the eastern and western halves are coupled by a Wittig reaction or Horner-Emmons reaction to form a-C (═ O) -CH ═ CH-moiety, and to give a compound of formula (C-1) wherein Z is an α β -unsaturated ketone of formula:

in some embodiments, the double bond of the above formula is provided in the cis configuration. In some embodiments, the double bond of the above formula is provided in the trans configuration.

The invention also relates to optional synthetic modifications of the-CH-C (═ O) -moieties and-C (═ O) -CH ═ CH-moieties. For example, the double bond may be reduced to a single bond, and optionally, the carbon alpha to the ketone may be replaced by a non-hydrogen group R^ZaAnd (4) substitution. Nucleophiles can be bound to the double bond via a non-hydrogen radical R^ZbOptionally followed by a non-hydrogen radical R^ZaAlpha substitution is performed. Accordingly, various synthetic modifications to the α β -unsaturated ketone structural formula contemplated by this application can be encompassed by the following formula:

wherein

Represents a single or double bond, and R^ZaAnd R^ZbEach independently is hydrogen or a non-hydrogen group (e.g., halogen, hydroxyl, substituted hydroxyl, amino, substituted amino, mercapto, substituted mercapto, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl). The above formula is still containedCap initiated Wittig reaction or Horner-Emmons reaction linker, i.e., wherein

Represents a double bond, and R^ZaAnd R^ZbEach hydrogen, and other synthetic modifications of the linker, e.g. thereinRepresents a single bond, and R^ZaAnd R^ZbEach independently being a hydrogen or non-hydrogen radical, or Represents a single or double bond, and R^ZaAnd R^ZbEach independently is hydrogen or a non-hydrogen group, provided that R^ZaAnd R^ZbIs a non-hydrogen group. In some embodiments, whereinRepresents a double bond, R^ZaAnd R^ZbIn the cis configuration. In some embodiments, whereinRepresents a double bond, R^ZaAnd R^ZbIn the trans configuration.

In some embodiments, when Y is¹is-Z⁴H, and Y²When it is a Leaving Group (LG), or when Y is²is-Z⁴H and Y¹In the case of a Leaving Group (LG), the eastern and Western moieties are coupled by nucleophilic displacement (nucleophilic substitution), optionally in the presence of a base, to give a compound of formula (C-1) wherein Z is an ether, thioether or amine of formula:

wherein Z⁴is-O-, -S-or-NR^Z2-, and wherein R^Z2Is a hydrogen or non-hydrogen group. Exemplary bases include, but are not limited to, organic bases (A), (B), (C), (E.g., pyridine, DMAP, suniting) and inorganic bases (e.g., sodium bicarbonate, sodium carbonate). Exemplary leaving groups include bromo, chloro, iodo, tosylate, triflate, mesylate and benzenesulfonate.

In some embodiments, when Y is¹is-Z⁴H, and Y²is-C (═ O) OR^Z3or-C (═ O) LG, the eastern and western moieties are coupled by 1, 2-nucleophilic addition, optionally in the presence of a base, to give a compound of formula (C-1) wherein Z is an ester, thioester or amide of the formula:

Wherein Z⁴is-O-, -S-or-NR^Z2-, and wherein R^Z2Is a hydrogen or non-hydrogen group. In some embodiments, wherein R is^Z3For hydrogen, the reaction is carried out in the presence of a coupling agent, such as a carbodiimide reagent. Exemplary bases include, but are not limited to, organic bases (e.g., pyridine, DMAP, schnixi base) and inorganic bases (e.g., sodium bicarbonate, sodium carbonate). Exemplary leaving groups include bromo, chloro, iodo, tosylate, mesylate, triflate and benzenesulfonate.

Alternatively, in some embodiments, when Y is²is-Z⁴H, and Y¹is-C (═ O) OR^Z3or-C (═ O) LG, the eastern and western moieties are coupled by 1, 2-nucleophilic addition, optionally in the presence of a base, to give a compound of formula (C-1) wherein Z is an ester, thioester or amide of the formula:

wherein Z⁴is-O-, -S-or-NR^Z2-, and wherein R^Z2Is a hydrogen or non-hydrogen group. In some embodiments, wherein R is^Z3For hydrogen, the reaction is carried out in the presence of a coupling agent, such as a carbodiimide reagent. Exemplary bases include, but are not limited to, organic bases (e.g., pyridine)Pyridine, DMAP, sunitinib base) and inorganic bases (e.g., sodium bicarbonate, sodium carbonate). Exemplary leaving groups include bromo, chloro, iodo, tosylate, mesylate, triflate and benzenesulfonate.

In some embodiments, wherein Y is¹is-NH₂or-NHR^Z2And Y is²is-C (═ O) R^Z3The east moiety is coupled to the west moiety by reductive amination, optionally followed by a non-hydrogen R^Z2Protecting the amine group to provide a compound of formula (C-1) wherein Z is an amine of the formula:

wherein R is^Z2Is a hydrogen or non-hydrogen group. Exemplary reductive amination conditions include, but are not limited to, the use of B₁₀H₁₄、InCl₃/Et₃SiH、NaBH₄、NaBH₄/H₃BO₃、NaBH₃CN or NaBH (OAc)₃Optionally in the presence of an acid (e.g., AcOH, TFA) or a protic solvent (e.g., MeOH). In some embodiments, R^Z2Is hydrogen. In some embodiments, R^Z2Is methyl. In some embodiments, R^Z2is-C (═ O) R^Z8. In some embodiments, R^Z2is-C (═ O) Me. In some embodiments, R^Z2Is a nitrogen protecting group.

In some embodiments, wherein Y is¹is-NH₂And Y is²is-C (═ O) R^Z3The east moiety is coupled to the west moiety by imine formation, optionally followed by the group R^Z4Addition to the imine double bond and optionally subsequent passage through a non-hydrogen R^Z2Protecting the amine group to give a compound of formula (C-1) wherein Z is an imine or amine of formula:

wherein R is^Z2Is a hydrogen or non-hydrogen group. In some embodiments，R^Z2Is hydrogen. In some embodiments, R^Z2Protection being methyl, -C (═ O) R ^Z8Or a nitrogen protecting group. In some embodiments, by nucleophile R^Z4M is to R^Z4Addition to an imine double bond, where M is an anion, Li, K, CuX, or MgX, where X is a halogen.

Or, in some embodiments, wherein Y is²is-NH₂or-NHR^Z2And Y is¹is-C (═ O) R^Z3The east moiety is coupled to the west moiety by reductive amination, optionally followed by a non-hydrogen R^Z2Protecting said amine group to provide a compound of formula (C-1) wherein Z is an amine of the formula:

wherein R is^Z2Is a hydrogen or non-hydrogen group. Exemplary reductive amination conditions include, but are not limited to, the use of B₁₀H₁₄、InCl₃/Et₃SiH、NaBH₄、NaBH₄/H₃BO₃、NaBH₃CN or NaBH (OAc)₃Optionally in the presence of an acid (e.g., AcOH, TFA) or a protic solvent (e.g., MeOH). In some embodiments, R^Z2Is hydrogen. In some embodiments, R^Z2Protection being methyl, -C (═ O) R^Z8Or a nitrogen protecting group.

In some embodiments, wherein Y is²is-NH₂And Y is¹is-C (═ O) R^Z3The east and west halves are coupled by imine formation, optionally followed by addition of a group R to the imine double bond^Z4Optionally via a non-hydrogen R^Z2Protecting the amine group to give a compound of formula (C-1) wherein Z is an imine or amine of formula:

wherein R is^Z2Is a hydrogen or non-hydrogen group. In some embodiments, R ^Z2Is hydrogen. In some embodimentsIn the scheme, R^Z2Protection being methyl, -C (═ O) R^Z8Or a nitrogen protecting group. In some embodiments, by nucleophile R^Z4M addition of R to the imine double bond^Z4Wherein M is an anion, Li, K, CuX, or MgX, wherein X is a halogen.

Further contemplated are nitro-aldol reaction (Henry reaction) coupling products, and oxidation, reduction and/or addition products formed therefrom. The nitroaldol reaction may be catalyzed or promoted by a variety of different sets of conditions, for example, using organic bases, inorganic bases, quaternary ammonium salts, and/or catalysts; and the use of protic or aprotic solvents and/or the use of solvent-free conditions. See, e.g., Luzzio Tetrahedron (2001)915-945, which is a review of the various conditions used in nitroaldol reactions.

For example, in some embodiments, wherein Y is¹is-CH₂NO₂And Y is²is-C (═ O) R^Z3Coupling the east moiety with the west moiety gives a compound of formula (C-1) wherein Z is a group of formula:

or, in some embodiments, wherein Y is²is-CH₂NO₂And Y is¹is-C (═ O) R^Z3Coupling the east moiety with the west moiety gives a compound of formula (C-1) wherein Z is a group of formula:

after obtaining the nitro-aldol coupling product, the nitro (-NO) group can be reacted at any stage of the synthesis ₂) And processing the part.

For example, reducing the double bond of a nitro-aldol product of the formula:

to give a Z group of the formula:

a radical R^Z4Addition to nitro-aldol products of the formula:

to give a Z group of the formula:

reducing a nitro group provided in the formula:

to give a free amine, which may optionally be mono-or di-protected, to give a Z group of the formula:

oxidizing a nitro group provided in the formula:

to give a keto (oxo) product of the formula:

the present application also relates to alternative syntheses, forming keto (oxo) products.

Various macrolides (depending on the group G) can be obtained from these coupling products of formula (C-1) by macrocyclization²The nature of (d). For example, as shown in scheme 9, when G²Is a group of the formula:

and R⁶When it is a hydrogen or non-hydrogen group, a macrocyclic compound of formula (C-1) (e.g. wherein P is¹Hydrogen) to give the macrolide of formula (C-2). Enolizing the macrolide of formula (C-2) and then adding to the non-hydrogen radical R¹⁰(e.g., using a base and R¹⁰Alkylating agents, e.g. R¹⁰-LG or if R¹⁰For halogen, a halogenating agent is used) to give a macrolide of the formula (C-3).

Scheme 9.

Alternatively, as shown in scheme 10, when G²Is a group of the formula:

and wherein R⁶And R¹⁰Each being a hydrogen or non-hydrogen group, a macrocyclic compound of formula (C-1) (e.g., wherein P ¹Hydrogen) to give the macrolide of formula (C-3).

Scheme 10.

The application also relates to the further functionalization of said macrolides. For example, as shown in schemes 11 and 12, the C3 ketone of macrolides (C-2) and (C-3) is reduced to the hydroxy group, optionally followed by protection, to give the macrolides (C-4) and (C-5), respectively. Alternatively, as shown in schemes 13A-13B, the hydroxyl group at C3 can be modified by O-alkylation or acylation, wherein LG is a leaving group as defined herein. In some embodiments, R¹⁷is-C (═ O) R^Z8Wherein R is^Z8Is optionally substituted alkyl (e.g., optionally substituted aralkyl or optionally substituted heteroaralkyl).

This ability allows protection of the position as a carbonyl when other free hydroxyl groups are modified (e.g., O-alkylated) since the oxidation state of the oxygen at C3 is easily changed. Thus, the present application also relates to oxidation or reduction of the site at different points in a particular synthetic sequence.

Scheme 11.

Scheme 12.

Scheme 13A.

Scheme 13B.

The invention also relates to further modifications of ketones or reduced macrolides. For example, as shown in schemes 14A-14B and 15A-15B, C3 ketone C-2 or C-3 or C-4 or C-5 (e.g., hydroxy at C3, where R is R at ¹⁷Hydrogen) can be halogenated with an electrophilic halogenating agent (e.g., Deoxo-Fluor) to yield a geminal dihalide such as C-6 or a monohalide such as C-7, respectively, wherein X is halogen (e.g., fluorine, bromine, iodine).

Scheme 14A.

Scheme 14B.

Scheme 15A.

Scheme 15B.

As demonstrated in schemes 16A-16B and 17A-17B, in which R³Or R⁴In the case of allyl groups, rapid derivatization into novel macrolides is possible. Various groups such as heteroaryl or aryl moieties can be introduced by transition metal catalyzed cross-coupling (e.g., heck reaction) or by olefin metathesis (e.g., cross-metathesis using Grubbs or Schrock metal carbene catalysts) to give derivatives such as C-9 or C-15. Subsequent processing (e.g., hydrogenation) of the olefin can result in other diverse structures (e.g., C-10a-b, C-16 a-b). Alternatively, the olefin functionality may be oxidatively cleaved to yield a carbonyl functionality (C-11a-b or C-17a-b), which may be further modified by conversion, e.g., reduction, nucleophilic addition (C-13a-b or C-19a-b), or reductive amination (C-12a-b or C-18a-b), wherein R in each case²²Independently hydrogen or optionally substituted alkyl, and R²⁴Is hydrogen, optionally substituted alkyl or optionally substituted aryl. In some embodiments, R ²²is-CH₂C (═ O) OH. In some embodiments, R²²Is composed ofIn some embodiments, R²²Is composed ofAlthough the modifications shown herein are performed in the context of a preformed macrocycle, the present application also relates to the same transformation of macrolide building blocks prior to assembly.

Scheme 16A.

Scheme 16B.

Scheme 17A.

Scheme 17B.

When R is^1a、R^1b、R^2a、R^2bOr R^Z3When any of these is allyl, further derivatization can be performed with the transformations described herein before or after macrocyclization. Although only the macrocyclic C-20a-B in schemes 18A-B is depicted, such modifications are contemplated where R is^1a、R^1b、R^2a、R^2bOr R^Z3At least one of which is any macrocyclic ring of allyl groups. wherein-CH in the chain₂Derivatives from which part has been removed may be used in which R^1a、R^1b、R^2a、R^2bOr R^Z3Any of which is a vinyl precursor (schemes 19A-19B). In some embodiments, R²²is-CH₂C (═ O) OH. In some embodiments, R²²Is composed ofIn some embodiments, R²²Is composed of

Although the modifications shown herein are made in the context of a preformed macrocycle, the application also relates to the same transformation on macrolide assembly parts prior to assembly.

Scheme 18A.

Scheme 18B.

Scheme 19A.

Scheme 19B.

When R is ^1aAnd R^1bOr R^2aAnd R^2bMay together form a moiety alpha to an oxo (═ O)

When used, the transformations described herein may be used to further derivatize before or after macrocyclization. With nucleophiles R²³Substances (e.g. X-R)²³Or M-R²³Where M is an anion, Li, Na, K, CuX, or MgX, and X is a halogen) to give a compound of formula C-42 a-b. Although only the macrocyclic ring C41a-B in schemes 20A-20B is depicted, such modifications also involve those in which R is^1aAnd R^1bOr R^2aAnd R^2bAlpha to an oxo (═ O) moiety

Any macrocycle of (1). Although the modifications shown herein are made in the context of a preformed macrocycle, the application also relates to the same transformation on macrolide assembly parts prior to assembly.

Scheme 20A.

Scheme 20B.

When R is^1a、R^1b、R^2a、R^2bOr R^Z3When either is hydrogen (attached to the alpha position of an oxo (═ O) moiety), further derivatization before or after macrocyclization can be carried out using the transformations described herein. Base-mediated deprotonation and enolization with leaving group conjugate R^1aWherein LG is a leaving group as defined herein, to give an alpha-functionalized ketolactone of formula C-44 a-b. Although only the macrocyclic ring C-43a-B in schemes 21A-21B is depicted, such modifications also involve those in which R is ^1a、R^1b、R^2a、R^2bOr R^Z3Is hydrogen and Z is any macrocyclic ring containing a ketone moiety. Although the modifications shown herein are made in the context of a preformed macrocycle, the application also relates to the same transformation on macrolide assembly parts prior to assembly.

Scheme 21A.

Scheme 21B.

As shown in schemes 22A-2B, the nitrogen of the macrocycle may be further substituted by R^Z2The groups are functionalized. Non-limiting examples of double bond functionalization include:

(i) conjugation of R with a leaving group^Z2(i.e., C32a-b, R^Z2LG, wherein LG is a leaving group as defined herein) to N-alkylate an amine. In some embodiments, the leaving group conjugate R^Z2Is an organic halide. In some embodiments, the organic halide is a methyl halide (e.g., methyl iodide).

(ii) With reagents such as carboxylic acid, anhydride, or other acid leaving group conjugates (i.e. with，C33a-b、R^Z2(C＝O)OH、R^Z2(C＝O)O(C＝O)R^Z2Or R^Z2(C ═ O) -LG wherein LG is a leaving group as defined herein) acylating an amine. In some embodiments, the anhydride is acetic anhydride.

(iii) With reagents such as aldehydes or ketones (i.e., C34a-b, R)^Z2(C ═ O) H or R^Z2(C＝O)R^Z2) And (3) reductive amination. In some embodiments, the aldehyde is formaldehyde.

Although only the macrocyclic ring C31A-B in schemes 21A-B is depicted, such modifications are directed to any macrocyclic ring wherein Z contains an amine moiety. Although the modifications shown herein are made in the context of a preformed macrocycle, the application also relates to the same transformation on macrolide assembly parts prior to assembly.

Scheme 22A.

Scheme 22B.

Further, as shown in schemes 23-26, wherein G¹is-NHR¹³By reacting an alcohol with a compound of formula LG-L^C1The reaction scheme (L) for the LG compound^C1I) a group, then with a nucleophilic group A¹Displacement of the second leaving group to give formula (L)^C1-ii) a group, then the group A¹And formula A²-L^C2-R²³The compound reacts to assemble the above formula (L)^C1-iii) a group, which is also relevant for the present invention.

Scheme 23.

Scheme 24.

Scheme 25.

Scheme 26.

Or, the group-L^C1-A¹Can be reacted with an amine of the formula LG-L^C1-A¹Reaction of the compounds was directly assembled. Wherein G is¹The case of being-OH also relates to such a reaction.

Further, as depicted in scheme 27 (wherein L³Is of the formula (L)³-i) a group wherein R³Is hydrogen (called (L)³Ia)) by reacting an alcohol with a compound of formula LG-L^C1Reaction of LG Compound to assemble formula (L)^C1I) a group, and then converting (e.g., by nucleophilic displacement or other synthetic processing) the second leaving group to a group A¹To obtain formula (L)^C1Ii) a group, then A¹And formula A²-L^C2-R²³The compound reacts to assemble the above formula (L)^C1-iii) a group, which is also relevant for the present invention.

Scheme 27.

Or, the group-L^C1-A¹Can be directly assembled on (L)³Ia) to obtain (L)³-ic) by reacting hydroxy with a compound of formula LG-L^C1-A¹Reaction of the compoundShould be used.

In addition, there are various ways to add formula (L) ^C1-iii) a group, these modes not involving A¹And A²Reacted to form a, and thus a may be any group, such as a cyclic moiety selected from: optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl. For example, via the group-OR¹²、-NR¹³R¹⁴and/OR-OR³(wherein R is¹²、R¹⁴And/or R³Is hydrogen) and formula (L)^C1Vii) reaction of the Compound for example, Assembly of formula (L) by nucleophilic Displacement^C1-iii) a group, to obtain wherein R¹²、R¹⁴And/or R³Is of the formula (L)^C1-iii) of the group. See, e.g., scheme 28.

Scheme 28.

Further, as depicted in scheme 28, wherein L³Is of the formula (L)³-i) a group, eliminating the group-OR³To give an alkenyl moiety which may be reduced (e.g. by hydrogenation) or substituted with a group R²⁰And R²¹Further functionalization as described in scheme 29. Functionalization of the double bond to give the radical R²⁰And R²¹Are known in the art. See, e.g., Organic Chemistry, Thomas Sorrell, University Science Books, Sausalitio, 1999; smith March March's advanced organic Chemistry,5^thEdition,JohnWiley&Sons, inc., New York, 2001; larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruther, Some model Methods of Organic Synthesis,3 ^rdEdition, Cambridge university Press, Cambridge, 1987. Non-limiting examples of double bond functionalization include:

(i) reaction of the double bond with a cyclopropanating reagent to give the group (L)³-iii) wherein R²⁰And R²¹Together form an optionally substituted cyclopropyl ring;

(ii) reaction of the double bond with an epoxidizing agent to giveGroup (L)³-iii) wherein R²⁰And R²¹Together form an oxetanyl ring;

(iii) double bond with dihydroxylation reagents (e.g., OsO)₄) Reaction, optionally followed by protection of the hydroxyl group, to give the group (L)³-iii) wherein R²⁰And R²¹Each independently is hydroxy or substituted hydroxy;

(iv) HX is added to the double bond, where X is halogen or hydroxy or substituted hydroxy, to give the radical (L)³-iii) wherein R²⁰And R²¹One of which is halogen or hydroxy or substituted hydroxy, and R²⁰And R²¹One of them is hydrogen;

(v)X₂addition to a double bond, where X is halogen, gives the radical (L)³-iii) wherein R²⁰And R²¹Each independently is halogen;

(vi)X₂/H₂o or X₂Alcohol addition to a double bond, where X is halogen, gives the radical (L)³-iii) wherein R²⁰And R²¹One of which is hydroxy or substituted hydroxy, and R²⁰And R²¹One is halogen; and

(viii) oxidative hydroboration of the double bond to give the radical (L)³-iii) wherein R²⁰And R²¹One of which is hydroxy or substituted hydroxy, and R ²⁰And R²¹One of which is hydrogen.

Scheme 29.

For all transformations associated with the previously formed macrocycles, the present invention involves the introduction of these groups by the general transformations described as being carried out in various steps prior to ring formation. Readjusting the steps as necessary to accommodate a particular intermediate or functional group is understood by those skilled in the art.

Alternative methods for the synthesis of ketolides

The present invention also relates to alternative processes for preparing ketone (oxo) products wherein Z has the formula:

for example, the Z linker described above may be formed by a Wittig or horner-illion reaction between an aldehyde and a ylide or phosphonate, thereby forming an α, β -unsaturated ketone linked intermediate. See, e.g., schemes 30 and 31. In some embodiments, wherein

Indicating that the double bond, ketone moiety and beta-substituent are in cis configuration. In some embodiments, whereinIndicating that the double bond, ketone moiety and beta-substituent are in the trans configuration.

Cyclic carbamates assembled before macrocyclization (see, e.g., scheme 30) or after macrocyclization (see, e.g., scheme 31) can be attached via amine NH₂R¹⁴Michael addition to an α, β -unsaturated ketone moiety, followed by an attached amino-NHR ¹⁴And ortho hydroxyl (i.e., R)¹¹Hydrogen) with a reagent LG-C (═ O) -LG, wherein each LG is a leaving group as defined herein (e.g., chloro), a substituted hydroxy group (e.g., to give a carbonate), a substituted mercapto group, a substituted amino group (e.g., imidazolyl). In some embodiments, the free hydroxyl group is first treated with the reagent LG-C (═ O) -LG, and then the amine NH is added₂R¹⁴Resulting in the initial formation of a cyclic carbamate, followed by the intermediate-NHR¹⁴The radical is added in a conjugated manner to the unsaturated ketone.

Alternatively, cyclic carbamates that are assembled before macrocyclization (see, e.g., scheme 30) or after macrocyclization (see, e.g., scheme 31) can be attached through the free hydroxyl group (i.e., R)¹¹Hydrogen) with an isocyanate reagent O ═ C ═ N-R¹⁴Is then intermediate-NHR¹⁴The radical is added in a conjugated manner to the unsaturated ketone. In some embodiments, the isocyanate and the free hydroxyl groupsand-NHR¹⁴The conjugate addition reaction is performed in a single step. In some embodiments, the intermediate cyclic carbamate is isolated. In some embodiments, a base is added to the isolated cyclic carbamate to facilitate the conjugate addition reaction.

Scheme 30.

Scheme 31.

Scheme 32 describes various synthetic modifications that are referred to elsewhere in the application and are described in more detail. For example, after formation of a cyclic carbamate, the carbon alpha to the assembled ketone moiety may be monosubstituted (e.g., where R is^Z3Is hydrogen and R^Z4Is non-hydrogen) or di-substituted (i.e. wherein R is^Z3And R^Z4Both non-hydrogen groups). The invention also relates to the use of the compounds of formula (I) as intermediates in the preparation of the compounds by dihalogenation (e.g. wherein R is^Y1And R^Y2Each halogen (e.g., fluorine)) or synthetic modification of a C3 ketone by reduction to give an alcohol, wherein R is^Y1is-OR¹⁷And R^Y2Is hydrogen, then monohalogenated to give the product, in which R is^Y1Is halogen (e.g. fluorine) and R^Y2Is hydrogen.

Scheme 32.

Scheme 33 describes additional functionalization of ketolides prepared via enolates or trapped enolates by the methods described herein, where PG is an oxygen protecting group as defined herein. In some embodiments, the captured enolate is captured as a protected enol ether using a reagent of the formula LG-PG, wherein LG is a leaving group and PG is a protecting group as defined herein. In some embodiments, the compound isProtected enol ethers or said enolates can be used in combination with compounds of formula R²³-CHO aldehyde is subjected to an aldol condensation reaction. Alternatively, the protected enol ether can be contacted with an iminium salt under suitable conditions to provide an amino-substituted product. The amines produced by this process can be eliminated to yield exocyclic olefins.

Scheme 33.

Group G¹And R¹¹

As defined generally herein, G¹is-OR¹²or-NR¹³R¹⁴。

In some embodiments, G¹is-OR¹²Then R is¹¹And R¹²The combination forms a group of formula-C (═ O) -, yielding a cyclic carbonate.

In some embodiments, G¹is-OR¹²And R¹¹And R¹²Not combined to form a cyclic carbonate. In this case, in some embodiments, R¹¹Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or an oxygen protecting group, and R¹²Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group or a group of the formula:

as defined herein.

In some embodiments, wherein R is¹²Not being hydrogen, R¹²Is of formula R as defined in the application²³The non-hydrogen groups are optionally substituted.

In some embodiments, G¹is-NR¹³R¹⁴And R¹¹And R¹³The combination forms a group of formula-C (═ O) -, yielding a cyclic carbamate.

In some embodiments, G¹is-NR¹³R¹⁴And R ¹¹And R¹³Not binding to form cyclic carbamate. In such cases, in some embodiments, R¹¹Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or an oxygen protecting group, R¹³Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or a nitrogen protecting group.

In some embodiments, wherein R is¹³Not being hydrogen, R¹³Is of formula R as defined in the application²³The non-hydrogen groups are optionally substituted.

In some embodiments, wherein G¹is-NR¹³R¹⁴，R¹⁴Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, -C (═ O) R^Z8OR-C (═ O) OR^Z8Or a group of the formula:

as defined herein.

In some embodiments, wherein R is¹⁴Not being hydrogen, R¹⁴Is of formula R as defined in the application²³The non-hydrogen groups are optionally substituted.

In some embodiments, wherein G¹is-NR¹³R¹⁴，R¹³And R¹⁴Together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. In some embodiments, R is selected from the group consisting of¹³And R¹⁴The heterocyclyl or heteroaryl ring systems formed by the combination being as defined hereinThe formula R as defined in²³The non-hydrogen groups are optionally substituted.

Radical R^1a、R^1b、R^2aAnd R^2b

R in each case as generally defined herein^1a、R^1b、R^2aR is^2bIndependently is hydrogen, halogen, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl or, wherein R is^1aAnd R^1bOr R^2aAnd R^2bCan be formed together

In some embodiments, R^1aAnd R^1bThe carbon attached is the stereocenter of the (R) -configuration. In some embodiments, R^1aAnd R^1bThe attached carbon is a stereocenter of (S) -configuration.

In some embodiments, R^1aAnd R^1bAt least one of which is hydrogen. In some embodiments, R^1aAnd R^1bAre both hydrogen.

In some embodiments, R^1aAnd R^1bAt least one of which is halogen; for example, -F, -Cl, -Br or I. In some embodiments, R^1aAnd R^1bAre all halogen; for example, -F, -Cl, -Br or I.

In some embodiments, R^1aAnd R^1bAt least one of which is a carbonyl group. In some embodiments, R^1aAnd R^1bAt least one of which is a carboxylic acid. In some embodiments, R^1aAnd R^1bAt least one of which is a ketone. In some embodiments, R^1aAnd R^1bIs an aldehyde (-CHO).

In some embodiments, R^1aAnd R^1bAt least one of (A) is optionally substituted alkyl, e.g. optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. In some embodiments, R^1aAnd R^1bAt least one of is-CH₃. In some embodiments, R^1aAnd R^1bAre all-CH₃. In some embodiments, R^1aAnd R^1bAt least one of (a) is an alkyl group substituted with one or more halogen atoms, for example, an optionally substituted haloalkyl group; for example, -CF₃、-CF₂CF₃or-CF₂H. In some embodiments, R^1aAnd R^1bAt least one of which is-CH₂CHO。

In some embodiments, R^1aAnd R^1bAt least one of (a) is an optionally substituted alkenyl group, e.g., an optionally substituted C_2–6Alkenyl, optionally substituted C_2–3Alkenyl, optionally substituted C_3–4Alkenyl, optionally substituted C_4–5Alkenyl or optionally substituted C _5–6An alkenyl group. In some embodiments, R^1aAnd R^1bAt least one of (a) is vinyl, allyl or isoprenyl.

In some embodiments, R^1aAnd R^1bAt least one of (A) is optionally substituted alkynyl, e.g. optionally substituted C_2–6Alkynyl, optionally substituted C_2–3Alkynyl, optionally substituted C_3–4Alkynyl, optionally substituted C_4–5Alkynyl or optionally substituted C_5–6Alkynyl.

In some embodiments, R^1aAnd R^1bAt least one of (A) is an optionally substituted carbocyclic group, e.g. optionally substituted C_3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group. In some embodiments, R^1aAnd R^1bAt least one of (a) and (b) is an optionally substituted cyclopropyl group. In some embodiments, R^1aAnd R^1bAt least one of (a) is an unsubstituted cyclopropyl group. In thatIn some embodiments, R^1aAnd R^1bAt least one of (a) and (b) is an optionally substituted cyclobutyl group. In some embodiments, R^1aAnd R^1bAt least one of (a) is an unsubstituted cyclobutyl group. In some embodiments, R^1aAnd R^1bAt least one of (a) is an optionally substituted cyclopentyl group. In some embodiments, R^1aAnd R^1bAt least one of (a) is an unsubstituted cyclopentyl group. In some embodiments, R^1aAnd R^1bAt least one of (a) and (b) is an optionally substituted cyclohexyl group. In some embodiments, R ^1aAnd R^1bAt least one of (a) is an unsubstituted cyclohexyl group.

In some embodiments, R^1aAnd R^1bAt least one of (a) is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heterocyclic group or an optionally substituted 5-6-membered heterocyclic group.

In some embodiments, R^1aAnd R^1bAt least one of (a) is an optionally substituted aryl group, for example, an optionally substituted phenyl group.

In some embodiments, R^1aAnd R^1bAt least one of (a) is an optionally substituted heteroaryl group, e.g., an optionally substituted 5-to 6-membered heteroaryl group.

In some embodiments, R^1aAnd R^1bAre formed together

In some embodiments, R^2aAnd R^2bThe carbon attached is the stereocenter of the (R) -configuration. In some embodiments, R^2aAnd R^2bThe attached carbon is the stereocenter of the (S) -configuration.

In some embodiments, R^2aAnd R^2bAt least one of (a) is hydrogen. In some embodiments, R^2aAnd R^2bAre both hydrogen.

In some embodiments, R^2aAnd R^2bAt least one of which is halogen; for example-F, -Cl, -Br or I. In some embodiments, R^2aAnd R^2bAre all halogen; for example, -F, -Cl, -Br or I.

In some embodiments, R ^2aAnd R^2bAt least one of which is a carbonyl group. In some embodiments, R^2aAnd R^2bAt least one of which is a carboxylic acid. In some embodiments, R^2aAnd R^2bAt least one of which is a ketone. In some embodiments, R^2aAnd R^2bIs an aldehyde (-CHO).

In some embodiments, R^2aAnd R^2bAt least one of (A) is optionally substituted alkyl, e.g. optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. In some embodiments, R^2aAnd R^2bAt least one of is-CH₃. In some embodiments, R^2aAnd R^2bAre all-CH₃. In some embodiments, R^2aAnd R^2bAt least one of (a) is an alkyl group optionally substituted with one or more halogen atoms, for example, an optionally substituted haloalkyl group; for example, -CF₃、-CF₂CF₃or-CF₂H. In some embodiments, R^2aAnd R^2bAt least one of which is-CH₂CHO。

In some embodiments, R^2aAnd R^2bAt least one of (a) is an optionally substituted alkenyl group, e.g., an optionally substituted C_2–6Alkenyl, optionally substituted C_2–3Alkenyl, optionally substituted C_3–4Alkenyl, optionally substituted C_4–5Alkenyl or optionally substituted C_5–6An alkenyl group. In some embodiments, R ^2aAnd R^2bAt least one of (a) is vinyl, allyl or isoprenyl.

In some embodiments, R^2aAnd R^2bAt least one of (A) is optionally substituted alkynyl, e.g.Optionally substituted C_2–6Alkynyl, optionally substituted C_2–3Alkynyl, optionally substituted C_3–4Alkynyl, optionally substituted C_4–5Alkynyl or optionally substituted C_5–6Alkynyl.

In some embodiments, R^2aAnd R^2bAt least one of (A) is an optionally substituted carbocyclic group, e.g. optionally substituted C_3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group.

In some embodiments, R^2aAnd R^2bAt least one of (a) is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heterocyclic group or an optionally substituted 5-6-membered heterocyclic group.

In some embodiments, R^2aAnd R^2bAt least one of (a) is an optionally substituted aryl group, for example, an optionally substituted phenyl group.

In some embodiments, R^2aAnd R^2bAt least one of (a) is an optionally substituted heteroaryl group, e.g., an optionally substituted 5-to 6-membered heteroaryl group.

In some embodiments, R^2aAnd R^2bAre formed together

Group L³And a group R³、R⁴、R¹⁸、R¹⁹、R²⁰And R ²¹

As generally defined herein, L³Is a group of the formula:

represents a single bond or a double bond;

R³is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -C (═ O) R^Z8、-C(＝O)OR^Z8、-C(＝O)N(R^Z8)₂An oxygen protecting group or a group of the formula:

R⁴is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;

r in each case¹⁸And R¹⁹Independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and

r in each case²⁰And R²¹Independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, substituted hydroxy, mercapto, substituted mercapto, amino, substituted amino, halogen, carbonyl or R ²⁰And R²¹Together form an optionally substituted cyclopropyl or oxetanyl ring.

In some embodiments, R³The carbon attached is the stereocenter of the (R) -configuration. In some embodiments, R³The attached carbon is the stereocenter of the (S) -configuration.

In some embodiments, R³Is hydrogen.

In some embodiments, R³Is optionally substituted alkyl; for example, optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. In some embodiments, R³is-CH₃. In some embodiments, R³is-CH₂CHO. In some embodiments, R³is-CH₂N(R²²)₂Wherein R in each case²²Independently hydrogen or optionally substituted alkyl. In some embodiments, R³is-CH₂NH(R²²). In some embodiments, R³is-CH₂NH₂. In some embodiments, R³is-CH₂CH(OH)R²⁴Wherein R is²⁴Is hydrogen, optionally substituted alkyl or optionally substituted aryl. In some embodiments, R³is-CH₂CH₂And (5) OH. In some embodiments, R³is-CH₂CH₂R²³Wherein R is²³As defined herein.

In some embodiments, R³Is optionally substituted alkenyl; for example, optionally substituted C _2–6Alkenyl, optionally substituted C_2–3Alkenyl, optionally substituted C_3–4Alkenyl, optionally substituted C_4–5Alkenyl or optionally substituted C_5–6An alkenyl group. In some embodiments, R³Is vinyl, allyl or isoprenyl. In some embodiments, R³Is an optionally substituted allyl group, e.g., a substituted allyl group, e.g.,wherein R is²³As defined herein, or unsubstituted allylIn some embodiments, R³Is an optionally substituted vinyl group, e.g., a substituted vinyl group, e.g.,

wherein R is²³As defined in the present applicationPara, or unsubstituted vinyl

In some embodiments, R³Is optionally substituted alkynyl, e.g. optionally substituted C_2–6Alkynyl, optionally substituted C_2–3Alkynyl, optionally substituted C_3–4Alkynyl, optionally substituted C_4–5Alkynyl or optionally substituted C_5–6Alkynyl.

In some embodiments, R³Is an optionally substituted carbocyclyl; for example, optionally substituted C_3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group.

In some embodiments, R³Is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heterocyclic group or an optionally substituted 5-6-membered heterocyclic group.

In some embodiments, R³Is an optionally substituted aryl group, for example, an optionally substituted phenyl group.

In some embodiments, R³Is optionally substituted heteroaryl, e.g., optionally substituted 5-to 6-membered heteroaryl.

In some embodiments, R³is-C (═ O) R^Z8、-C(＝O)OR^Z8、-C(＝O)N(R^Z8)₂Or an oxygen protecting group.

In some embodiments, R³Is a group of the formula:

wherein L is^C1、LG、A¹、A、L^C2And R²³As defined herein.

In some embodiments, R⁴The carbon attached is the stereocenter of the (R) -configuration. In some embodiments of the present invention, the substrate is,R⁴the attached carbon is the stereocenter of the (S) -configuration.

In some embodiments, R⁴Is hydrogen.

In some embodiments, R⁴Is optionally substituted alkyl, e.g. optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. In some embodiments, R⁴is-CH₃. In some embodiments, R⁴is-CH₂CHO. In some embodiments, R⁴is-CH₂N(R²²)₂Wherein R in each case²²Independently hydrogen or optionally substituted alkyl. In some embodiments, R⁴is-CH₂NH(R²²). In some embodiments, R⁴is-CH ₂NH₂. In some embodiments, R⁴is-CH₂CH(OH)R²⁴Wherein R is²⁴Is hydrogen, optionally substituted alkyl or optionally substituted aryl. In some embodiments, R⁴is-CH₂CH₂And (5) OH. In some embodiments, R⁴is-CH₂CH₂R²³Wherein R is²³As defined herein.

In some embodiments, R⁴Optionally substituted alkenyl, e.g. optionally substituted C_2–6Alkenyl, optionally substituted C_2–3Alkenyl, optionally substituted C_3–4Alkenyl, optionally substituted C_4–5Alkenyl or optionally substituted C_5–6An alkenyl group. In some embodiments, R⁴Is an optionally substituted allyl group, e.g., a substituted allyl group, e.g.,wherein R is²³As defined herein, or unsubstituted allylIn some embodiments, R⁴Is an optionally substituted vinyl group, for example, a substituted vinyl group, for example,

wherein R is²³Unsubstituted vinyl radical as defined or

The present application relates to R⁴And R²¹Various combinations of (a). For example, in some embodiments, R⁴Is optionally substituted C_1–3Alkyl and R²¹Is hydrogen. In some embodiments, R³is-CH₂CHO、–CH₂N(R²²)₂、–CH₂CH(OH)R²⁴or-CH₂CH₂R²³And R²¹Is hydrogen. In some embodiments, R⁴Is optionally substituted C_2–3Alkenyl and R²¹Is hydrogen. In some embodiments, R⁴Is composed of

And R²¹Is hydrogen.

In some embodiments, R⁴Is optionally substituted alkynyl, e.g. optionally substituted C_2–6Alkynyl, optionally substituted C_2–3Alkynyl, optionally substituted C_3–4Alkynyl, optionally substituted C_4–5Alkynyl or optionally substituted C_5–6Alkynyl.

In some embodiments, R⁴Is an optionally substituted carbocyclic group, e.g. optionally substituted C_3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group.

In some embodiments, R⁴Is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heteroCyclyl or optionally substituted 5-6 membered heterocyclyl.

In some embodiments, R⁴Is an optionally substituted aryl group, for example, an optionally substituted phenyl group.

In some embodiments, R⁴Is optionally substituted heteroaryl, for example, optionally substituted 5-to 6-membered heteroaryl.

In some embodiments, each occurrence of R¹⁸And R¹⁹Independently hydrogen or optionally substituted alkyl, e.g. hydrogen or-CH₃. In some embodiments, R¹⁸And R¹⁹The attached carbon is a stereocenter of (R) configuration. In some embodiments, R¹⁸And R¹⁹The attached carbon is a stereocenter of (S) configuration.

In some embodiments, each occurrence of R²⁰And R²¹Independently hydrogen, hydroxy, substituted hydroxy, mercapto, substituted mercapto, amino, substituted amino, halogen or R²⁰And R²¹Together form an optionally substituted cyclopropyl or oxetanyl ring. In some embodiments, R²⁰And R²¹Are cis to each other. In some embodiments, R²⁰And R²¹Are in trans to each other.

In some embodiments, L is³Comprises the following steps:

in some embodiments, L is³Comprises the following steps:

wherein L is^C1And A¹As defined herein.

In some embodiments, L is³Is of the formula:

wherein L is^C1、A、L^C2And R²³As defined herein.

Radical R^5aAnd R^5b

R in each case as generally defined herein^5aAnd R^5bIndependently hydrogen, halogen, silyl, optionally substituted alkyl, optionally substituted carbocyclyl or optionally substituted heterocyclyl.

In some embodiments, R^5aAnd R^5bOne of (A) is hydrogen, and R^5aAnd R^5bIs a non-hydrogen group. In some embodiments, each occurrence of R^5aAnd R^5bIs hydrogen. In some embodiments, each occurrence of R^5aAnd R^5bIs a non-hydrogen group, for example, halogen, optionally substituted alkyl, optionally substituted carbocyclyl or optionally substituted heterocyclyl.

In some embodiments, R^5aAnd R^5bThe carbon attached is the stereocenter of the (R) -configuration. In some embodiments, R^5aAnd R^5bThe attached carbon is the stereocenter of the (S) -configuration.

In some embodiments, R^5aAnd R^5bAt least one of (A) is optionally substituted alkyl, e.g. optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. In some embodiments, R^5aAnd R^5bAt least one of is-CH₃. In some embodiments, R^5aAnd R^5bAre all-CH₃。

In some embodiments, R^5aAnd R^5bAt least one of (A) is an optionally substituted carbocyclic group, e.g. optionally substituted C_3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group.

At one endIn some embodiments, R^5aAnd R^5bAt least one of (a) is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heterocyclic group or an optionally substituted 5-6-membered heterocyclic group.

In some embodiments, R^5aAnd R^5bIs halogen, for example, bromine, iodine, chlorine or fluorine. In some embodiments, R ^5aAnd R^5bAt least one of (a) and (b) is fluorine. In some embodiments, R^5aAnd R^5bAre both fluorine. In some embodiments, R^5aAnd R^5bOne of them is hydrogen and R^5aAnd R^5bThe other of (a) and (b) is fluorine.

In some embodiments, R^5aAnd R^5bAt least one of (a) and (b) is a silyl group.

Radical R⁶And R¹⁰

As generally defined herein, R⁶And/or R¹⁰Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, hydroxy, substituted hydroxy, mercapto, substituted mercapto, amino, substituted amino, carbonyl, silyl or halo.

In some embodiments, R⁶And/or R¹⁰Is hydrogen. In some embodiments, R⁶Is hydrogen. In some embodiments, R¹⁰Is hydrogen. In some embodiments, R⁶Is hydrogen, and R¹⁰Is hydrogen. In some embodiments, R⁶And R¹⁰Are all non-hydrogen groups.

In some embodiments, R⁶And R¹⁰The carbon attached is the stereocenter of the (R) -configuration. In some embodiments, R⁶And R¹⁰The attached carbon is the stereocenter of the (S) -configuration.

In some embodiments, R⁶And R¹⁰At least one ofIs optionally substituted alkyl; for example, optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. In some embodiments, R⁶And R¹⁰At least one of is-CH₃. In some embodiments, R⁶And R¹⁰At least one of is-CH₃. In some embodiments, R⁶And R¹⁰At least one of is-CH₂And (C) CN. In some embodiments, R⁶And R¹⁰At least one of is-CH₂C(＝O)OR²³Wherein R is³²Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl. In some embodiments, R³²Is optionally substituted alkyl, e.g. C_1-6An alkyl group. In some embodiments, R³²Is unsubstituted C_1-6An alkyl group. In some embodiments, R³²Is methyl, ethyl or propyl. In some embodiments, R³²Is substituted C_1-6An alkyl group. In some embodiments, R³²Is hydrogen.

In some embodiments, R⁶And R¹⁰At least one of (a) is an optionally substituted alkenyl group, e.g., an optionally substituted C _2–6Alkenyl, optionally substituted C_2–3Alkenyl, optionally substituted C_3–4Alkenyl, optionally substituted C_4–5Alkenyl or optionally substituted C_5–6An alkenyl group. In some embodiments, R⁶And R¹⁰At least one of (a) is a substituted or unsubstituted allyl group. In some embodiments, R⁶And R¹⁰At least one of (a) is a substituted or unsubstituted vinyl group. Said group being derived from the compound wherein R is present after the macrocyclization step⁶And/or R¹⁰Enolate of macrolide which is hydrogen.

In some embodiments, R⁶And R¹⁰At least one of (A) is optionally substituted alkynyl, e.g. optionally substituted C_2–6Alkynyl, optionally substituted C_2–3Alkynyl, optionally substituted C_3–4Alkynyl, optionally substituted C_4–5Alkynyl or optionally substituted C_5–6Alkynyl. Said group being derived from the compound wherein R is present after the macrocyclization step⁶And/or R¹⁰Enolate of macrolide which is hydrogen.

In some embodiments, R⁶And R¹⁰At least one of (A) is an optionally substituted carbocyclic group, e.g. optionally substituted C_3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group.

In some embodiments, R⁶And R¹⁰At least one of (a) is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heterocyclic group or an optionally substituted 5-6-membered heterocyclic group.

In some embodiments, R⁶And R¹⁰At least one of (a) is an optionally substituted aryl group; for example, optionally substituted phenyl.

In some embodiments, R⁶And R¹⁰At least one of (a) is optionally substituted aralkyl; for example, an optionally substituted benzyl group.

In some embodiments, R⁶And R¹⁰At least one of (a) is an optionally substituted heteroaryl group, e.g., an optionally substituted 5-to 6-membered heteroaryl group.

In some embodiments, R⁶And R¹⁰At least one of (a) is optionally substituted heteroaralkyl; for example, optionally substituted pyrazolylalkyl, imidazolylalkyl, thiazolylalkyl, oxazolylalkyl, pyridylalkyl, pyrimidylalkyl or pyrazinylalkyl.

In some embodiments, R⁶And R¹⁰At least one of (a) is hydroxyl, substituted hydroxyl, mercapto, substituted mercapto, amino or substituted amino. The radicals being in macrocyclizationAfter step (ii) from wherein R⁶And/or R¹⁰Macrolides that are halogen are transformed.

In some embodiments, R⁶And R¹⁰At least one of (a) is a carbonyl group, for example, acetyl.

In some embodiments, R⁶And R¹⁰At least one of (a) and (b) is a silyl group. In some embodiments, R⁶The cyclization to silyl groups is carried out but is removed after the formation of the macrolide and is replaced by, for example, hydrogen.

In some embodiments, R⁶And R¹⁰Is halogen, for example, fluorine, bromine, chlorine or iodine.

Radical R⁷And R⁸

As generally defined herein, R⁷Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, R⁷Is hydrogen. However, in some embodiments, R⁷Is a non-hydrogen radical, and R⁷The carbon attached is the stereocenter of the (R) -configuration. In some embodiments, R⁷Is a non-hydrogen radical, and R⁷The attached carbon is the stereocenter of the (S) -configuration.

In some embodiments, R⁷Is optionally substituted alkyl, e.g. optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. In some embodiments, R⁷is-CH₃or-CH₂CH₃。

In some embodiments, R⁷Is optionally substituted alkenyl, e.g. optionally substituted C_2–6Alkenyl, optionally substituted C_2–3Alkenyl, optionally substituted C_3–4Alkenyl, optionally substituted C_4–5Alkenyl or optionally substitutedSubstituted C _5–6An alkenyl group. In some embodiments, R⁷Is vinyl, allyl or isoprenyl.

In some embodiments, R⁷Is optionally substituted alkynyl, e.g. optionally substituted C_2–6Alkynyl, optionally substituted C_2–3Alkynyl, optionally substituted C_3–4Alkynyl, optionally substituted C_4–5Alkynyl or optionally substituted C_5–6Alkynyl.

In some embodiments, R⁷Is an optionally substituted carbocyclic group, e.g. optionally substituted C_3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group.

In some embodiments, R⁷Is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heterocyclic group or an optionally substituted 5-6-membered heterocyclic group.

In some embodiments, R⁷Is an optionally substituted aryl group; for example, optionally substituted phenyl.

In some embodiments, R⁷Is optionally substituted heteroaryl, for example, optionally substituted 5-to 6-membered heteroaryl.

As generally defined herein, R⁸Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, R⁸Is hydrogen.

In some embodiments, R⁸Is optionally substituted alkyl, e.g. optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. In some embodiments, R⁸is-CH₃or-CH₂CH₃。

In some embodiments, R⁸Is optionally substituted alkenyl, e.g. optionally substituted C_2–6Alkenyl, optionally substituted C_2–3Alkenyl, optionally substituted C_3–4Alkenyl, optionally substituted C_4–5Alkenyl or optionally substituted C_5–6An alkenyl group. In some embodiments, R⁸Is vinyl, allyl or isoprenyl.

In some embodiments, R⁸Is optionally substituted alkynyl, e.g. optionally substituted C_2–6Alkynyl, optionally substituted C_2–3Alkynyl, optionally substituted C_3–4Alkynyl, optionally substituted C_4–5Alkynyl or optionally substituted C_5–6Alkynyl.

In some embodiments, R⁸Is an optionally substituted carbocyclic group, e.g. optionally substituted C_3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group.

In some embodiments, R⁸Is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heterocyclic group or an optionally substituted 5-6-membered heterocyclic group.

In some embodiments, R⁸Is an optionally substituted aryl group, for example, an optionally substituted phenyl group.

In some embodiments, R⁸Is optionally substituted heteroaryl, for example, optionally substituted 5-to 6-membered heteroaryl.

Radical R^ZaAnd R^Zb

As generally defined herein, R^ZaAnd R^ZbEach independently is hydrogen, halogen, hydroxy, substituted hydroxy, amino, substituted amino, mercapto, substituted mercapto, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

In some embodiments, R^ZaAnd R^ZbBond between two carbons attached

Represents a double bond, and R^ZaAnd R^ZbEach independently hydrogen.

In some embodiments, R^ZaAnd R^ZbBond between two carbons attached

Represents a single bond (e.g. obtained by hydrogenation of a double bond), and R^ZaAnd R^ZbEach independently hydrogen.

In some embodiments, R^ZaAnd R^ZbAt least one of is hydrogen and R^ZaAnd R^ZbAt least one of which is a non-hydrogen group, e.g., halogen, hydroxyl, substituted hydroxyl, amino, substituted amino, mercapto, substituted mercapto, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R ^ZaIs hydrogen and R^ZbAre non-hydrogen radicals. In some embodiments, R^ZaIs a non-hydrogen radical and R^ZbIs hydrogen. In some embodiments, R^ZaAnd R^ZbAre all non-hydrogen groups. In any of the above cases, in some embodiments, R^ZaAnd R^ZbBond between two carbons attached

Represents a single bond. Alternatively, in either case, in some embodiments, R^ZaAnd R^ZbBond between two carbons attached

Represents a double bond.

In some embodiments, R^ZaIs hydrogen, R^ZbIs hydrogen, and R^ZaAnd R^ZbBond between two carbons attachedRepresents a double bond.

In some embodiments, R^ZaIs halogen (e.g. fluorine) or optionally substituted alkyl (e.g. methyl), R^ZbIs hydrogen, and R^ZaAnd R^ZbBond between two carbons attachedRepresents a single bond.

In some embodiments, R^ZaAnd R^ZbBond between two carbons attachedRepresents a double bond, and R^ZaAnd R^ZbIn the cis configuration. In some embodiments, R^ZaAnd R^ZbBond between two carbons attached

Represents a double bond, and R^ZaAnd R^ZbIn the trans configuration.

Radical R^Z2、R^Z3And R^Z4

R in each case as generally defined herein^Z2Independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, substituted hydroxy, amino, substituted amino, -C (═ O) R ^Z8、-C(＝O)OR^Z8、-C(＝O)N(R^Z8)₂Or a nitrogen protecting group, or two R^Z2The groups together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring.

In some embodiments, R^Z2Is hydrogen.

In some embodiments, R^Z2Is optionally substituted alkyl;for example, optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. In some embodiments, R^Z2is-CH₃。

In some embodiments, R^Z2Is optionally substituted alkenyl, e.g. optionally substituted C_2–6Alkenyl, optionally substituted C_2–3Alkenyl, optionally substituted C_3–4Alkenyl, optionally substituted C_4–5Alkenyl or optionally substituted C_5–6An alkenyl group.

In some embodiments, R^Z2Is optionally substituted alkynyl, e.g. optionally substituted C_2–6Alkynyl, optionally substituted C_2–3Alkynyl, optionally substituted C_3–4Alkynyl, optionally substituted C_4–5Alkynyl or optionally substituted C_5–6Alkynyl.

In some embodiments, R^Z2Is an optionally substituted carbocyclic group, e.g. optionally substituted C_3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group.

In some embodiments, R^Z2Is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heterocyclic group or an optionally substituted 5-6-membered heterocyclic group.

In some embodiments, R^Z2Is an optionally substituted aryl group, for example, an optionally substituted phenyl group.

In some embodiments, R^Z2Is optionally substituted heteroaryl, for example, optionally substituted 5-to 6-membered heteroaryl.

In some embodiments, R^Z2Is hydroxyl, substituted hydroxyl, amino or substituted amino.

In some embodiments, R^Z2is-C (═ O) R^Z8、-C(＝O)OR^Z8、-C(＝O)N(R^Z8)₂。

In some embodiments, R^Z2Is a nitrogen protecting group.

In some embodiments, two R are^Z2The groups together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring.

As generally defined herein, R^Z3Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, R^Z3Is hydrogen.

In some embodiments, R^Z3Is optionally substituted alkyl; for example, optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. In some embodiments, R^Z3is-CH₃. In some embodiments, R ^Z3is-CH₂CHO. In some embodiments, R^Z3is-CH₂CH₂And (5) OH. In some embodiments, R^Z3is-CH₂CH₂N(R²²)₂. In some embodiments, R^Z3is-CH₂CH₂N(CH₃)₂. In some embodiments, R^Z3is-CH₂CH(OH)R²⁴. In some embodiments, R^Z3Is alkyl optionally substituted with one or more halogen atoms, e.g., optionally substituted haloalkyl; for example, -CF₃、-CF₂CF₃or-CF₂H. In some embodiments, R^Z3is-CF₃。

In some embodiments, R^Z3Is optionally substituted alkenyl, e.g. optionally substituted C_2–6Alkenyl, optionally substituted C_2–3Alkenyl, optionally substituted C_3–4Alkenyl, optionally substitutedSubstituted C_4–5Alkenyl or optionally substituted C_5–6An alkenyl group. In some embodiments, R^Z3Is an optionally substituted vinyl group. In some embodiments, R^Z3Is an unsubstituted vinyl group. In some embodiments, R^Z3Is an optionally substituted allyl group. In some embodiments, R^Z3Is unsubstituted allyl.

In some embodiments, R^Z3Is optionally substituted alkynyl, e.g. optionally substituted C_2–6Alkynyl, optionally substituted C_2–3Alkynyl, optionally substituted C_3–4Alkynyl, optionally substituted C_4–5Alkynyl or optionally substituted C_5–6Alkynyl.

In some embodiments, R^Z3Is an optionally substituted carbocyclic group, e.g. optionally substituted C _3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group. In some embodiments, R^Z3Is an optionally substituted cyclopropyl group. In some embodiments, R^Z3Is unsubstituted cyclopropyl. In some embodiments, R^Z3Is an optionally substituted cyclobutyl group. In some embodiments, R^Z3Is unsubstituted cyclobutyl.

In some embodiments, R^Z3Is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heterocyclic group or an optionally substituted 5-6-membered heterocyclic group.

In some embodiments, R^Z3Is an optionally substituted aryl group, for example, an optionally substituted phenyl group.

In some embodiments, R^Z3Is an optionally substituted aralkyl group. In some embodiments, R^Z3Is unsubstituted aralkyl. In some embodiments, R^Z3Is an optionally substituted benzyl group. In some embodiments, R^Z3Is composed of

Wherein X is halogen. In some embodiments, R^Z3Is unsubstituted benzyl.

In some embodiments, R^Z3Is optionally substituted heteroaryl, for example, optionally substituted 5-to 6-membered heteroaryl.

In some embodiments, R ^Z3Is optionally substituted heteroaralkyl. In some embodiments, R^Z3Is unsubstituted heteroaralkyl.

As generally defined herein, R^Z4Is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, R^Z4Is optionally substituted alkyl, e.g. optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. In some embodiments, R^Z4is-CH₃. In some embodiments, R^Z4Is alkyl optionally substituted with one or more halogen atoms, e.g., optionally substituted haloalkyl; for example, -CF₃、-CF₂CF₃or-CF₂H。

In some embodiments, R^Z4Is optionally substituted alkenyl, e.g. optionally substituted C_2–6Alkenyl, optionally substituted C_2–3Alkenyl, optionally substituted C_3–4Alkenyl, optionally substituted C_4–5Alkenyl or optionally substituted C_5–6An alkenyl group.

In some embodiments, R^Z4Is optionally substituted alkynyl, e.g. optionally substituted C_2–6Alkynyl, optionally substituted C_2–3Alkynyl, optionally substituted C _3–4Alkynyl, optionally substituted C_4–5Alkynyl or optionally substituted C_5–6Alkynyl.

In some embodiments, R^Z4Is optionally substitutedCarbocyclic radicals, e.g. optionally substituted C_3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group.

In some embodiments, R^Z4Is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heterocyclic group or an optionally substituted 5-6-membered heterocyclic group.

In some embodiments, R^Z4Is an optionally substituted aryl group, for example, an optionally substituted phenyl group.

In some embodiments, R^Z4Is optionally substituted heteroaryl, for example, optionally substituted 5-to 6-membered heteroaryl.

In some embodiments, R^Z3And R^Z4Are formed together

Radical R⁹And R¹⁷、R^Y1、R^Y2

As generally defined herein, R^Y1is-OR¹⁷And R^Y2Is hydrogen, or R^Y1Is halogen and R^Y2Is hydrogen, or R^Y1Is halogen and R^Y2Is halogen, or R^Y1And R^Y2Together form an oxo (═ O) group.

In some embodiments, R^Y1And R^Y2Together form an oxo (═ O) group.

In some embodiments, R^Y1is-OR¹⁷And R^Y2Is hydrogen.

In some embodiments, R^Y1Is halogen (e.g. fluorine) and R ^Y2Is hydrogen.

In some embodiments, R^Y1Is halogen (e.g. fluorine) and R^Y2Is halogen (e.g., fluorine).

As generally defined herein, R⁹And/or R¹⁷Each independently hydrogen, optionally substituted alkylOptionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -C (═ O) R^Z8、–C(＝O)OR^Z8、–C(＝O)N(R^Z8)₂Oxygen protecting groups or carbohydrates, in which R in each case^Z8Independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, or two R^Z8The groups together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ring.

In some embodiments, R⁹The attached carbon is in the (R) -configuration. In some embodiments, R⁹The attached carbon is in the (S) -configuration.

In some embodiments, R¹⁷The attached carbon is in the (R) -configuration. In some embodiments, R¹⁷The attached carbon is in the (S) -configuration.

In some embodiments, R⁹Is hydrogen. In some embodiments, R¹⁷Is hydrogen.

In some embodiments, R ⁹And/or R¹⁷Each independently being optionally substituted alkyl, e.g. optionally substituted C_1–6Alkyl, optionally substituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6Alkyl radicals, e.g., -CH₃。

In some embodiments, R⁹Is composed of

Wherein R is^S1、R^S2a、R^S2b、R^S3aAnd R^S3bAs defined herein. In some embodiments, R⁹Is composed ofIn some implementationsIn the scheme, R⁹Is composed ofIn some embodiments, R⁹Is composed of

In some embodiments, R⁹And/or R¹⁷Each independently being optionally substituted alkenyl, e.g. substituted or unsubstituted C_2–6Alkenyl, substituted or unsubstituted C_2–3Alkenyl, substituted or unsubstituted C_3–4Alkenyl, substituted or unsubstituted C_4–5Alkenyl or substituted or unsubstituted C_5–6An alkenyl group.

In some embodiments, R⁹And/or R¹⁷Each independently is optionally substituted alkynyl, e.g. substituted or unsubstituted C_2–6Alkynyl, substituted or unsubstituted C_2–3Alkynyl, substituted or unsubstituted C_3–4Alkynyl, substituted or unsubstituted C_4–5Alkynyl or substituted or unsubstituted C_5–6Alkynyl.

In some embodiments, R⁹And/or R¹⁷Each independently being an optionally substituted carbocyclic group, e.g. substituted or unsubstituted C _3–6Carbocyclyl, substituted or unsubstituted C_3–4Carbocyclyl, substituted or unsubstituted C_4–5Carbocyclyl or substituted or unsubstituted C_5–6A carbocyclic group.

In some embodiments, R⁹And/or R¹⁷Each independently is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6 membered heterocyclic group, an optionally substituted 3-4 membered heterocyclic group, an optionally substituted 4-5 membered heterocyclic group or an optionally substituted 5-6 membered heterocyclic group.

In some embodiments, R⁹And/or R¹⁷Each independently is an optionally substituted aryl group, for example, an optionally substituted phenyl group.

In some embodiments, R⁹And/or R¹⁷Each independently is optionally substituted heteroaryl, e.g., optionally substituted 5-to 6-membered heteroaryl.

In some embodiments, R⁹And/or R¹⁷Each independently is-C (═ O) R^Z8、–C(＝O)OR^Z8or-C (═ O) N (R)^Z8)₂. For example, in some embodiments, R¹⁷is-C (═ O) R^Z8Wherein R is^Z8Is an optionally substituted aryl or an optionally substituted heteroaryl. In some embodiments, R¹⁷is-C (═ O) R^Z8Wherein R is^Z8Is optionally substituted aralkyl or optionally substituted heteroaralkyl.

In some embodiments, R⁹And/or R¹⁷Each independently an oxygen protecting group.

In some embodiments, R ⁹And/or R¹⁷Each independently a carbohydrate.

In some embodiments, R⁹And/or R¹⁷Is a group of formula (s-1), which includes carbohydrates, but also optionally substituted heterocyclyl groups:

wherein:

R^S1、R^S2a、R^S2b、R^S3a、R^S3b、R^S4a、R^S4b、R^S5aand R^S5bEach of which is independently hydrogen, optionally substituted alkyl, -OR^SO、–N(R^SN)₂Or wherein R is^S2aOr R^S2bCan be reacted with R^S3aOr R^S3bTogether form an optionally substituted fused heterocycle;

r in each case^SOIndependently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl or an oxygen protecting group; and

r in each case^SNIndependently hydrogen, optionally substituted alkyl or a nitrogen protecting group; or optionally, two R^SNTogether with the intervening atoms, form a heterocyclic ring.

R in each case as generally defined herein^S1Independently hydrogen, optionally substituted alkyl, -OR^SOor-N (R)^SN)₂。

In some embodiments, R^S1Is hydrogen.

In some embodiments, R^S1Is an optionally substituted alkyl group. In some embodiments, R^S1Is substituted C_1–6An alkyl group. In some embodiments, R^S1Is unsubstituted C_1–6An alkyl group. In some embodiments, R^S1Is methyl, ethyl, propyl, butyl, pentyl or hexyl. In some embodiments, R^S1Is isopropyl, isobutyl or isoamyl. In some embodiments, R ^S1Is an isobutyl group. In some embodiments, R^S1Is a tert-butyl group.

In some embodiments, R^S1is-OR^SOWherein R is^SOIndependently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl or an oxygen protecting group. In some embodiments, R^S1is-OH. In some embodiments, R^S1is-OR^SOWherein R is^SOIs an optionally substituted alkyl group. In some embodiments, R^S1is-O-methyl, -O-ethyl or-O-propyl. In some embodiments, R^S1Is optionally substituted-O-alkyl-aryl. In some embodiments, R^S1is-O-Bz. In some embodiments, R^S1Is optionally substituted-O-alkyl-heteroaryl. In some embodiments, R^S1Is optionally substituted-O-alkenyl-aryl. In some embodiments, R^S1Is an optionally substituted-O-arylalkenyl-heteroaryl. In some embodiments, R^S1is-OR^SOWherein R is^SOIs composed of

In some embodiments, R^S1is-OR^SOWhereinR^SOIs composed of

In some embodiments, R^S1is-OR^SOWherein R is^SOIs composed ofIn some embodiments, R^S1is-OR^SOWherein R is^SOIs an oxygen protecting group. In some embodiments, R^S1is-OR^SOWherein R is ^SOIs a carbonyl group. In some embodiments, R^S1is-OR^SOWherein R is^SOIs acetyl. In some embodiments, R^S1is-OR^SOWherein R is^SOIs an optionally substituted heterocyclic group.

In some embodiments, R^S1is-N (R)^SN)₂. In some embodiments, R^S1is-N (R)^SN)₂Wherein each R is^SNAre the same. In some embodiments, R^S1is-N (R)^SN)₂Wherein each R is^SNIs different.

In some embodiments, R^S1is-NH₂。

In some embodiments, R^S1is-NHR^SN. In some embodiments, R^S1is-NHR^SNWherein R is^SNIs optionally substituted C_1–6An alkyl group. In some embodiments, R^S1is-NHR^SNWherein R is^SNIs unsubstituted C_1–6An alkyl group. In some embodiments, R^S1is-NHR^SNWherein R is^SNIs substituted C_1–6An alkyl group. In some embodiments, R^S1is-NH-benzyl.

In some embodiments, R^S1is-NHR^SNWherein R is^SNIs a nitrogen protecting group. In some embodiments, R^S1is-NHFmoc. In some embodiments, R^S1is-NHBoc.

In some embodiments, R^S1is-N (R)^SN)₂Wherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S1is-N (R)^SN)₂Wherein each R is^SNIndependently is unsubstituted C _1–6An alkyl group. In some embodiments, R^S1is-N (CH)₃)R^SNWherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S1is-N (CH)₃)R^SNWherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S1is-N (CH)₂CH₃)R^SNWherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S1is-N (CH)₂CH₃)R^SNWherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S1is-N (R)^SN)₂Wherein each R is^SNIndependently selected from methyl, ethyl, isopropyl, isobutyl, isoamyl and benzyl.

In some embodiments, R^S1is-N (R)^SN)₂Wherein two R are^SNTogether with intervening atoms, form an optionally substituted heterocyclic ring. For example, in some embodiments, R^S1Is of the formula:

wherein R is^sqAs defined herein and sn is 0, 1, 2 or 3.

R in each case as defined generally above^S2aAnd R^S2bIndependently hydrogen, optionally substituted alkyl, -OR^SOor-N (R)^SN)₂。

In some embodiments, R^S2aAnd R^S2bAt least one of (a) is hydrogen.

In some embodiments, R^S2aAnd R^S2bAt least one of (a) and (b) is an optionally substituted alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (A) is substituted C _1–6An alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (A) is unsubstituted C_1–6An alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (a) is methyl, ethyl, propyl, butyl, pentyl or hexyl. In some embodiments, R^S2aAnd R^S2bIs isopropyl, isobutyl or isoamyl. In some embodiments, R^S2aAnd R^S2bAt least one of (a) is an isobutyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (a) is a tert-butyl group.

In some embodiments, R^S2aAnd R^S2bAt least one of is-OR^SOWherein R is^SOIndependently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl or an oxygen protecting group. In some embodiments, R^S2aAnd R^S2bAt least one of (a) and (b) is-OH. In some embodiments, R^S2aAnd R^S2bAt least one of is-OR^SOWherein R is^SOIs an optionally substituted alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (a) and (b) is-O-methyl, -O-ethyl or-O-propyl. In some embodiments, R^S2aAnd R^S2bAt least one of (a) is optionally substituted-O-alkyl-aryl. In some embodiments, R^S2aAnd R^S2bAt least one of (a) and (b) is-O-Bz. In some embodiments, R ^S2aAnd R^S2bAt least one of (a) is-O-alkyl-heteroaryl. In some embodiments, R^S2aAnd R^S2bAt least one of (a) is optionally substituted-O-alkenyl-aryl. In some embodiments, R^S2aAnd R^S2bAt least one of (a) is optionally substituted-O-alkenyl-heteroaryl. In some embodiments, R^S2aAnd R^S2bAt least one of is-OR^SOWherein R is^SOIs composed ofWherein aryl is an optionally substituted aryl group. In some embodiments, R^S2aAnd R^S2bAt least one of is-OR^SOWherein R is^SOIs composed of

Wherein heteroaryl is an optionally substituted heteroaryl group. In some embodiments, R^S2aAnd R^S2bAt least one of is-OR^SOWherein R is^SOIs composed ofIn some embodiments, R^S2aAnd R^S2bAt least one of is-OR^SOWherein R is^SOIs an oxygen protecting group. In some embodiments, R^S2aAnd R^S2bAt least one of is-OR^SOWherein R is^SOIs a carbonyl group. In some embodiments, R^S2aAnd R^S2bAt least one of is-OR^SOWherein R is^SOIs acetyl. In some embodiments, R^S2aAnd R^S2bAt least one of is-OR^SOWherein R is^SOIs an optionally substituted heterocyclic group.

In some embodiments, R^S2aAnd R^S2bAt least one of (A) and (B) is-N (R)^SN)₂. In some embodiments, R^S2aAnd R^S2bAt least one of (A) and (B) is-N (R) ^SN)₂Wherein each R is^SNAre the same. In some embodiments, R^S2aAnd R^S2bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIs different.

In some embodiments, R^S2aAnd R^S2bAt least one of (a) is-NH₂。

In some embodiments, R^S2aAnd R^S2bAt least one of (A) is-NHR^SN. In thatIn some embodiments, R^S2aAnd R^S2bAt least one of (A) is-NHR^SNWherein R is^SNIs optionally substituted C_1–6An alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (A) is-NHR^SNWherein R is^SNIs unsubstituted C_1–6An alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (A) is-NHR^SNWherein R is^SNIs substituted C_1–6An alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (a) and (b) is-NH-benzyl.

In some embodiments, R^S2aAnd R^S2bAt least one of (A) is-NHR^SNWherein R is^SNIs a nitrogen protecting group. In some embodiments, R^S2aAnd R^S2bAt least one of (a) is-NHFmoc. In some embodiments, R^S2aAnd R^S2bAt least one of (a) is-NHBoc.

In some embodiments, R^S2aAnd R^S2bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently is unsubstituted C _1–6An alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (A) and (B) is-N (CH)₃)R^SNWherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (A) and (B) is-N (CH)₃)R^SNWherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (A) and (B) is-N (CH)₂CH₃)R^SNWherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (A) and (B) is-N (CH)₂CH₃)R^SNWherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S2aAnd R^S2bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently selected from methyl, ethyl, isopropyl, isobutyl, isoamyl and benzyl.

In some embodiments, R^S2aAnd R^S2bAt least one of (A) and (B) is-N (R)^SN)₂Wherein two R are^SNThe groups together with intervening atoms form an optionally substituted heterocyclic ring. For example, in some embodiments, R^S2aAnd R^S2bIs of the formula:

wherein R is^sqAs defined herein and sn is 0, 1, 2 or 3.

R in each case, as generally defined herein^S3aAnd R^S3bIndependently hydrogen, optionally substituted alkyl, -OR^SOor-N (R)^SN)₂。

In some embodiments, R^S3aAnd R^S3bAt least one of (a) is hydrogen.

In some embodiments, R^S3aAnd R^S3bAt least one of (a) and (b) is an optionally substituted alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (A) is substituted C_1–6An alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (A) is unsubstituted C_1–6An alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (a) is methyl, ethyl, propyl, butyl, pentyl or hexyl. In some embodiments, R^S3aAnd R^S3bIs isopropyl, isobutyl or isoamyl. In some embodiments, R^S3aAnd R^S3bAt least one of (a) is an isobutyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (a) is a tert-butyl group.

In some embodiments, R^S3aAnd R^S3bAt least one of is-OR^SOWherein R is^SOIndependently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl or an oxygen protecting group. In some embodiments, R^S3aAnd R^S3bAt least one of (a) and (b) is-OH. In some embodiments, R^S3aAnd R^S3bAt least one of is-OR^SOWherein R is^SOIs an optionally substituted alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (a) and (b) is-O-methyl, -O-ethyl or-O-propyl. In some embodiments, R ^S3aAnd R^S3bAt least one of (a) is optionally substituted-O-alkyl-aryl. In some embodiments, R^S3aAnd R^S3bAt least one of (a) and (b) is-O-Bz. In some embodiments, R^S3aAnd R^S3bAt least one of (a) is-O-alkyl-heteroaryl. In some embodiments, R^S3aAnd R^S3bAt least one of (a) is optionally substituted-O-alkenyl-aryl. In some embodiments, R^S3aAnd R^S3bAt least one of (a) is optionally substituted-O-alkenyl-heteroaryl. In some embodiments, R^S3aAnd R^S3bAt least one of is-OR^SOWherein R is^SOIs composed ofAryl is an optionally substituted aryl group. In some embodiments, R^S3aAnd R^S3bAt least one of is-OR^SOWherein R is^SOIs composed ofThe heteroaryl group is an optionally substituted heteroaryl group. In some embodiments, R^S2aAnd R^S3bAt least one of is-OR^SOWherein R is^SOIs composed of

In some casesIn the embodiment, R^S3aAnd R^S3bAt least one of is-OR^SOWherein R is^SOIs an oxygen protecting group. In some embodiments, R^S3aAnd R^S3bAt least one of is-OR^SOWherein R is^SOIs a carbonyl group. In some embodiments, R^S3aAnd R^S3bAt least one of is-OR^SOWherein R is^SOIs acetyl. In some embodiments, R^S3aAnd R^S3bAt least one of is-OR^SOWherein R is^SOIs an optionally substituted heterocyclic group.

In some embodiments, R^S3aAnd R^S3bAt least one of (A) and (B) is-N (R)^SN)₂. In some embodiments, R^S3aAnd R^S3bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNAre the same. In some embodiments, R^S3aAnd R^S3bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIs different.

In some embodiments, R^S3aAnd R^S3bAt least one of (a) is-NH₂。

In some embodiments, R^S3aAnd R^S3bAt least one of (A) is-NHR^SN. In some embodiments, R^S3aAnd R^S3bAt least one of (A) is-NHR^SNWherein R is^SNIs optionally substituted C_1–6An alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (A) is-NHR^SNWherein R is^SNIs unsubstituted C_1–6An alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (A) is-NHR^SNWherein R is^SNIs substituted C_1–6An alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (a) and (b) is-NH-benzyl.

In some embodiments, R^S3aAnd R^S3bAt least one of (A) is-NHR^SNWherein R is^SNIs a nitrogen protecting group. In some embodiments, R^S3aAnd R^S3bAt least one of (a) is-NHFmoc. In some embodiments, R^S3aAnd R^S3bAt least one of (a) is-NHBoc.

In some embodiments, R^S3aAnd R^S3bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently is optionally substituted C _1–6An alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (A) and (B) is-N (CH)₃)R^SNWherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (A) and (B) is-N (CH)₃)R^SNWherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (A) and (B) is-N (CH)₂CH₃)R^SNWherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (A) and (B) is-N (CH)₂CH₃)R^SNWherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S3aAnd R^S3bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently selected from methyl, ethyl, isopropyl, isobutyl, isoamyl and benzyl.

In some embodiments, R^S3aAnd R^S3bAt least one of (A) and (B) is-N (R)^SN)₂Wherein two R are^SNThe groups together with intervening atoms form an optionally substituted heterocyclic ring. For example, in some embodiments, R^S3aAnd R^S3bIs of the formula:

wherein R is^sqAs defined herein and sn is 0, 1, 2 or 3.

In some embodiments, R^S2aOr R^S2bAnd R ^S3aOr R^S3bTogether form an optionally substituted fused heterocyclic ring. In some embodiments, R^S2aAnd R^S3aTogether form an optionally substituted fused heterocyclic ring. In some embodiments, R^S2bAnd R^S3bTogether form an optionally substituted fused heterocyclic ring. In some embodiments, R^S2aAnd R^S3bTogether form an optionally substituted fused heterocyclic ring. In some embodiments, R^S2bAnd R^S3aTogether form an optionally substituted fused heterocyclic ring.

In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused pyrrolidine. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused piperidine. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused piperidone. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused piperazine. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused piperazinone. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused morpholine. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused morpholinone.

In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused pyrrolidine; and R ^SNIs methyl. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form a renAn optionally substituted fused piperidine; and R^SNIs methyl. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused piperidone; and R^SNIs methyl. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused piperazine; and R^SNIs methyl. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused piperazinone; and R^SNIs methyl. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused morpholine; and R^SNIs methyl. In some embodiments, R^S2aOr R^S2bAnd R^S3aOr R^S3bTogether form an optionally substituted fused morpholinone; and R^SNIs methyl.

In some embodiments, R^S2aAnd R^S3aAre formed together

In some embodiments, R^S2aAnd R^S3aAre formed together

In some embodiments, R^S2aAnd R^S3aAre formed together

In some embodiments, R^S2aAnd R^S3aAre formed together

In some embodiments, R^S2aAnd R^S3aAre formed together

And R^SNIs methyl.

In some embodiments, R^S2aAnd R^S3aAre formed togetherAnd R^SNIs methyl.

In some embodiments, R^S2aAnd R^S3aAre formed togetherAnd R^SNIs methyl.

In some embodiments, R ^S2aAnd R^S3aAre formed together

And R^SNIs methyl.

R in each case, as generally defined herein^S4aAnd R^S4bIndependently hydrogen, optionally substituted alkyl, -OR^SOor-N (R)^SN)₂。

In some embodiments, R^S4aAnd R^S4bAt least one of (a) is hydrogen.

In some embodiments, R^S4aAnd R^S4bAt least one of (a) and (b) is an optionally substituted alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (A) is substituted C_1–6An alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (A) is unsubstituted C_1–6An alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (a) is methyl, ethyl, propyl, butyl, pentyl or hexyl. In some embodiments, R^S4aAnd R^S4bIs isopropyl, isobutyl or isoamyl. In some embodiments, R^S4aAnd R^S4bAt least one of (a) is an isobutyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (a) is a tert-butyl group.

In some embodiments, R^S4aAnd R^S4bAt least one of is-OR^SOWherein R is^SOIndependently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl or an oxygen protecting group. In some embodiments, R^S4aAnd R^S4bAt least one of (a) and (b) is-OH. In some embodiments, R ^S4aAnd R^S4bAt least one of is-OR^SOWherein R is^SOIs an optionally substituted alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (a) and (b) is-O-methyl, -O-ethyl or-O-propyl. In some embodiments, R^S4aAnd R^S4bAt least one of (a) is optionally substituted-O-alkyl-aryl. In some embodiments, R^S4aAnd R^S4bAt least one of (a) and (b) is-O-Bz. In some embodiments, at least one is R^S4aAnd R^S4bis-OR^SOWherein R is^SOIs composed ofWherein aryl is an optionally substituted aryl group. In some embodiments, R^S4aAnd R^S4bAt least one of is-OR^SOWherein R is^SOIs composed of

Wherein heteroaryl is an optionally substituted heteroaryl group. In some embodiments, R^S4aAnd R^S4bAt least one of is-OR^SOWherein R is^SOIs composed ofIn some embodiments, R^S4aAnd R^S4bAt least one of is-OR^SOWherein R is^SOIs an oxygen protecting group. In some embodiments, R^S4aAnd R^S4bAt least one of is-OR^SOWherein R is^SOIs a carbonyl group. In some embodiments, R^S4aAnd R^S4bAt least one of is-OR^SOWherein R is^SOIs acetyl. In some embodiments, R^S4aAnd R^S4bAt least one of is-OR^SOWherein R is^SOIs an optionally substituted heterocyclic group.

In some embodiments, R^S4aAnd R ^S4bAt least one of (A) and (B) is-N (R)^SN)₂. In some embodiments, R^S4aAnd R^S4bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNAre the same. In some embodiments, R^S4aAnd R^S4bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIs different.

In some embodiments, R^S4aAnd R^S4bAt least one of (a) is-NH₂。

In some embodiments, R^S4aAnd R^S4bAt least one of (A) is-NHR^SN. In some embodiments, R^S4aAnd R^S4bAt least one of (A) is-NHR^SNWherein R is^SNIs optionally substituted C_1–6An alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (A) is-NHR^SNWherein R is^SNIs unsubstituted C_1–6An alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (A) is-NHR^SNWherein R is^SNIs substituted C_1–6An alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (a) and (b) is-NH-benzyl.

In some embodiments, R^S4aAnd R^S4bAt least one of (A) is-NHR^SNWherein R is^SNIs a nitrogen protecting group. In some embodiments, R^S4aAnd R^S4bAt least one of (a) is-NHFmoc. In some embodiments, R^S4aAnd R^S4bAt least one of (a) is-NHBoc.

In some embodiments, R^S4aAnd R^S4bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R ^S4aAnd R^S4bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (A) and (B) is-N (CH)₃)R^SNWherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (A) and (B) is-N (CH)₃)R^SNWherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (A) and (B) is-N (CH)₂CH₃)R^SNWherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (A) and (B) is-N (CH)₂CH₃)R^SNWherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S4aAnd R^S4bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently selected from methyl, ethyl, isopropyl, isobutyl, isoamyl and benzyl.

In some embodiments, R^S4aAnd R^S4bAt least one of (A) and (B) is-N (R)^SN)₂Wherein two R are^SNThe groups together with intervening atoms form an optionally substituted heterocyclic ring. For example, in some embodiments, R^S4aAnd R^S4bIs of the formula:

wherein R is^sqAs defined herein and sn is 0, 1, 2 or 3.

R in each case, as generally defined herein^S5aAnd R^S5bIndependently hydrogen, optionally substituted alkyl, -OR ^SOor-N (R)^SN)₂。

In some embodiments, R^S5aAnd R^S5bAt least one of (a) is hydrogen.

In some embodiments, R^S5aAnd R^S5bAt least one of (a) and (b) is an optionally substituted alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (A) is substituted C_1–6An alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (A) is unsubstituted C_1–6An alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (a) is methyl, ethyl, propyl, butyl, pentyl or hexyl. In some embodiments, R^S5aAnd R^S5bIs isopropyl, isobutyl or isoamyl. In some embodiments, R^S5aAnd R^S5bAt least one of (a) is an isobutyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (a) is a tert-butyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (a) is alkoxyalkyl, e.g., -CH₂OMe、-CH₂OEt or-CH₂And (4) OBn. In some embodiments, R^S5aAnd R^S5bAt least one of is-CH₂And (5) OH. In some embodiments, R^S5aAnd R^S5bAt least one of is-CH₂And (3) OBz. In some embodiments, R^S5aAnd R^S5bAt least one of is-CH₂OPG, wherein PG is an oxygen protecting group. In some embodiments, R^S5aAnd R^S5bAt least one of (a) is aminoalkyl, e.g., -CH₂NHMe、-CH₂NMe₂or-CH₂NHBn. In some embodiments, R ^S5aAnd R^S5bAt least one of is-CH₂NH₂. In some embodiments, R^S5aAnd R^S5bAt least one of is-CH₂NHPG, wherein PG is a nitrogen protecting group.

In some embodiments, R^S5aAnd R^S5bAt least one of is-OR^SOWherein R is^SOIndependently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkyneA group, an optionally substituted heterocyclic group or an oxygen protecting group. In some embodiments, R^S5aAnd R^S5bAt least one of (a) and (b) is-OH. In some embodiments, R^S5aAnd R^S5bAt least one of is-OR^SOWherein R is^SOIs an optionally substituted alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (a) and (b) is-O-methyl, -O-ethyl or-O-propyl. In some embodiments, R^S5aAnd R^S5bAt least one of (a) is optionally substituted-O-alkyl-aryl. In some embodiments, R^S5aAnd R^S5bAt least one of (a) and (b) is-O-Bz. In some embodiments, at least one is R^S5aAnd R^S5bis-OR^SOWherein R is^SOIs composed ofWherein aryl is an optionally substituted aryl group. In some embodiments, R^S5aAnd R^S5bAt least one of is-OR^SOWherein R is^SOIs composed ofWherein heteroaryl is an optionally substituted heteroaryl group. In some embodiments, R^S5aAnd R^S5bAt least one of is-OR ^SOWherein R is^SOIs composed of

In some embodiments, R^S5aAnd R^S5bAt least one of is-OR^SOWherein R is^SOIs an oxygen protecting group. In some embodiments, R^S5aAnd R^S5bAt least one of is-OR^SOWherein R is^SOIs a carbonyl group. In some embodiments, R^S5aAnd R^S5bAt least one of is-OR^SOWherein R is^SOIs acetyl. In some embodiments, R^S5aAnd R^S5bAt least one of is-OR^SOWherein R is^SOIs an optionally substituted heterocyclic group.

In some embodiments, R^S5aAnd R^S5bAt least one of (A) and (B) is-N (R)^SN)₂. In some embodiments, R^S5aAnd R^S5bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNAre the same. In some embodiments, R^S5aAnd R^S5bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIs different.

In some embodiments, R^S5aAnd R^S5bAt least one of (a) is-NH₂。

In some embodiments, R^S5aAnd R^S5bAt least one of (A) is-NHR^SN. In some embodiments, R^S5aAnd R^S5bAt least one of (A) is-NHR^SNWherein R is^SNIs optionally substituted C_1–6An alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (A) is-NHR^SNWherein R is^SNIs unsubstituted C_1–6An alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (A) is-NHR^SNWherein R is^SNIs substituted C_1–6An alkyl group. In some embodiments, R ^S5aAnd R^S5bAt least one of (a) and (b) is-NH-benzyl.

In some embodiments, R^S5aAnd R^S5bAt least one of (A) is-NHR^SNWherein R is^SNIs a nitrogen protecting group. In some embodiments, R^S4aAnd R^S4bAt least one of (a) is-NHFmoc. In some embodiments, R^S5aAnd R^S5bAt least one of (a) is-NHBoc.

In some embodiments, R^S5aAnd R^S5bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (A) and (B) is-N (CH)₃)R^SNWherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (A) and (B) is-N (CH)₃)R^SNWherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (A) and (B) is-N (CH)₂CH₃)R^SNWherein each R is^SNIndependently is optionally substituted C_1–6An alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (A) and (B) is-N (CH)₂CH₃)R^SNWherein each R is^SNIndependently is unsubstituted C_1–6An alkyl group. In some embodiments, R^S5aAnd R^S5bAt least one of (A) and (B) is-N (R)^SN)₂Wherein each R is^SNIndependently selected from methyl, ethyl, isopropyl, isobutyl, isoamyl and benzyl.

In some embodiments, R^S5aAnd R^S5bAt least one of (A) and (B) is-N (R)^SN)₂Wherein two R are^SNThe groups together with intervening atoms form an optionally substituted heterocyclic ring. For example, in some embodiments, R^S5aAnd R^S5bIs of the formula:

wherein R is^sqAs defined herein and sn is 0, 1, 2 or 3.

R in each case as used herein^sqIndependently halogen, optionally substituted alkyl, -OR^SO1or-N (R)^SN1)₂Wherein R is^SO1Independently hydrogen, optionally substituted alkyl or an oxygen protecting group; and R^SN1Independently hydrogen, optionally substituted alkyl or a nitrogen protecting group; or optionally twoR^SN1Together with intervening atoms, form an optionally substituted heterocyclic ring.

R in each case as generally defined herein^SOIndependently hydrogen, optionally substituted alkyl, carbonyl, optionally substituted heterocyclyl or an oxygen protecting group.

In some embodiments, R^SOIs hydrogen. In some embodiments, R^SOIs an optionally substituted alkyl group. In some embodiments, R^SOIs optionally substituted C_1–6An alkyl group. In some embodiments, R^SOIs methyl, ethyl or propyl. In some embodiments, R^SOIs an optionally substituted aralkyl group, for example, an optionally substituted benzyl (Bn). In some embodiments, R ^SOIs an optionally substituted heterocyclic group. In some embodiments, R^SOIs a carbonyl group. In some embodiments, R^SOis-C (═ O) CH₃(acetyl, Ac). In some embodiments, R^SOis-C (═ O) Ph (benzoyl, Bz). In some embodiments, R^SOIs composed ofWherein aryl is an optionally substituted aryl group. In some embodiments, R^SOIs composed ofWherein heteroaryl is an optionally substituted heteroaryl group. In some embodiments, R^SOIs composed of

In some embodiments, R^SOIs an oxygen protecting group.

R in each case as generally defined herein^SNIndependently hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl or a nitrogen protecting group; or optionally two R^SNTogether with intervening atoms, form an optionally substituted heterocyclic ring. In some embodiments, R^SNIs hydrogen. In some embodiments, R^SNIs an optionally substituted alkyl group. In some embodiments，R^SNIs optionally substituted C_1–6An alkyl group. In some embodiments, R^SNIs methyl, ethyl or propyl. In some embodiments, R^SNIs a substituted aralkyl group, for example, an optionally substituted benzyl (Bn). In some embodiments, R^SNIs an optionally substituted heterocyclic group. In some embodiments, R ^SNIs a carbonyl group. In some embodiments, R^SNIs a carbonyl group. In some embodiments, R^SNis-C (═ O) CH₃(acetyl, Ac). In some embodiments, R^SNis-C (═ O) Ph (benzoyl, Bz). In some embodiments, R^SNIs a nitrogen protecting group.

In some embodiments, R⁹And/or R¹⁷Is of formula (s-2):

in some embodiments, R⁹And/or R¹⁷Is of formula (s-2 a):

in some embodiments, R⁹And/or R¹⁷Is one of the following formulas:

in some embodiments, R⁹And/or R¹⁷Is of formula (s-2 b):

in some embodiments, R⁹And/or R¹⁷Is one of the following formulas:

in some embodiments, R⁹And/or R¹⁷Is of formula (s-3):

in some embodiments, R⁹And/or R¹⁷Is of formula (s-3 a):

in some embodiments, R⁹And/or R¹⁷Is one of the following formulas:

in some embodiments, R^SOIs an optionally substituted heterocyclic group.

For example, in some embodiments, R^SOIs of the formula:

in some embodiments, R^SOIs of the formula:

in some embodiments, R^SOIs of the formula:

in some embodiments, R^SOIs of the formula:

in some embodiments, R⁹And/or R¹⁷Is of the formula:

in some embodiments, R⁹And/or R¹⁷Having one of the following formulae:

group A¹、A²And A

As generally understood from the above, in some embodiments, R ¹²、R¹⁴And/or R³Is of the formula (L)^C1-i) a group, wherein LG is a leaving group as defined herein. In some embodiments, nucleophilic displacement of the leaving group results in formula (L)^C1-ii) a group. See scheme a1. It is generally understood that A¹Is represented by the formula A²–L^C2–R²³A of the Compound²The reactive group and the reaction between the two halves gives the formula (L)^C1-iii) a group. See scheme a1. These reactions are carried out from (L)^C1-i) to (L)^C1-ii) and from (L)^C1-ii) to (L)^C1-iii) occurs at any stage of the synthesis, e.g., during construction of the east or west half, after coupling of the east or west halves, or after a macrocyclization step.

Scheme a1.

In some embodiments, from (L)^C1-ii) to (L)^C1The coupling reaction of-iii) includes a reaction commonly referred to as click chemistry. Click chemistry is a chemical method introduced by Sharpless in 2001, which describes the process of making smallThe units are joined together to rapidly and reliably produce a fine chemistry of the substance. See, e.g., Kolb, Finland Sharpless Angewandte Chemie International Edition (2001)40: 2004-2021; evans, Australian Journal of Chemistry (2007)60: 384-. Exemplary coupling reactions (some of which may be classified as "click chemistry") include, but are not limited to, the formation of esters, thioesters, amides from activated acids or acid halides (e.g., peptide coupling); nucleophilic displacement reactions (e.g., nucleophilic displacement of halides or ring opening of ring systems with strain); huisgon cycloaddition of azide-alkyne; mercapto-alkyne addition; forming an imine; and michael addition (e.g., maleimide addition).

In general, for the group (L)^C1-ii)，A¹Should be reacted with the group A²Complementary and react to form a group (L)^C1-iii). For example, if A²–L^C2–R²³Group A of²Is a nucleophilic group, then the group A¹Must be an electrophilic group. Similarly, if A²–L^C2–R²³Group A of²Is an electrophilic group, then the group A¹Must be a nucleophilic group. Although A is¹And A²The definitions in the present invention are the same, but it must be understood that the groups are pairwise complements.

As generally defined herein, A¹And A²May be selected from Leaving Groups (LG), -SH, -OH, -NH₂、–NH–NH₂、–N₃、–O–NH₂、–C(＝O)R^X1、

Wherein:

R^X1is hydrogen, a leaving group OR-OR^X2Wherein R is^X2Is hydrogen; optionally substituted alkyl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocycleA group; an optionally substituted heterocyclic group; optionally substituted aryl; optionally substituted heteroaryl; an oxygen protecting group;

leaving Group (LG) is-Br, -I, -Cl, -O (C ═ O) R^LGor-O (SO)₂R^LGWherein R is^LGIs optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl;

w is O, S or NR^W1；

R^W1Is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; optionally substituted heteroaryl; or a nitrogen protecting group; and

R^W2Is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; optionally substituted heteroaryl, or two R^W2The groups combine to form an optionally substituted cyclic moiety.

In some embodiments, a is²is-SH. In some embodiments, a is¹is-SH.

In some embodiments, a is²is-OH. In some embodiments, a is¹is-OH.

In some embodiments, a is²is-NH₂. In some embodiments, a is¹is-NH₂。

In some embodiments, a is²is-NH₂. In some embodiments, a is¹is-NH₂。

In some embodiments, a is²is-O-NH₂. In some embodiments, a is¹is-O-NH₂。

In some embodiments, a is²is-N₃. In some embodiments, a is¹is-N₃。

In some embodiments, a is²Is a leaving group, for example, -Cl, -Br or-I. In some embodimentsIn a scheme, A¹Is a leaving group, for example, -Cl, -Br or-I.

In some embodiments, a is²is-C (═ O) R^X1Wherein R is^X1Is hydrogen, i.e. gives A in the aldehyde-CHO form². In some embodiments, a is ¹is-C (═ O) R^X1Wherein R is^X1Is hydrogen, i.e. gives A in the aldehyde-CHO form¹。

In some embodiments, a is²is-C (═ O) R^X1Wherein R is^X1Is a Leaving Group (LG).

In some embodiments, a is¹is-C (═ O) R^X1Wherein R is^X1Is a Leaving Group (LG).

In some embodiments, a is²is-C (═ O) R^X1Wherein R is^X1is-OR^X2And wherein R is^X2To hydrogen, i.e. to give a in the form of carboxylic acid-C (═ O) OH²。

In some embodiments, a is¹is-C (═ O) R^X1Wherein R is^X1is-OR^X2And wherein R is^X2To hydrogen, i.e. to give a in the form of carboxylic acid-C (═ O) OH¹。

In some embodiments, a is²is-C (═ O) R^X1Wherein R is^X1is-OR^X2And wherein R is^X2Is a non-hydrogen radical, i.e. gives ester-C (═ O) OR^X2Form A²。

In some embodiments, a is¹is-C (═ O) R^X1Wherein R is^X1is-OR^X2And wherein R is^X2Is a non-hydrogen radical, i.e. gives ester-C (═ O) OR^X2Form A¹。

In some embodiments, a is²Is an oxetanyl, thietanyl or aziridinyl group of the formula:

wherein W is O,S or NR^W1. In some embodiments, W is O. In some embodiments, W is S. In some embodiments, W is NR^W1。

In some embodiments, a is¹Is an oxetanyl, thietanyl or aziridinyl group of the formula:

Wherein W is O, S or NR^W1. In some embodiments, W is O. In some embodiments, W is S. In some embodiments, W is NR^W1。

In some embodiments, a is¹Or A²Is an ethynyl group:

in some embodiments, a is¹Or A²Is vinyl or propenyl:

in some embodiments, a is¹Or A²Is an α, β -unsaturated carbonyl group:

in some embodiments, a is¹Or A²Is a maleimide group:

in some embodiments, a is¹Or A²Is the group:

wherein R is^W2Is an alkyl group, for example, methyl.

In some embodiments, a is¹Or A²Is the group:

further, as defined generally herein, A¹Or A²Together react to form a group a, wherein a is a group of the formula:

–NH–、–NH–NH–、–NH–O–、–O–NH–、–S–、–O–、

wherein:

q is-NH-, -NH-NH-, -O-NH-, -NH-O-, -S-or-O-;

w is O, S or NR^W1；

R^W1Is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; optionally substituted heteroaryl; or a nitrogen protecting group; and

R^W2is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; optionally substituted heteroaryl, or two R ^W2The groups together form an optionally substituted cyclic moiety.

In some embodiments, A is-NH-.

In some embodiments, A is-NH-.

In some embodiments, A is-S-.

In some embodiments, A is-O-.

In some casesIn one embodiment, A is a disulfide group

In some embodiments, a isWherein Q is-NH-, -NH-NH-, -O-NH-, -NH-O-, -S-, -O-.

For example, in some embodiments, wherein Q is-NH-, A is an amide group of the formula:

in some embodiments, wherein Q is-NH-NH-, A is a hydrazide group of the formula:

in some embodiments, wherein Q is-S-, A is a thioester group of the formula:

in some embodiments, wherein Q is-O-, A is an ester group of the formula:

in some embodiments, a is:

in some embodiments, R^W2Is an alkyl group, for example, methyl.

In some embodiments, a is:

in some embodiments, R^W2Is an alkyl group, for example, methyl. In some embodiments, R^W1Is hydrogen.

In some embodiments, a is:

in some embodiments, R^W2Is an alkyl group, for example, methyl.

In some embodiments, a is:

in some embodiments, a is:

wherein W is O, S or NR^W1、R^W1Is hydrogen, optionally substituted alkyl or amino protecting group; and Q is-NH-, -NH-NH-, -O-NH-, -NH-O-, -S-or-O-. In some embodiments, W is O. In some embodiments, W is S. In some embodiments, W is NR^W1. In some embodiments, Q is-NH-. In some embodiments, Q is-NH-NH-. In some embodiments, Q is-S-. In some embodiments, Q is-O-.

In some embodiments, a is:

wherein Q is-NH-, -NH-NH-, -O-NH-, -NH-O-, -S-or-O-. In some embodiments, Q is-NH-. In some embodiments, Q is-NH-NH-. In some embodiments, Q is-S-. In some embodiments, Q is-O-.

In some embodiments, a is:

wherein Q is-NH-, -NH-NH-, -O-NH-, -NH-O-, -S-or-O-. In some embodiments, Q is-NH-. In some embodiments, Q is-NH-NH-. In some embodiments, Q is-S-. In some embodiments, Q is-O-.

In some embodiments, a is:

wherein Q is-NH-, -NH-NH-, -O-NH-, -NH-O-, -S-or-O-. In some embodiments, Q is-NH-. In some embodiments, Q is-NH-NH-. In some embodiments, Q is-S-. In some embodiments, Q is-O-.

In some embodiments, the method comprises reacting formula (L)^C1-ii) a group of formula A²–L^C2–R²³Reaction of a compound in which A¹And A²One of them is-C (═ O) R^X1Wherein R is^X1Is a Leaving Group (LG) OR-OR^X2And A and¹and A²The other of which is-SH, -OH, -NH₂or-NH₂To give part a, wherein a is an amide, thioester or ester group. See, e.g., scheme a2 and table a 1.

Scheme A2. preparation by amide, thioester and ester formation

In some embodiments, the method comprises reacting formula (L)^C1-ii) a group of formula A²–L^C2–R²³Coupling of compounds in which A¹And A²One of them is a Leaving Group (LG) and A¹And A²The other of which is-SH, -OH, -NH₂or-NH₂To obtain formula (L)^C1-iii) a group wherein A is-S-, -O-, -NH-or-NH-NH-, respectively. See, e.g., scheme A3 and table a2.

Scheme A3 nucleophilic Displacement of halides or other leaving groups

In some embodiments, the method comprises reacting formula (L)^C1-ii) a group of formula A²–L^C2–R²³Coupling of compounds in which A¹And A²One of them isAnd A¹And A²The other of which is-SH, -OH, -NH₂or-NH₂To obtain formula (L)^C1-iii) a group. See, e.g., scheme a4 and table A3.

Scheme A4 nucleophilic addition to Ring systems having tonicity

In some implementationsIn one embodiment, the method comprises reacting a compound of formula (L)^C1-ii) a group of formula A²–L^C2–R²³Coupling of compounds in which A¹And A²One of them isAnd A¹And A²Is the other of-N₃To obtain formula (L)^C1-iii) a group. See, e.g., scheme a5 and table a4.

Scheme A5. Huisgen cycloaddition of azide-alkynes

In some embodiments, the method comprises reacting formula (L)^C1-ii) a group of formula A²–L^C2–R²³Coupling of compounds in which A¹And A²One of them isAnd A¹And A²The other of which is-SH, to give the formula (L)^C1-iii) a group. See, e.g., scheme a6 and table a5.

Scheme A6. mercapto-alkyne addition

In some embodiments, the method comprises reacting formula (L)^C1-ii) a groupAnd formula A²–L^C2–R²³Coupling of compounds in which A¹And A²One of them is aldehyde-CHO or ketone and A¹And A²Another of (a) is-NH_2、–NH–NH₂or-O-NH₂To obtain formula (L)^C1-iii) a group. See, e.g., scheme a7 and table a6.

Scheme A7. imine formation

In some embodiments, the method comprises reacting formula (L)^C1-ii) a group of formula A²–L^C2–R²³Coupling of compounds in which A¹And A²One of them is an alpha, beta-unsaturated carbonyl group and A¹And A²The other of them is-OH, -SH, -NH₂、–NHNH₂or-O-NH₂To obtain formula (L)^C1-iii) a group. See, e.g., scheme A8 and table a7.

Scheme A8. Michael addition

In some embodiments, the method comprises reacting formula (L)^C1-ii) a group of formula A²–L^C2–R²³Coupling of compounds in which A¹And A²One of them is a maleimide group and A¹And A²Another one of themis-OH, -SH, -NH₂、–NHNH₂or-O-NH₂To obtain formula (L)^C1-iii) a group. See, e.g., scheme a9 and table A8.

Scheme A9. Maleimide addition

In some embodiments, the method comprises reacting formula (L)^C1-ii) a group of formula A²–L^C2–R²³Compound coupling (e.g., palladium catalyzed coupling) wherein A¹And A²One of them is propenyl and A¹And A²Is a leaving group to give formula (L) after treatment with a palladium catalyst^C1-iii) a group. See, for example, table a9.

In some embodiments, the method comprises reacting formula (L)^C1-ii) a group of formula A²–L^C2–R²³Coupling of compounds in which A¹And A²One of which is-SH, to give, after treatment with an oxidizing agent, the formula (L) ^C1-iii) a group wherein a is a disulfide bond. See, for example, scheme A8.

Scheme A8. disulfide formation

In some preferred embodiments, A¹is-N₃And A²Is composed ofThereby making formula A²–L^C2–R²³The compound is of the formula:

and A¹And A²–L^C2–R²³Together react to give a group of the formula:

in some preferred embodiments, A¹Is composed ofAnd A²Is a leaving group and A¹And A²–L^C2–R²³Reacted together (e.g., by palladium catalysis) to give a group of the formula:

furthermore, as described herein, there are a number of addition formulas (L)^C1-iii) a group, which does not involve the addition of A¹And A²React to form a. For example, via the group-OR¹²、-NR¹³R¹⁴and/OR-OR³(wherein R is¹²、R¹⁴And/or R³Is hydrogen) and formula (L)^C1-vii) reacting the compound to assemble formula (L)^C1-iii) a group, e.g. by nucleophilic displacement, to give R therein¹²、R¹⁴And/or R³Is of the formula (L)^C1-iii) of the group. See, e.g., scheme a9.

Scheme a9.

Thus, in some embodiments, a may be any group as defined above and may furthermore be any cyclic moiety selected from: optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

In some embodiments, a is optionally substituted heteroaryl, e.g., 5-to 6-membered optionally substituted heteroaryl.

In some embodiments, wherein A is 5-membered optionally substituted heteroaryl, formula (L)^C1-iii) the group is of formula (L)^C1-v):

Wherein Y in each case¹、Y²、Y³、Y⁴And Y⁵Independently is CR^YO, S, N or NR^YWherein R is^YIs hydrogen or optionally substituted alkyl.

In some embodiments, wherein A is 5-membered heteroaryl, formula (L)^C1-iii) the group is selected from:

L^C1、L^C2and a group R²³

L in each case, as generally defined herein^C1And L^C2Independently a bond or a linker selected from: optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene; optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, and combinations thereof.

In some embodiments, L is^C1Is a bond. It is generally understood that if L is^C1Is a bond, then a group-LG, -A as described in the present application¹or-A-L^C2-R²³Directly to the parent moiety, for example, a macrolide or an intermediate compound. Further, in some embodiments, L^C2Is a bond. It is generally understood that if L is^C2Is a bond, then the group R²³Directly linked to a as defined in the application.

Alternatively, in some embodiments, the first and second electrodes may,L^C1is a linking group. In some embodiments, L is^C2Is a linking group.

In some embodiments, L is^C1And L^C2Are each optionally and independently a linking group, at least one of which is optionally substituted alkylene, e.g., substituted or unsubstituted C_1–6Alkylene, substituted or unsubstituted C_2–6Alkylene, substituted or unsubstituted C_3–6Alkylene, substituted or unsubstituted C_4–6Alkylene, substituted or unsubstituted C_5–6Alkylene, substituted or unsubstituted C_2–5Alkylene, substituted or unsubstituted C_2–4Alkylene, substituted or unsubstituted C_2–3Alkylene, substituted or unsubstituted C₁Alkylene, substituted or unsubstituted C₂Alkylene, substituted or unsubstituted C₃Alkylene, substituted or unsubstituted C₄Alkylene, substituted or unsubstituted C₅Alkylene or substituted or unsubstituted C₆An alkylene group. In some embodiments, L is^C1And L^C2Is each optionally and independently of the formula- (CH)₂)_n-wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

In some embodiments, L is^C1And L^C2Are each optionally and independently a linking group, at least one of which is included is a substituted or unsubstituted alkenylene group, e.g., substituted or unsubstituted C_2–6Alkenylene, substituted or unsubstituted C _3–6Alkenylene, substituted or unsubstituted C_4–6Alkenylene, substituted or unsubstituted C_5–6Alkenylene, substituted or unsubstituted C_2–5Alkenylene, substituted or unsubstituted C_2–4Alkenylene, substituted or unsubstituted C_2–3Alkenylene, substituted or unsubstituted C₂Alkenylene, substituted or unsubstituted C₃Alkenylene, substituted or unsubstituted C₄Alkenylene, substituted or unsubstituted C₅Alkenylene or substituted or unsubstituted C₆An alkenylene group.

In some embodiments, L is^C1And L^C2Is a linking group which is each optional and independent, at least one of which is included is a substituted or unsubstituted alkynylene group, e.g., substituted or unsubstituted C_2–6Alkynylene, substituted or unsubstituted C_3–6Alkynylene, substituted or unsubstituted C_4–6Alkynylene, substituted or unsubstituted C_5–6Alkynylene, substituted or unsubstituted C_2–5Alkynylene, substituted or unsubstituted C_2–4Alkynylene, substituted or unsubstituted C_2–3Alkynylene, substituted or unsubstituted C₂Alkynylene, substituted or unsubstituted C₃Alkynylene, substituted or unsubstituted C₄Alkynylene, substituted or unsubstituted C₅Alkynylene or substituted or unsubstituted C₆Alkynylene radical.

In some embodiments, L is^C1And L ^C2At least one included, being a linking group, each being optional and independent, is a substituted or unsubstituted heteroalkylene group, e.g., a substituted or unsubstituted heteroC_1–6Alkylene, substituted or unsubstituted hetero C_2–6Alkylene, substituted or unsubstituted hetero C_3–6Alkylene, substituted or unsubstituted hetero C_4–6Alkylene, substituted or unsubstituted hetero C_5–6Alkylene, substituted or unsubstituted hetero C_2–5Alkylene, substituted or unsubstituted hetero C_2–4Alkylene, substituted or unsubstituted hetero C_2–3Alkylene, substituted or unsubstituted hetero C₁Alkylene, substituted or unsubstituted hetero C₂Alkylene, substituted or unsubstituted hetero C₃Alkylene, substituted or unsubstituted hetero C₄Alkylene, substituted or unsubstituted hetero C₅Alkylene or substituted or unsubstituted heteroC₆An alkylene group.

In some embodiments, L is^C1And L^C2At least one included as a substituted or unsubstituted heteroalkenylene, e.g., substituted or unsubstituted heteroC, for each optional and independent linking group_2–6Alkenylene, substituted or unsubstitutedHetero compound C of_3–6Alkenylene, substituted or unsubstituted heteroC_4–6Alkenylene, substituted or unsubstituted heteroC_5–6Alkenylene, substituted or unsubstituted heteroC _2–5Alkenylene, substituted or unsubstituted heteroC_2–4Alkenylene, substituted or unsubstituted heteroC_2–3Alkenylene, substituted or unsubstituted heteroC₂Alkenylene, substituted or unsubstituted heteroC₃Alkenylene, substituted or unsubstituted heteroC₄Alkenylene, substituted or unsubstituted heteroC₅Alkenylene or substituted or unsubstituted hetero C₆An alkenylene group.

In some embodiments, L is^C1And L^C2At least one included as a substituted or unsubstituted heteroalkynylene group, e.g., a substituted or unsubstituted heteroC, for each optional and independent linker_2–6Alkynylene, substituted or unsubstituted heteroC_3–6Alkynylene, substituted or unsubstituted heteroC_4–6Alkynylene, substituted or unsubstituted heteroC_5–6Alkynylene, substituted or unsubstituted heteroC_2–5Alkynylene, substituted or unsubstituted heteroC_2–4Alkynylene, substituted or unsubstituted heteroC_2–3Alkynylene, substituted or unsubstituted heteroC₂Alkynylene, substituted or unsubstituted heteroC₃Alkynylene, substituted or unsubstituted heteroC₄Alkynylene, substituted or unsubstituted heteroC₅Alkynylene or substituted or unsubstituted heteroC₆Alkynylene radical.

In some embodiments, L is^C1Is optionally substituted alkylene and L^C2Is a bond, e.g. L^C1Is of the formula- (CH) ₂)_nOptionally substituted alkylene of (a) wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and L^C2Is of the formula (L) as described in the present application^C1-v) or (L)^C1-viii) a bond in a group.

In other embodiments, L^C1And L^C2Are all bonds, e.g. L^C1And L^C2Are all of formula (L) as described in the present application^C1-vi) a bond in the group.

Further, it is also generally understood that R²³May be an acyclic or cyclic moiety selected from: optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; and optionally substituted heteroaryl.

For example, in some embodiments, R²³Is an acyclic moiety selected from: optionally substituted alkyl; optionally substituted alkenyl; and optionally substituted alkynyl.

In some embodiments, R²³Is optionally substituted alkyl, e.g. optionally substituted C_1–6Alkyl, substituted or unsubstituted C_1–2Alkyl, optionally substituted C_2–3Alkyl, optionally substituted C_3–4Alkyl, optionally substituted C_4–5Alkyl or optionally substituted C_5–6An alkyl group. Exemplary R²³C_1–6Alkyl includes, but is not limited to, optionally substituted methyl (C)₁) Ethyl (C)₂) N-propyl (C)₃) Isopropyl (C) ₃) N-butyl (C)₄) Tert-butyl (C)₄) Sec-butyl (C)₄) Isobutyl (C)₄) N-pentyl group (C)₅) 3-pentyl (C)₅) Pentyl group (C)₅) Neopentyl (C)₅) 3-methyl-2-butylalkyl (C)₅) Tert-amyl (C)₅) And n-hexyl (C)₆)。

In some embodiments, R²³Is optionally substituted alkenyl, e.g. optionally substituted C_2–6Alkenyl, optionally substituted C_2–3Alkenyl, optionally substituted C_3–4Alkenyl, optionally substituted C_4–5Alkenyl or optionally substituted C_5–6An alkenyl group.

In some embodiments, R²³Is optionally substituted alkynyl, e.g. optionally substituted C_2–6Alkynyl, optionally substituted C_2–3Alkynyl, optionally substituted C_3–4Alkynyl, optionally substituted C_4–5Alkynyl or optionally substituted C_5–6Alkynyl.

In some embodiments, R²³Is a cyclic moiety selected from: optionally substituted carbocyclyl; an optionally substituted heterocyclic group; optionally substituted aryl; and optionally substituted heteroaryl.

In some embodiments, R²³Is an optionally substituted carbocyclic group, e.g. optionally substituted C_3–6Carbocyclyl, optionally substituted C_3–4Carbocyclyl, optionally substituted C_4–5Carbocyclyl or optionally substituted C_5–6A carbocyclic group.

In some embodiments, R²³Is an optionally substituted heterocyclic group, for example, an optionally substituted 3-6-membered heterocyclic group, an optionally substituted 3-4-membered heterocyclic group, an optionally substituted 4-5-membered heterocyclic group or an optionally substituted 5-6-membered heterocyclic group.

In some embodiments, R²³Is an optionally substituted aryl group, for example, an optionally substituted monocyclic aryl group, an optionally substituted 5, 6-fused bicyclic aryl group or an optionally substituted 6, 6-fused aryl group. In some embodiments, R²³Is optionally substituted phenyl. In some embodiments, R²³Is optionally substituted naphthyl.

In some embodiments, R²³Is optionally substituted heteroaryl, e.g., optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, optionally substituted 5,6 fused-bicyclic heteroaryl or optionally substituted 6,6 fused-bicyclic heteroaryl.

Specific aryl and heteroaryl radicals R²³The radicals are further as referred to in this application. For example, in some embodiments, R²³Is an aryl or heteroaryl ring system of the formula:

wherein:

v in each case as far as the valency permits¹、V²、V³、V⁴、V⁵、V⁶、V⁷、V⁸And V⁹May independently be O, S, N, NR^23NC or CR^23C；

R^23NIndependently hydrogen, optionally substituted alkyl, optionally substituted aryl or a nitrogen protecting group; and

R^23Cis hydrogen, halogen, -CN, -NO₂、–N₃Optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, substituted hydroxy, amino, substituted amino, mercapto, substituted mercapto or carbonyl.

In some embodiments, V¹Is O, S, N or NR^23N. In some embodiments, V¹Is N or NR^23N. In some embodiments, V¹Is O. In some embodiments, V¹Is S.

In some embodiments, V²Is O, S, N or NR^23N. In some embodiments, V²Is N or NR^23N. In some embodiments, V²Is O. In some embodiments, V²Is S.

In some embodiments, V³Is O, S, N or NR^23N. In some embodiments, V³Is N or NR^23N. In some embodiments, V³Is O. In some embodiments, V³Is S.

In some embodiments, V⁴Is O, S, N or NR^23N. In some embodiments, V⁴Is N or NR^23N. In some embodiments, V⁴Is O. In some embodiments, V⁴Is S.

In some embodiments, V⁵Is O, S, N or NR^23N. In some embodiments, V⁵Is N or NR^23N. In some embodiments, V⁵Is O. In some embodiments, V⁵Is S.

In some embodiments, V⁶Is O, S, N or NR^23N. In some embodiments, V⁶Is N or NR^23N. In some embodiments, V⁶Is O. In some embodiments, V⁶Is S.

In some embodiments, V⁷Is O, S, N or NR ^23N. In some embodiments, V⁷Is N or NR^23N. In some embodiments, V⁷Is O. In some embodiments, V⁷Is S.

In some embodiments, V⁸Is O, S, N or NR^23N. In some embodiments, V⁸Is N or NR^23N. In some embodiments, V⁸Is O. In some embodiments, V⁸Is S.

In some embodiments, V⁹Is O, S, N or NR^23N. In some embodiments, V⁹Is N or NR^23N. In some embodiments, V⁹Is O. In some embodiments, V⁹Is S.

In some embodiments, V¹、V²、V³、V⁴、V⁵、V⁶、V⁷、V⁸And V⁹Is selected from N and NR^23N. In some embodiments, V¹、V²、V³、V⁴、V⁵、V⁶、V⁷、V⁸And V⁹Only one of which is O. In some embodiments, V¹、V²、V³、V⁴、V⁵、V⁶、V⁷、V⁸And V⁹Only one of which is S. In any of the above cases, in some embodiments, V if the bond allows¹、V²、V³、V⁴、V⁵、V⁶、V⁷、V⁸And V⁹The remainder of (A) are independently C or CR^23C。

In some embodiments, V¹、V²、V³、V⁴、V⁵、V⁶、V⁷、V⁸And V⁹Wherein only two are each independently selected from N and NR^23N. In some embodiments, V¹、V²、V³、V⁴、V⁵、V⁶、V⁷、V⁸And V⁹Only two of which are each independently selected from O, N and NR^23N. In some embodiments, V¹、V²、V³、V⁴、V⁵、V⁶、V⁷、V⁸And V⁹Only two of which are each independently selected from S, N and NR^23N. In any of the above cases, in some embodiments, V, if allowed by a bond ¹、V²、V³、V⁴、V⁵、V⁶、V⁷、V⁸And V⁹The remainder of (A) is C or CR^23C。

In some embodiments, V if the bond allows¹、V²、V³、V⁴、V⁵、V⁶、V⁷、V⁸And V^{9 all of}And independently is C or CR^23C。

In some embodiments, R^23CIs hydrogen, halogen, -CN, hydroxyl, substituted hydroxyl, amino or substituted amino.

In some embodiments, R^23NIndependently hydrogen or optionally substituted alkyl (e.g., -CH)₃)。

In some embodiments, R²³Selected from any one of the following aryl or heteroaryl ring systems:

wherein R is^23CAs defined herein and x is 0, 1 or 2.

In some embodiments, R²³Selected from any one of the following aryl or heteroaryl ring systems:

other embodiments of the invention

The present application further relates to various combinations of the above embodiments. For example, in some embodiments, G¹is-NR¹³NR¹⁴To obtain a compound or macrolide of the formula:

or a salt thereof.

In some embodiments, G¹is-NR¹³NR¹⁴And R is¹³And R¹¹Combining to form a carbamate group to give a compound or macrolide of the formula:

or a salt thereof.

In some embodiments, G¹is-NR¹³NR¹⁴And R is¹³And R¹¹Combine to form a carbamate group, resulting in a compound or macrolide having the following stereochemistry:

or a salt thereof.

It further relates to combining various embodiments with any of the formulae described herein, such as any of the formulae (C-1-A) to (C-567-C') above.

For example, in some embodiments of any of the above formulae, Z is the formula:

wherein z1 and z2 are 1, L¹And L²Are all a bond, R⁷is-CH₂CH₃、R⁸is-CH₃、G³is-O-or-L³Is a group of the formula

And R¹⁸And R¹⁹Are all hydrogen;

in some embodiments of any of the foregoing formulae, Z is the formula:

wherein z1 is 1, z2 is 0, L¹And L²Are all a bond, R⁷is-CH₂CH₃、R⁸is-CH₃、G³is-O-or-L³Is a group of the formula

And R¹⁸Is hydrogen.

In some embodiments of any of the foregoing formulae, Z is the formula:

wherein z1 is 1, z2 is 2, L¹And L²Are all a bond, R⁷is-CH₂CH₃、R⁸is-CH₃、G³is-O-or-L³Is a group of the formulaAnd R¹⁸And R¹⁹Are both hydrogen.

In some embodiments of any of the foregoing formulae, Z is the formula:

wherein z1 and z2 are 1, L¹And L²Are all a bond, Z⁴is-O-or-NH-, R⁷is-CH₂CH₃、R⁸is-CH₃、G³is-O-or-L³Is a group of the formula

And R¹⁸Is hydrogen.

In some embodiments of any of the foregoing formulae, Z is the formula:

wherein z1 is 0, z2 is 1, L¹Is a bond, L²is-CH₂–、Z⁴is-O-or-NH-, R⁷is-CH₂CH₃、R⁸is-CH₃、G³is-O-or-L³Is a group of the formula

And R¹⁸Is hydrogen.

In some embodiments of any of the foregoing formulae, Z is the formula:

wherein z1 and z2 are 1, L¹And L²Are all a bond, R ⁷is-CH₂CH₃、R⁸is-CH₃、G³is-O-or-L³Is a group of the formulaAnd R¹⁸Is hydrogen.

In some embodiments of any of the foregoing formulae, Z is the formula:

wherein z1 is 0, z2 is 1, L¹And L²Are all a bond, R⁷is-CH₂CH₃、R⁸is-CH₃、G³is-O-and L³Is a group of the formulaAnd R¹⁸Is hydrogen.

In some aspects of the formulae described herein, e.g., any of formulae (C-1-A) to (C-567-C') above, further reference is made to specific combinations provided below.

For example, in some embodiments, R^Z3Is hydrogen. In some embodiments, R^Z3Is not hydrogen. In some embodiments, R^Z3The carbon attached is the stereocenter of the (R) -configuration. In some embodiments, R^Z3The attached carbon is the stereocenter of the (S) -configuration. In some embodiments, R^Z3Is optionally substituted C_1–6An alkyl group. In some embodiments，R^Z3Is optionally substituted C_1–2An alkyl group. In some embodiments, R^Z3is-CH₃. In some embodiments, R^Z3Is optionally substituted haloalkyl. In some embodiments, R^Z3is-CF₃. In some embodiments, R^Z3is-CH₂CH₂And (5) OH. In some embodiments, R^Z3is-CH₂CH₂N(R²²)₂. In some embodiments, R^Z3is-CH₂CH₂N(R²²)₂. In some embodiments, R^Z3is-CH ₂CH₂NHR²². In some embodiments, R^Z3is-CH₂CH₂NHR²²(ii) a And R²²is-CH₂C (═ O) OH. In some embodiments, R^Z3is-CH₂CH₂NHR²²(ii) a And R²²Is composed ofIn some embodiments, R^Z3is-CH₂CH₂NHR²²(ii) a And R²²Is composed ofIn some embodiments, R^Z3Is an optionally substituted aralkyl group. In some embodiments, R^Z3Is an optionally substituted benzyl group. In some embodiments, R^Z3Is unsubstituted benzyl. In some embodiments, R^Z3Is a substituted benzyl group. In some embodiments, R^Z3Is a monosubstituted benzyl group. In some embodiments, R^Z3Is benzyl substituted with one example of halogen. In some embodiments, R^Z3Is optionally substituted C_2–6An alkenyl group. In some embodiments, R^Z3Is an optionally substituted vinyl group. In some embodiments, R^Z3Is an unsubstituted vinyl group. In some embodiments, R^Z3Is an optionally substituted allyl group. In some embodiments, R^Z3Is unsubstitutedAn allyl group. In some embodiments, R^Z3Is an optionally substituted carbocyclyl. In some embodiments, R^Z3Is optionally substituted C_3–6A carbocyclic group. In some embodiments, R^Z3Is an optionally substituted cyclopropyl group. In some embodiments, R^Z3Is unsubstituted cyclopropyl.

In some embodiments, R^Z2Is hydrogen. In some embodiments, R^Z2Is optionally substituted C_1–6An alkyl group. In some embodiments, R^Z2Is optionally substituted C_1–2An alkyl group. In some embodiments, R^Z2is-CH₃. In some embodiments, R^Z2is-C (═ O) R^Z8(ii) a And R^Z8Is an optionally substituted alkyl group. In some embodiments, R^Z2Is acetyl. In some embodiments, R^Z2Is a nitrogen protecting group.

In some embodiments, R^1aAnd R^1bAt least one of which is hydrogen. In some embodiments, R^1aAnd R^1bAre both hydrogen. In some embodiments, R^1aAnd R^1bAre not hydrogen. In some embodiments, R^1aAnd R^1bThe carbon attached is the stereocenter of the (R) -configuration. In some embodiments, R^1aAnd R^1bThe attached carbon is the stereocenter of the (S) -configuration. In some embodiments, R^1aIs optionally substituted C_1–6An alkyl group; and R^1bIs hydrogen. In some embodiments, R^1aIs optionally substituted C_1–2An alkyl group; and R^1bIs hydrogen. In some embodiments, R^1ais-CH₃(ii) a And R^1bIs hydrogen. In some embodiments, R^1aAnd R^1bAre all-CH₃. In some embodiments, R^1aIs optionally substituted haloalkyl; and R^1bIs hydrogen. In some embodiments, R ^1ais-CF₃(ii) a And R^1bIs hydrogen. In some embodiments, R^1ais-CH₂CH₂OH; and R^1bIs hydrogen. In some embodiments, R^1ais-CH₂CH₂N(R²²)₂(ii) a And R^1bIs hydrogen. In some embodiments, R^1ais-CH₂CH₂N(R²²)₂；R²²is-CH₃(ii) a And R^1bIs hydrogen. In some embodiments, R^1ais-CH₂CH₂NHR²²(ii) a And R^1bIs hydrogen. In some embodiments, R^1ais-CH₂CH₂NHR²²；R²²is-CH₂C (═ O) OH; and R^1bIs hydrogen. In some embodiments, R^1ais-CH₂CH₂NHR²²；R²²Is composed ofAnd R^1bIs hydrogen. In some embodiments, R^1ais-CH₂CH₂NHR²²；R²²Is composed of

And R^1bIs hydrogen. In some embodiments, R^1aIs optionally substituted aralkyl; and R^1bIs hydrogen. In some embodiments, R^1aIs an optionally substituted benzyl group; and R^1bIs hydrogen. In some embodiments, R^1aIs unsubstituted benzyl; and R^1bIs hydrogen. In some embodiments, R^1aIs a substituted benzyl group; and R^1bIs hydrogen. In some embodiments, R^1aIs a monosubstituted benzyl group; and R^1bIs hydrogen. In some embodiments, R^1aIs benzyl substituted by one example of halogen; and R^1bIs hydrogen. In some embodiments, R^1aIs optionally substituted C_2–6An alkenyl group; and R^1bIs hydrogen. In some embodiments, R^1aIs an optionally substituted vinyl group; and R^1bIs hydrogen. In some embodiments, R ^1aIs unsubstituted vinyl; and R^1bIs hydrogen. In some embodiments, R^1aIs an optionally substituted allyl group; and R^1bIs hydrogen. In some embodiments, R^1aIs unsubstituted allyl; and R^1bIs hydrogen. In some embodiments, R^1aIs an optionally substituted carbocyclyl; and R^1bIs hydrogen. In some embodiments, R^1aIs optionally substituted C_3–6A carbocyclic group; and R^1bIs hydrogen. In some embodiments, R^1aIs an optionally substituted cyclopropyl group; and R^1bIs hydrogen. In some embodiments, R^1aIs unsubstituted cyclopropyl; and R^1bIs hydrogen.

In some embodiments, R^2aAnd R^2bAt least one of which is hydrogen. In some embodiments, R^2aAnd R^2bAre both hydrogen. In some embodiments, R^2aAnd R^2bAre not hydrogen. In some embodiments, R^2aIs optionally substituted C_1–6An alkyl group; and R^2bIs hydrogen. In some embodiments, R^2aIs optionally substituted C_1–2An alkyl group; and R^2bIs hydrogen. In some embodiments, R^2ais-CH₃(ii) a And R^2bIs hydrogen. In some embodiments, R^2aAnd R^2bAre all-CH₃. In some embodiments, R^2aIs optionally substituted haloalkyl; and R^2bIs hydrogen. In some embodiments, R^2ais-CF₃(ii) a And R^2bIs hydrogen. In some embodiments, R ^2aIs halogen; and R^2bIs hydrogen. In some embodiments, R^2ais-F; and R^2bIs hydrogen. In some embodiments, R^2aIs halogen; and R^2bIs C_1–6An alkyl group. In some embodiments, R^2ais-F; and R^2bIs C_1–6An alkyl group. In some embodiments, R^2aIs halogen; and R^2bis-CH₃. In some embodiments, R^2ais-F; and R^2bis-CH₃。

In some embodiments, R⁴The carbon attached is the stereocenter of the (R) -configuration. In some embodiments of the present invention, the substrate is,R⁴the attached carbon is the stereocenter of the (S) -configuration. In some embodiments, R³Is hydrogen; and R⁴Is not hydrogen. In some embodiments, R³And R⁴Are not hydrogen. In some embodiments, R³Is hydrogen. In some embodiments, R³Is optionally substituted C_1–6An alkyl group. In some embodiments, R³Is optionally substituted C_1–2An alkyl group. In some embodiments, R³is-CH₃. In some embodiments, R³Is optionally substituted C_2–6An alkenyl group. In some embodiments, R³Is an optionally substituted allyl group. In some embodiments, R³Is unsubstituted allyl. In some embodiments, R³Is allyl substituted with one optionally substituted heteroaryl ring. In some embodiments, R ³Is allyl substituted with one optionally substituted quinoline ring. In some embodiments, R³Is hydrogen; and R⁴is-CH₃. In some embodiments, R³Is optionally substituted C_1–6An alkyl group; and R⁴is-CH₃. In some embodiments, R³Is optionally substituted C_1–2An alkyl group; and R⁴is-CH₃. In some embodiments, R³is-CH₃(ii) a And R⁴is-CH₃. In some embodiments, R³Is optionally substituted C_2–6An alkenyl group; and R⁴is-CH₃. In some embodiments, R³Is an optionally substituted allyl group; and R⁴is-CH₃. In some embodiments, R³Is unsubstituted allyl; and R⁴is-CH₃. In some embodiments, R³Is allyl substituted with one optionally substituted heteroaryl ring; and R⁴is-CH₃. In some embodiments, R³Is allyl substituted with one optionally substituted quinoline ring; and R⁴is-CH₃. In some embodiments, R⁴Is optionally substituted C_1–6An alkyl group. In some casesIn the embodiment, R⁴Is optionally substituted C_1–2An alkyl group. In some embodiments, R⁴is-CH₃. In some embodiments, R⁴Is optionally substituted C_2–6An alkenyl group. In some embodiments, R⁴Is an optionally substituted allyl group. In some embodiments, R ⁴Is unsubstituted allyl. In some embodiments, R⁴Is allyl substituted with an optionally substituted heteroaryl ring. In some embodiments, R⁴Is allyl substituted with one optionally substituted quinoline ring. In some embodiments, R⁴is-CH₂CH₂And (5) OH. In some embodiments, R⁴is-CH₂CH₂N(R²²)₂. In some embodiments, R⁴is-CH₂CH₂N(R²²)₂(ii) a And R²²is-CH₃. In some embodiments, R⁴is-CH₂CHO. In some embodiments, R⁴Is optionally substituted C_1–6An alkyl group; and R³is-CH₃. In some embodiments, R⁴Is optionally substituted C_1–2An alkyl group; and R³is-CH₃. In some embodiments, R⁴Is optionally substituted C_2–6An alkenyl group; and R³is-CH₃. In some embodiments, R⁴Is an optionally substituted allyl group; and R³is-CH₃. In some embodiments, R⁴Is unsubstituted allyl; and R³is-CH₃. In some embodiments, R⁴Is allyl substituted with one optionally substituted heteroaryl ring; and R³is-CH₃. In some embodiments, R⁴Is allyl substituted with one optionally substituted quinoline ring; and R³is-CH₃. In some embodiments, R⁴is-CH₂CH₂OH; and R³is-CH ₃. In some embodiments, R⁴is-CH₂CH₂N(R²²)₂(ii) a And R³is-CH₃. In some embodiments, R⁴is-CH₂CH₂N(R²²)₂；R²²is-CH₃(ii) a And R³is-CH₃. In some embodiments, R⁴is-CH₂CHO; and R³is-CH₃. In some embodiments, R⁴Is optionally substituted C_1–6An alkyl group; and R³Is hydrogen. In some embodiments, R⁴Is optionally substituted C_1–2An alkyl group; and R³Is hydrogen. In some embodiments, R⁴Is optionally substituted C_2–6An alkenyl group; and R³Is hydrogen. In some embodiments, R⁴Is an optionally substituted allyl group; and R³Is hydrogen. In some embodiments, R⁴Is unsubstituted allyl; and R³Is hydrogen. In some embodiments, R⁴Is allyl substituted with one optionally substituted heteroaryl ring; and R³Is hydrogen. In some embodiments, R⁴Is allyl substituted with one optionally substituted quinoline ring; and R³Is hydrogen. In some embodiments, R⁴is-CH₂CH₂OH; and R³Is hydrogen. In some embodiments, R⁴is-CH₂CH₂N(R²²)₂(ii) a And R³Is hydrogen. In some embodiments, R⁴is-CH₂CH₂N(R²²)₂；R²²is-CH₃(ii) a And R³Is hydrogen. In some embodiments, R⁴is-CH₂CHO; and R³Is hydrogen. In some embodiments, R⁴Is optionally substituted C _1–6An alkyl group; and R²¹Is hydrogen. In some embodiments, R⁴Is optionally substituted C_1–2An alkyl group; and R²¹Is hydrogen. In some embodiments, R⁴Is optionally substituted C_2–6An alkenyl group; and R²¹Is hydrogen. In some embodiments, R⁴Is an optionally substituted allyl group; and R²¹Is hydrogen. In some embodiments, R⁴Is unsubstituted allylA group; and R²¹Is hydrogen. In some embodiments, R⁴Is allyl substituted with one optionally substituted heteroaryl ring; and R²¹Is hydrogen. In some embodiments, R⁴Is allyl substituted with one optionally substituted quinoline ring; and R²¹Is hydrogen. In some embodiments, R⁴is-CH₂CH₂OH; and R²¹Is hydrogen. In some embodiments, R⁴is-CH₂CH₂N(R²²)₂(ii) a And R²¹Is hydrogen. In some embodiments, R⁴is-CH₂CH₂N(R²²)₂；R²²is-CH₃(ii) a And R²¹Is hydrogen. In some embodiments, R⁴is-CH₂CHO; and R²¹Is hydrogen.

In some embodiments, R⁹Is hydrogen. In some embodiments, R⁹Is not hydrogen. In some embodiments, R⁹Is an oxygen protecting group. In some embodiments, R⁹Is composed ofIn some embodiments, R^SOIs hydrogen. In some embodiments, R^SOIs an oxygen protecting group. In some embodiments, R⁹Is methyl carbonate. In some embodiments, at least one R is ^SNIs hydrogen. In some embodiments, at least one R is^SNis-CH₃. In some embodiments, one R is^SNis-CH₃(ii) a And another R^SNIs hydrogen. In some embodiments, two R are^SNAre all-CH₃. In some embodiments, R^S4bIs hydrogen. In some embodiments, R^S4bIs not hydrogen. In some embodiments, R^S4bis-OR^SO(ii) a And R^SOIs hydrogen. In some embodiments, R^S4bis-OR^SO(ii) a And R^SOIs an oxygen protecting group. In some embodiments, R^S5aIs an optionally substituted alkyl group. In some embodiments, R^S5aIs an alkaneAn oxyalkyl group. In some embodiments, R^S5ais-CH₂And (5) OH. In some embodiments, R^S5ais-CH₂And (3) OBz. In some embodiments, R^S5aIs an aminoalkyl group. In some embodiments, R^S5ais-CH₂NH₂. In some embodiments, R⁹Is composed ofIn some embodiments, R⁹Is composed ofIn some embodiments, R⁹Is composed of

In some embodiments, R⁹Is composed of

In some embodiments, R⁹Is composed of

In some embodiments, R^5aAnd R^5bThe carbon attached is the stereocenter of the (R) -configuration. In some embodiments, R^5aAnd R^5bThe attached carbon is the stereocenter of the (S) -configuration. In some embodiments, R^5aAnd R^5bAt least one of which is hydrogen. In some embodiments, R ^5aAnd R^5bAre both hydrogen. In some embodiments, R^5aAnd R^5bAre not hydrogen. In some embodiments, R^5aAnd R^5bAt least one of (a) and (b) is an optionally substituted alkyl group. In some embodiments, R^5aAnd R^5bAt least one of (A) is optionally substituted C_1–6An alkyl group. In some embodiments, R^5aAnd R^5bAt least one of (A) is optionally substituted C_1–2An alkyl group. In some embodiments, R^5aAnd R^5bAt least one of isSubstituted C_1–2An alkyl group. In some embodiments, R^5aAnd R^5bAt least one of is-CH₃. In some embodiments, R^5aIs optionally substituted alkyl; and R^5bIs hydrogen. In some embodiments, R^5aIs optionally substituted C_1–6An alkyl group; and R^5bIs hydrogen. In some embodiments, R^5aIs optionally substituted C_1–2An alkyl group; and R^5bIs hydrogen. In some embodiments, R^5aIs unsubstituted C_1–2An alkyl group; and R^5bIs hydrogen. In some embodiments, R^5ais-CH₃(ii) a And R^5bIs hydrogen. In some embodiments, R^5aAnd R^5bAre all-CH₃. In some embodiments, R^5aAnd R^5bAre neither-CH₃。

In some embodiments, R¹⁷Is hydrogen. In some embodiments, R¹⁷Is not hydrogen. In some embodiments, R¹⁷Is an oxygen protecting group. In some embodiments, R ¹⁷is-C (═ O) R^Z8。

In some embodiments, R⁶And R¹⁰The carbon attached is the stereocenter of the (R) -configuration. In some embodiments, R⁶And R¹⁰The attached carbon is the stereocenter of the (S) -configuration. In some embodiments, R⁶And R¹⁰At least one of which is hydrogen. In some embodiments, R⁶And R¹⁰Are both hydrogen. In some embodiments, R⁶And R¹⁰Are not hydrogen. In some embodiments, R⁶And R¹⁰At least one of (a) and (b) is an optionally substituted alkyl group. In some embodiments, R⁶And R¹⁰At least one of (A) is optionally substituted C_1–6An alkyl group. In some embodiments, R⁶And R¹⁰At least one of (A) is optionally substituted C_1–2An alkyl group. In some embodiments, R⁶And R¹⁰At least one of is-CH₃. In some embodiments, R⁶And R¹⁰At least one ofis-CH₂And (C) CN. In some embodiments, R⁶And R¹⁰At least one of is-CH₂C(＝O)OR³²(ii) a And R³²Is optionally substituted alkyl or hydrogen. In some embodiments, R⁶And R¹⁰At least one of (a) is optionally substituted heteroaralkyl. In some embodiments, R⁶And R¹⁰At least one of (a) is an optionally substituted pyrazolylalkyl group. In some embodiments, R⁶And R¹⁰At least one of (a) is an imidazolylalkyl group. In some embodiments, R ⁶And R¹⁰At least one of (a) is a thiazolyl alkyl group. In some embodiments, R⁶And R¹⁰At least one of (a) is an oxazolidinyl group. In some embodiments, R⁶And R¹⁰At least one of (a) and (b) is a pyridylalkyl group. In some embodiments, R⁶And R¹⁰At least one of (a) is a pyrimidinylalkyl group. In some embodiments, R⁶And R¹⁰At least one of (a) is pyrazinylalkyl. In some embodiments, R⁶And R¹⁰At least one of (a) is an optionally substituted alkenyl group. In some embodiments, R⁶And R¹⁰At least one of (a) is an optionally substituted allyl group. In some embodiments, R⁶And R¹⁰At least one of (a) is an unsubstituted allyl group. In some embodiments, at least one is R⁶And R¹⁰Is an optionally substituted aralkyl group. In some embodiments, R⁶And R¹⁰At least one of (a) is an optionally substituted benzyl group. In some embodiments, R⁶And R¹⁰At least one of (a) is an unsubstituted benzyl group. In some embodiments, R⁶Is optionally substituted alkyl; and R¹⁰Is hydrogen. In some embodiments, R⁶Is optionally substituted C_1–6An alkyl group; and R¹⁰Is hydrogen. In some embodiments, R⁶Is optionally substituted C_1–2An alkyl group; and R¹⁰Is hydrogen. In some embodiments, R ⁶is-CH₃(ii) a And R¹⁰Is hydrogen. In some embodiments, R⁶is-CH₂CN; and R¹⁰Is hydrogen. In some embodiments, R⁶is-CH₂C(＝O)OR³²；R³²Is optionally substituted alkyl or hydrogen; and R¹⁰Is hydrogen. In some embodiments, R⁶Is optionally substituted heteroaralkyl; and R¹⁰Is hydrogen. In some embodiments, R⁶Is optionally substituted pyrazolyl alkyl; and R¹⁰Is hydrogen. In some embodiments, R⁶Is an imidazolyl alkyl group; and R¹⁰Is hydrogen. In some embodiments, R⁶Is thiazolyl alkyl; and R¹⁰Is hydrogen. In some embodiments, R⁶Is oxazolylalkyl; and R¹⁰Is hydrogen. In some embodiments, R⁶Is a pyridylalkyl group; and R¹⁰Is hydrogen. In some embodiments, R⁶Is a pyrimidinylalkyl group; and R¹⁰Is hydrogen. In some embodiments, R⁶Is pyrazinylalkyl; and R¹⁰Is hydrogen. In some embodiments, R⁶Is optionally substituted alkenyl; and R¹⁰Is hydrogen. In some embodiments, R⁶Is an optionally substituted allyl group; and R¹⁰Is hydrogen. In some embodiments, R⁶Is unsubstituted allyl; and R¹⁰Is hydrogen. In some embodiments, R⁶Is optionally substituted aralkyl; and R¹⁰Is hydrogen. In some embodiments, R⁶Is an optionally substituted benzyl group; and R ¹⁰Is hydrogen. In some embodiments, R⁶Is unsubstituted benzyl; and R¹⁰Is hydrogen. In some embodiments, R⁶And R¹⁰At least one of (a) and (b) is halogen. In some embodiments, R⁶And R¹⁰At least one of (a) and (b) is fluorine. In some embodiments, R⁶And R¹⁰Are all halogen. In some embodiments, R⁶And R¹⁰Are both fluorine. In some embodiments, R⁶Is optionally substituted alkyl; and R¹⁰Is halogen. In some embodiments, R⁶Is optionally substituted C_1–6An alkyl group; and R¹⁰Is halogen. In some embodiments, R⁶Is optionally substituted C_1–2An alkyl group;and R¹⁰Is halogen. In some embodiments, R⁶is-CH₃(ii) a And R¹⁰Is halogen. In some embodiments, R⁶Is optionally substituted alkyl; and R¹⁰Is fluorine. In some embodiments, R⁶Is optionally substituted C_1–6An alkyl group; and R¹⁰Is fluorine. In some embodiments, R⁶Is optionally substituted C_1–2An alkyl group; and R¹⁰Is fluorine. In some embodiments, R⁶is-CH₃(ii) a And R¹⁰Is fluorine.

In some embodiments, R¹⁴Is hydrogen. In some embodiments, R¹⁴Is not hydrogen. In some embodiments, R¹⁴Is composed of

And A¹is-N₃. In some embodiments, R¹⁴Is composed of

And L^C2Is a bond. In some embodiments, L is ^C1Is a linking group comprising at least one alkylene group which is optionally substituted. In some embodiments, L is^C1Is a linking group, at least one of which comprised is substituted or unsubstituted C_3–6An alkylene group. In some embodiments, L is^C1Is of the formula- (CH)₂)_n-wherein n is 3,4 or 5. In some embodiments, L is^C1Is a linking group, at least one of which is included is an optionally substituted alkenylene group. In some embodiments, L is^C1Is a linking group, at least one of which comprised is substituted or unsubstituted C_3–6An alkenylene group. In some embodiments, L is^C1Is a linker, at least one of which is optionally substituted alkynylene. In some embodiments, L is^C1A linking group comprising at least one substituted or unsubstituted C_3–6Alkynylene radical. In some embodiments, R²³Is an optionally substituted aryl group. In some embodiments, R²³Is optionally substituted phenyl. In some embodiments, R²³Is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R²³Is an optionally substituted aniline. In some embodiments, R²³Is an optionally substituted pyridazine. In some embodiments, R²³Is optionally substituted pyridine. In some embodiments, R ²³Is an optionally substituted aminopyridine. In some embodiments, R²³Is optionally substituted thiazole. In some embodiments, R²³Is an optionally substituted aminothiazole. In some embodiments, R²³Is optionally substituted thiadiazole. In some embodiments, R²³Is an optionally substituted aminothiadiazole. In some embodiments, R²³Is an optionally substituted 5,6 fused bicyclic heteroaryl. In some embodiments, R²³Is optionally substituted benzothiazole.

In some embodiments, known macrolides, such as those disclosed in figure 1, are specifically excluded. Exemplary novel macrolides of the invention include, but are not limited to, any of the following macrolides provided in tables a-L and salts thereof.

Pharmaceutical compositions and administration

The present invention provides a pharmaceutical composition comprising a macrolide described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients include any or all solvents, diluents or other liquid vehicles, dispersing agents, suspending agents, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. General considerations in formulating and/or preparing Pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, e.w. martin (mack publishing co., Easton, Pa.,1980) and Remington: The Science and Practice of pharmacy,21st Edition (Lippincott Williams & Wilkins, 2005).

The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacy. Generally, the process of preparation comprises the step of combining a macrolide of the invention with a carrier and/or one or more other auxiliary agents (access ingredients) and then, if necessary and/or desired, shaping and/or packaging the product into the desired single or multiple dosage units.

The pharmaceutical compositions may be prepared, packaged and/or sold in bulk form, as a single unit dose, and/or as multiple single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of a macrolide of the present invention. The amount of macrolide is typically equal to the dose of macrolide to be administered to the subject, and/or a convenient fraction of that dose, e.g., half or one third of that dose.

The relative amounts of macrolide, pharmaceutically acceptable excipient and/or any other ingredient in the pharmaceutical compositions of the invention will vary depending on the nature, size and/or condition of the subject being treated and also depending on the route by which the composition is to be administered. For example, the composition may comprise 0.1% to 100% (w/w) macrolide.

Pharmaceutically acceptable excipients used in the preparation of the pharmaceutical compositions provided herein include inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifiers, disintegrating agents, binders, preservatives, buffering agents, lubricants, and/or oils. Excipients such as cocoa butter and suppository waxes, colorants, coatings, sweeteners, flavorants and perfumes may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dicalcium phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponges, anion exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly (ethylene-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

Exemplary surfactants and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondlux, cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, and lecithin), colloidal clays (e.g., bentonite [ aluminum silicate ] and Veegum [ magnesium aluminum silicate ]), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glycerol monostearate, propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carbopol (carbopol oxypolymethylene), polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, cellulose powder, hydroxymethylcellulose, hydroxypropylcellulose, and mixtures thereof, Hydroxypropyl methylcellulose, methylcellulose), sorbitan esters of fatty acids (e.g., polyoxyethylene sorbitan monolaurate [ Tween 20], polyoxyethylene sorbitan [ Tween 60], polyoxyethylene sorbitan monooleate [ Tween 80], sorbitan monopalmitate [ Span40], sorbitan monostearate [ Span 60], sorbitan tristearate [ Span 65], glycerol monooleate, sorbitan monooleate [ Span 80], polyoxyethylene esters (e.g., polyoxyethylene monostearate [ Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylen stearate and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., cremophor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [ Brij 30]), poly (vinyl-pyrrolidone), Diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, pluronic F-68, poloxamer-188, cetrimide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, and the like), natural and synthetic gums (e.g., acacia, sodium alginate, carrageenin extract, pantoea, ghatti, mucilaginous mucilage of isapol husks, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly (vinyl-pyrrolidone), magnesium aluminum silicate (Veegum) and arabinogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohols, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, alcohol preservatives, acid preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, thioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate, disodium calcium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, nitropropanediol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerol, hexetidine, imidurea, phenol, phenoxyethanol, phenylethanol, phenylmercuric nitrate, propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, biphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

Exemplary acid preservatives include vitamin a, vitamin C, vitamin E, beta carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deferoxamine mesylate, cetrimide, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), ethylenediamine, Sodium Lauryl Sulfate (SLS), Sodium Lauryl Ether Sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methyl paraben, germll 115, Germaben II, Neolone, Kathon, and Euxyl. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium glucoheptonate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, dibasic calcium phosphate, phosphoric acid, calcium phosphate, calcium hydroxy phosphate, potassium acetate, potassium chloride, potassium gluconate, pottasium complex, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol, and mixtures thereof.

Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond oil, avocado oil, babassu (a species of babassu) oil, bergamot oil, black currant seed (black current seed) oil, borage oil, juniper oil, chamomile oil, canola oil, caraway oil, palm oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol oil, gourd oil, grape seed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, shiquan oil, lavender oil, lemon oil, orange oil, cubeb oil, hawaiana nut oil, mallow nut oil, mango kernel oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, sea bream oil, palm kernel oil, peach seed oil, poppy seed oil, meadowfoam seed oil, olive oil, sea buckthorn seed oil, hazelnut oil, sea buckthorn, Pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, camellia oil, savory (savoury) oil, sea buckthorn oil, sesame oil, cedar butter, silicone oil, soybean oil, sunflower oil, tea oil, thistle oil, ailanthus altissima oil, turfgrass oil, walnut oil and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride (capric triglyceride), capric triglyceride (capric triglyceride), cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the macrocyclic lactones, the liquid dosage forms may include inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In a specific embodiment for parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the prior art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable carriers and solvents that can be employed are water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

To prolong the effect of the drug, it is often necessary to slow the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the drug then depends on its rate of dissolution, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle.

Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax (which is solid at room temperature but liquid at body temperature) so that it melts in the rectum or vaginal cavity and releases the macrolide.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the macrolide is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, such as glycerol, (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents, such as paraffin, (f) absorption accelerators, such as quaternary ammonium compounds, (g) wetting agents, such as cetyl alcohol and glycerol monostearate, (h) absorbents, such as kaolin and bentonite, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may contain buffering agents.

Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally include opacifying agents and may be of such composition that they release the macrolide only or preferentially, optionally in a delayed manner, in a particular part of the intestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using, for example, the excipients lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The macrolide may be in microencapsulated form using one or more of the above excipients. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the art of pharmaceutical formulation. In the solid dosage form, the macrolide may be mixed with at least one inert diluent such as sucrose, lactose or starch. The dosage form may include, as is standard practice, other substances besides inert diluents, e.g., tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may include buffering agents. They may optionally include opacifying agents and may be of such composition that they release the macrolide only or preferentially, optionally in a delayed manner, in a particular part of the intestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of the macrolides of the present invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Typically, the macrolide is mixed under sterile conditions with a pharmaceutically acceptable carrier and/or any required preservatives and/or buffers. Furthermore, the present invention encompasses the use of transdermal patches, which generally have the additional advantage of providing controlled delivery of the macrolide to the body. The dosage form may be prepared, for example, by providing a solution and/or dispersion of the macrolide in a suitable medium. Alternatively or additionally, the speed may be controlled by providing a rate controlling membrane and/or by dispersing the macrolide into the polymer matrix and/or gel.

Suitable devices for delivering the intradermal pharmaceutical compositions described herein include short needle devices, such as described in the following patents: U.S. Pat. nos. 4,886,499; 5,190,521, respectively; 5,328,483, respectively; 5,527,288; 4,270,537, respectively; 5,015,235, respectively; 5,141,496, respectively; and 5,417,662. The intradermal composition may be administered by a device that limits the effective penetration length of the needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof. Suitable rapid injection devices deliver liquid vaccines to the dermis via a liquid rapid injector and/or via a needle that pierces the stratum corneum and produces a jet that reaches the dermis. Rapid injection devices are disclosed, for example, in us patent 5,480,381; 5,599,302, respectively; 5,334,144, respectively; 5,993,412, respectively; 5,649,912, respectively; 5,569,189, respectively; 5,704,911, respectively; 5,383,851, respectively; 5,893,397, respectively; 5,466,220, respectively; 5,339,163, respectively; 5,312,335, respectively; 5,503,627, respectively; 5,064,413, respectively; 5,520,639, respectively; 4,596,556, respectively; 4,790,824, respectively; 4,941,880, respectively; 4,940,460, respectively; and PCT publications WO 97/37705 and WO 97/13537. A suitable ballistic powder/particle delivery device uses compressed gas to accelerate the vaccine in powder form through the outer layer of the skin to the dermis. Alternatively or additionally, conventional syringes may be used for the classic mandible method of intradermal administration.

Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid formulations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions, such as creams, ointments and/or pastes and/or solutions and/or suspensions. Formulations which can be administered topically may, for example, contain from about 1% to about 10% (w/w) macrolide, although the concentration of macrolide may be as high as the solubility limit of the macrolide in the solvent. Formulations for topical administration may also contain one or more of the other ingredients described herein.

The pharmaceutical compositions of the present invention may be prepared, packaged and/or sold in a formulation suitable for oral administration for pulmonary administration. The formulation may include dry particles comprising a macrolide and having a diameter in the range of about 0.5 to about 7 nanometers or about 1 to about 6 nanometers. The compositions are conveniently administered in the form of a dry powder using a device comprising a dry powder reservoir into which a stream of propellant can be introduced to disperse the powder and/or using a self-propelled solvent/powder dispersion container, e.g. a device containing the macrolide dissolved and/or suspended in a low boiling propellant in a closed container. The powder comprises particles, wherein at least 98% by weight of the particles have a diameter greater than 0.5 nm and at least 95% by number of the particles have a diameter less than 7 nm. Alternatively, at least 95% by weight of the particles have a diameter greater than 1 nanometer and at least 90% by number of the particles have a diameter less than 6 nanometers. The dry powder composition may include a solid finely divided diluent (e.g. sugar) and is conveniently provided in unit dosage form.

Low boiling point propellants typically include liquid propellants, the boiling point of which is less than 65 ° F at atmospheric pressure. Typically, the propellant may comprise from 50 to 99.9% (w/w) of the composition and the macrolide may comprise from 0.1 to 20% (w/w) of the composition. The propellant may also include other ingredients such as liquid non-ionic and/or solid anionic surfactants and/or solid diluents (of a size of one order of magnitude to that of the macrolide-containing particles).

Pharmaceutical compositions of the invention configured for pulmonary delivery also provide macrolides in the form of droplets of solution and/or suspension. The formulations may be prepared, packaged and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions containing the macrolide, optionally sterile, and may conveniently be administered using any spraying and/or atomising device. The formulation may also contain one or more other ingredients including, but not limited to, flavoring agents (e.g., sodium saccharin), volatile oils, buffering agents, surfactants, and/or preservatives (e.g., methylparaben). The droplets provided by this route of administration may have an average diameter in the range of about 0.1 to about 200 nanometers.

The formulations described herein as useful for pulmonary delivery may be used for intranasal delivery of the pharmaceutical compositions of the present invention. Another formulation suitable for intranasal administration is a coarse powder comprising the macrolide and having an average particle of about 0.2 to 500 microns. The formulation is administered by rapid inhalation through the nasal passage from a powder container placed in the vicinity of the nostrils.

Formulations for nasal administration may, for example, comprise about as little as 0.1% (w/w) to as much as 100% (w/w) macrolide, and may comprise one or more of the other ingredients described herein. The pharmaceutical compositions of the present invention may be prepared, packaged and/or sold in a formulation for buccal administration. The formulations may, for example, be in the form of tablets and/or lozenges formulated using conventional methods and may comprise, for example, 0.1 to 20% (w/w) of an active ingredient comprising a balance of orally dissolving and/or degradable components, optionally one or more of the macrolides described herein. Alternatively, formulations for buccal administration may comprise a powder form comprising the macrolide and/or a vaporized and/or atomised solution and/or suspension. Upon dispersion, the powdered, vaporized and/or atomized formulation may have an average particle and/or droplet size in the range of about 0.1 to about 200 nanometers, and further comprise one or more other ingredients described herein.

The pharmaceutical compositions of the present invention may be prepared, packaged and/or sold in a formulation for ocular administration. The formulation may, for example, be in the form of eye drops comprising, for example, a solution and/or suspension of 0.1/1.0% (w/w) macrolide in an aqueous or oily liquid carrier. The eye drops may also include a buffer, a salt, and/or one or more other ingredients described herein. Other useful ophthalmic administrable formulations include those comprising the macrolide in microcrystalline and/or liposomal formulations. Ear drops and/or eye drops are also included in the scope of the present invention.

Although the description of the pharmaceutical compositions provided herein refers in principle to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that the compositions are generally suitable for administration to all kinds of animals. It will also be readily appreciated that modifications to pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals may be readily made, and that modifications may be devised and/or made by those skilled in the veterinary art using routine experimentation.

The macrolides provided herein are generally formulated in unit dosage form for ease of administration and uniformity of dosage. However, it will be appreciated that the total daily amount of macrolide used will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for a particular subject or organism will depend upon a variety of factors including the disease, disorder and condition to be treated and the severity of the disorder; the activity of the particular macrolide employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; time of administration, route of administration, and rate of excretion of the particular macrolide employed; the duration of treatment; drugs used in combination or concomitantly with the specific macrolide employed; and similar factors well known in the medical arts.

The macrolides and compositions provided herein may be administered by any route, including enterally (e.g., oral), parenterally, intravenously, intramuscularly, intraarterially, intramedullary, intramembranally, subcutaneously, intraventricularly, transdermally, intradermally (intradermal), rectally, intravaginally, intraperitoneally, topically (as powders, ointments, creams, and/or drops), mucosally, nasally, buccally, sublingually; by intratracheal instillation, bronchial instillation and/or inhalation; and/or as an oral spray, nasal spray and/or aerosol. Generally, the most suitable route of administration will depend on a variety of factors, including the nature of the agent, the treatment regimen, and/or the condition of the subject. Oral administration is the most preferred mode of administration. However, in some embodiments, the subject may be intolerant to oral administration, and thus intravenous, intramuscular, and/or rectal administration is also a preferred alternative mode of administration.

The exact amount of compound required to achieve an effective amount will vary from subject to subject, depending on, for example, the species, age, and general condition of the subject, the severity of the side effects or conditions, the nature of the particular macrolide, the mode of administration, and the like. The desired dose may be delivered three times daily, twice daily, once every other day, once every three days, once weekly, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, a desired dose can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

In some embodiments, an effective amount of macrolide for administration one or more times per day to a 70kg adult may comprise about 0.1mg to about 3000mg, about 0.1mg to about 2000mg, about 0.1mg to about 1000mg, about 0.1mg to about 100mg, about 1mg to about 100mg, or about 10mg to about 100mg of macrolide per unit dosage form.

In some embodiments, the dosage level of the macrolide of the invention may be sufficient to deliver from about 0.001mg/kg to about 100mg/kg of subject body weight, from about 0.01mg/kg to about 100mg/kg of subject body weight, from about 0.1mg/kg to about 100mg/kg of subject body weight, from about 0.5mg/kg to about 100mg/kg of subject body weight, from about 10mg/kg to about 100mg/kg of subject body weight, from about 20mg/kg to about 100mg/kg of subject body weight, and from about 25mg/kg to about 100mg/kg of subject body weight per day to achieve the desired therapeutic effect.

It will be appreciated that the macrolides or compositions described herein may be administered in combination with one or more other therapeutically active agents. The macrolide or composition may be administered simultaneously with, before or after one or more other therapeutically active agents. Generally, each drug may be administered at a dose and/or on a schedule determined for that drug. It is further understood that the other therapeutically active agents used in the combination may also be administered together in a single composition or separately in different compositions. The particular combination employed in the dosage regimen will take into account the compatibility of the macrolide of the invention with other therapeutically active agents, and/or the desired therapeutic effect to be achieved. In general, it is contemplated that the other therapeutically active agents used in combination are used at levels not exceeding those when they are used alone. In some embodiments, the levels used in combination will be lower than they are used alone.

In any of the above methods, one or more additional therapeutic agents (also referred to as "drugs") may be administered simultaneously with, before or after the macrolide of the invention. The medicament may be for simultaneous use with (simultaneous administration of) the macrolide of the invention, for administration before or after (sequential administration of) the macrolide of the invention or any combination thereof. For example, in some embodiments, the drug may be administered first, followed by simultaneous administration of the drug and macrolide of the invention. In some embodiments, the macrolide of the invention is administered first, followed by the simultaneous administration of the drug and macrolide of the invention. In any of the above embodiments, the medicaments or macrolides of the invention may be further administered separately following simultaneous administration.

Exemplary additional therapeutically active agents include, but are not limited to, antibiotics, antivirals, anesthetics, anticoagulants, enzyme inhibitors, steroidal drugs, steroidal or non-steroidal anti-inflammatory drugs, antihistamines, immunosuppressants, antigens, vaccines, antibodies, decongestants, sedatives, opioids, pain relief medications, analgesics, antipyretics (anti-pyretics), hormones, and prostaglandins. Therapeutically active agents include small organic molecules such as pharmaceutical compounds (e.g., compounds approved by the U.S. food and drug administration according to federal regulations (CFR)), therapeutically active agents, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

In some embodiments, the additional therapeutically active agent is an antibiotic. Exemplary antibiotics include, but are not limited to, penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g., cephalexin), macrolides (e.g., erythromycin, clarithromycin, azithromycin, oleandomycin), fluoroquinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin), sulfonamides (e.g., cotrimine, trimethoprim), tetracyclines (e.g., tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, doxycycline, chlortetracycline, oxytetracycline, minocycline, 6-desoxytetracycline, lycycline, meclocycline, methacycline, roxycycline and glycylcycline antibiotics (e.g., tigecycline)), aminoglycosides (e.g., gentamycin, tobramycin, paromomycin), aminocyclopolyols (e.g., spectinomycin), chloramphenicol, spiramycin and quinupristin/dalfopristin (synderid)^TM)。

The invention also includes kits (e.g., pharmaceutical packages). The provided kits may include the inventive pharmaceutical compositions or macrolides and a container (e.g., a vial, ampoule, bottle, syringe, and/or dispensable package or other suitable container). In some embodiments, provided kits may also optionally include a second container comprising a pharmaceutically acceptable excipient for diluting or suspending the inventive pharmaceutical composition or macrolide. In some embodiments, the pharmaceutical composition or macrolide of the invention provided in a container and a second container are combined to form one unit dosage form.

Method of treatment

The present invention relates to the use of the macrolides of the invention for the treatment of infectious diseases, for example, fungal, bacterial, viral or parasitic infections, and for the treatment of inflammatory disorders. Macrolides are known to exhibit anti-bacterial and anti-parasitic activity. See, for example, Clark et al, Bioorganic & Medicinal Chemistry Letters (2000)10: 815-819 (anti-bacterial activity); and Lee et al, j.med.chem. (2011)54: 2792-. Macrolides are also known to exhibit anti-inflammatory effects. See, for example, Amsden, Journal of Antichronobiochemical therapy (2005)55: 10-21 (Chronic Pneumoniae).

Thus, as generally described herein, there is provided a method of treating an infectious disease comprising administering to a subject in need thereof an effective amount of a macrolide of the invention or a pharmaceutically acceptable salt thereof. Such methods can be performed in vivo (i.e., by administration to a subject) or in vitro (e.g., contact with a pathogen, tissue, or cell culture). Treatment as used herein includes both therapeutic treatment and prophylactic treatment.

In some embodiments, the effective amount is a therapeutically effective amount. For example, in some embodiments, the method slows progression of an infectious disease in the subject. In some embodiments, the method improves the condition of a subject having an infectious disease. In some embodiments, the subject is suspected of having an infectious disease or does have an infectious disease.

In some embodiments, the effective amount is a prophylactically effective amount. For example, in some embodiments, the method prevents or reduces the likelihood of an infectious disease, e.g., in some embodiments, the method comprises administering to a subject in need thereof a macrolide of the invention in an amount sufficient to prevent or reduce the likelihood of an infectious disease. In some embodiments, the subject is at risk for an infectious disease (e.g., has been exposed to another subject suspected of having an infectious disease or indeed has an infectious disease, or has been exposed to or is considered to have been exposed to a pathogen).

In another aspect, provided herein is an in vitro method of inhibiting the growth of a pathogen, comprising contacting an effective amount of a macrolide of the invention with a pathogen (e.g., a bacterium, virus, fungus, or parasite) in cell culture.

As used herein, "infectious disease" and "microbial infection" are used interchangeably and refer to infection by a pathogen, such as a fungus, bacterium, virus, or parasite. In some embodiments, the infectious disease is caused by an agent that is resistant to other treatments. In some embodiments, the infectious disease is caused by a pathogen that has multidrug resistance or drug resistance, e.g., the infectious disease is caused by a pathogen that neither grows nor dies in the presence of other treatments or that neither grows nor dies as a result of other treatments.

In some embodiments, the infectious disease is a bacterial infection. For example, in some embodiments, provided herein is a method of treating a bacterial infection comprising administering to a subject in need thereof an effective amount of a macrolide of the invention or a pharmaceutically acceptable salt thereof.

In some embodiments, the macrolide has a Mean Inhibitory Concentration (MIC) less than 50 μ g/mL, less than 25 μ g/mL, less than 20 μ g/mL, less than 10 μ g/mL, less than 5 μ g/mL, or less than 1 μ g/mL for a particular bacterium.

In some embodiments, the bacteria are sensitive (e.g., responsive) or resistant to known commercial macrolides such as azithromycin, clindamycin, telithromycin, erythromycin, spiramycin, and the like. Reference is also made to FIG. 1, which lists known macrolides. In some embodiments, the bacterium is resistant to a known macrolide. For example, in some embodiments, the bacterium is anti-Erythromycin (ER).

In some embodiments, the bacterial infection is resistant to other antibiotic (e.g., non-macrolide) therapies. For example, in some embodiments, the pathogen is vancomycin-resistant (VR). In some embodiments, the pathogen is methicillin-resistant (MR), for example, in some embodiments, the bacterial infection is a methicillin-resistant staphylococcus aureus infection (MRSA infection).

In some embodiments, the bacterium has an efflux (e.g., mef, msr) genotype. In some embodiments, the bacterium has a methylase (e.g., erm) genotype. In some embodiments, the bacterium has a constitutive genotype. In some embodiments, the bacterium has an inducible genotype.

Exemplary bacterial interference includes, but is not limited to, bacterial infections of: gram-positive bacteria (e.g., phylum actinomycetes, phylum firmicutes, or phylum tenericutes); gram-negative bacteria (e.g., phylum aquaticum (phylum Aquiforce), phylum Thermus (phylum Deinococcus-Thermus), phylum filamentous/green/bacteroides (phylum Fibrobacter/chlorobi/Bacteroides (FCB)), phylum Fusobacterium (phylum Fusobacterium), phylum geometimonade, phylum Nitrospira (phylum Ntrospirae), phylum Apylobacter/Micromyces verruculosus/Chlamydia (PVC)), phylum Proteobacterium (phylum Proteobacterium), phylum spirochaeta (Spirochaetes), or phylum heterotrophytes (phylum Synergites)); or other bacteria (e.g., phylum Acidobacterium, phylum Chlorobium, phylum Chloroflexi, phylum Chrysogenetes, phylum Cyanobacterium, phylum deferribacteria, phylum Dictyoglycobacterium, phylum Dictyoglomi, phylum Thermobacter, or phylum Thermotoga).

In some embodiments, the bacterial infection is a gram-positive bacterial infection.

In some embodiments, the gram-positive bacterium is a bacterium of the phylum firmicutes.

In some embodiments, the bacterium is a member of the phylum firmicutes and Enterococcus (genus Enterococcus), i.e., the bacterial infection is an Enterococcus infection. Exemplary enterococcus bacteria include, but are not limited to, enterococcus avium (e.avium), enterococcus durans (e.durans), enterococcus faecalis (e.faecis), enterococcus faecium (e.faecium), enterococcus gallinarum (e.gallinarum), enterococcus insulans (e.solitarius), enterococcus casseliflavus (e.casseliflavus), and enterococcus raffinosus (e.raffinosus).

In some embodiments, the bacterium is a member of the phylum firmicutes and Staphylococcus (genus Staphylococcus), i.e., the bacterial infection is a Staphylococcus infection. Exemplary staphylococcus bacteria include, but are not limited to: staphylococcus aureus (s.arlettae), staphylococcus aureus (s.aureus), staphylococcus aureus (s.auricularis), staphylococcus capitis (s.capitis), staphylococcus caprae (s.caprae), staphylococcus carnosus (s.carnosus), staphylococcus chromogenes (s.chromomogens), staphylococcus cohnii (s.cohii, s.contrast, s.creosolvestris, staphylococcus dolphin (s.delphini), s.devriesei, staphylococcus epidermidis (s.epidermidis), staphylococcus equinovarum (s.equivum), staphylococcus felis (s.felis), s.flu, staphylococcus gallinarum (s.gallinarum), staphylococcus haemolyticus (s.haemolyticus), staphylococcus hominis(s), staphylococcus suis (s.hyicus), staphylococcus intermedium (s.intermedium), staphylococcus aureus (s.intestinalis), staphylococcus aureus (s.tenuis), staphylococcus lentus (s.s.tenuis), staphylococcus lentus (s.s.s.fermentation Staphylococcus saprophyticus, staphylococcus schleiferi (s.schleiferi), staphylococcus squirrel (s.sciuri), s.simiae, s.simulans, s.stepanovicii, s.succininus, s.vitulinus, staphylococcus wovensis (s.wanneri), and staphylococcus xylosus (s.xylosus). In some embodiments, the staphylococcal infection is a staphylococcus aureus infection. In some embodiments, the staphylococcus aureus has an efflux (e.g., mef, msr) genotype. In some embodiments, the staphylococcus aureus has a methylase (e.g., erm) genotype.

In some embodiments, the bacterium is a member of the phylum firmicutes and the genus Bacillus (genus Bacillus), i.e., the bacterial infection is a Bacillus infection. Exemplary bacillus bacteria include, but are not limited to: bacillus alcalophilus (b.alcalophilus), bacillus alvei (b.alvei), bacillus aminophagus (b.aminovorans), bacillus amyloliquefaciens (b.amyloliquefaciens), bacillus thiolyticus (b.aminourolyticus), bacillus anthracis (b.antrhacis), b.aquaris, bacillus atrophaeus (b.atrophaeus), b.boroniphilus, bacillus brevis (b.bris), bacillus caldolyticus (b.caldolyticus), bacillus mesosporus (b.centrosporus), bacillus cereus (b.cereus), bacillus circulans (b.circulans), bacillus subtilis (b.coelogens), bacillus firmus (b.fischeri), bacillus flavus (b.flavus), bacillus fusobacterium (b.fusciparum), bacillus subtilis (b.sporotrichioides), bacillus megaterium (b.macrorrhinum), bacillus megaterium (b.granulosus), bacillus megaterium (b.laterosporus), bacillus mucilaginosus), bacillus megaterium (b.bacillus megaterium), bacillus megaterium (b.laterosporus), bacillus megateri (b.granulosus) Bacillus natto (b.natto), bacillus pantothenic acid (b.panto), bacillus polymyxa (b.polymyxa), bacillus pseudoanthracis (b.pseudoanthrasis), bacillus pumilus (b.pumlius), bacillus schlegelii (b.schlegelii), bacillus sphaericus (b.sphaericus), b.sporotherm moderans, bacillus stearothermophilus (b.stearothermophilus), bacillus subtilis (b.subtilis), bacillus thermoglucosides (b.thermoglucosidasius), bacillus thuringiensis (b.thuringiensis), bacillus vulgaris (b.vulgatitis), and b.phasehenensis. In some embodiments, the bacillus infection is a bacillus subtilis infection. In some embodiments, the bacillus subtilis has an efflux (e.g., mef, msr) genotype. In some embodiments, the bacillus subtilis methylase (e.g., erm) genotype.

In some embodiments, the bacterium is a member of the phylum firmicutes and streptococcus. That is, the bacterial infection is a streptococcal infection. Exemplary streptococcus bacteria include, but are not limited to, streptococcus agalactiae (s.agalactiae), streptococcus anginosus (s.anginosus), streptococcus bovis (s.bovis), streptococcus canis (s.canis), streptococcus anginosus (s.constellatus), streptococcus dysgalactiae (s.dysgalactiae), streptococcus equi (s.equinus), streptococcus iniae (s.iniae), streptococcus intermedius (s.intermedia), streptococcus mitis (s.mitis), streptococcus mutans(s), streptococcus oralis (s.oralis), streptococcus paracoccus (s.paraangualis), s.peroris, streptococcus pneumoniae (s.pneumoniae), streptococcus pyogenes (s.pyogenes), streptococcus murinus (s.ratus), streptococcus salivarius (s.salivarius), subspecies salivarius (s.thermophilus), streptococcus sanguis thermophilus (s.thermophilus), streptococcus uberis (s.streptococcus uberis), streptococcus uberis (s.green streptococcus suis), streptococcus uberis (s.streptococcus uberis). In some embodiments, the streptococcal infection is a streptococcus pyogenes infection. In some embodiments, the streptococcal infection is a streptococcus pneumoniae infection. In some embodiments, the streptococcus pneumoniae has an efflux (e.g., mef, msr) genotype. In some embodiments, the streptococcus pneumoniae has a methylase (e.g., erm) genotype.

In some embodiments, the bacterial infection is a gram-negative bacterial infection.

In some embodiments, the gram-negative bacteria are bacteria of the phylum proteobacteria and the genus escherichia (genese escherichia). That is, the bacterial infection is an escherichia infection. Exemplary escherichia bacteria include, but are not limited to, escherichia coli (e.albertii), escherichia mantis (e.blattae), escherichia coli, escherichia fergusonii, escherichia coli (e.hermannii), and escherichia wounding (e.vulneris). In some embodiments, the escherichia infection is an escherichia coli infection.

In some embodiments, the gram-negative bacteria are bacteria of the phylum bacteroidetes and the genus haemophilus (genushaemaphilus). That is, the bacterial infection is a haemophilus infection. Exemplary Haemophilus bacteria include, but are not limited to, Haemophilus aegyptius (h.aegyptius), Haemophilus foamphilus (h.aphrophilus), pasteurella avicularis (h.avium), Haemophilus ducreyi (h.ducreyi), h.felis, Haemophilus haemolyticus (h.haemolyticus), Haemophilus influenzae (h.infiluenzae), Haemophilus parainfluenzae (h.paraflunuue), Haemophilus parahaemophilus (h.parahaemophilus), h.pittmania, Haemophilus inerticus (haemangphilus segnis), and Haemophilus somnus (h.somnus). In some embodiments, the escherichia infection is a haemophilus influenzae infection.

In some embodiments, the infectious disease is a parasitic infection. Thus, in some embodiments, provided herein are methods of treating a parasitic infection comprising administering to a subject in need thereof an effective amount of a macrolide of the invention or a pharmaceutically acceptable salt thereof.

In some embodiments, the macrolide has an IC of less than 50uM, less than 25uM, less than 20uM, less than 10uM, less than 5uM, or less than 1uM against a particular parasite₅₀(uM)。

Exemplary parasites include, but are not limited to, Trypanosoma spp (e.g., Trypanosoma cruzi (Trypanosoma cruzi), Trypanosoma brucei (Trypanosoma brucei), leishmania spp (leishmania spp.), Giardia spp (Giardia spp.), Trichomonas spp (Trichomonas spp.), amebiasis (entamoeba spp.), Plasmodium sp), Plasmodium spp (natamoeba spp.), Plasmodium spp.), amebiasis (Naegleria spp.), amebiasis spp. (Acanthamoeba spp.), hematophaga spp (Schistosoma spp.), Plasmodium spp (Plasmodium spp.), cryptosporium (crysporum, Plasmodium sp.), Plasmodium parvum (Plasmodium parvum), cryptosporium spp (cryptosporidium parvum, Plasmodium sp., Isospora, Plasmodium parvum (Plasmodium parvum), Toxoplasma (Plasmodium parvum, Plasmodium parvus (e.e.g.), Toxoplasma (Toxoplasma spp.), Toxoplasma (e.e.g.p (Toxoplasma spp.), and Toxoplasma (e.g.

The present invention further relates to a method of treating an inflammatory disorder comprising administering to a subject in need thereof an effective amount of a macrolide of the invention or a pharmaceutically acceptable salt thereof, as generally described herein. The method can be performed in vivo (i.e., by administration to a subject) or in vitro (e.g., contact with pathogens, tissues, and cell cultures). Treatment as used herein includes both therapeutic treatment and prophylactic treatment.

In some embodiments, the effective amount is a therapeutically effective amount. For example, in some embodiments, the method slows progression of an inflammatory disorder in the subject. In some embodiments, the method improves the condition of a subject having an inflammatory disorder. In some embodiments, the subject is suspected of having an inflammatory disorder or does have an inflammatory disorder.

In some embodiments, the effective amount is a prophylactically effective amount. For example, in some embodiments, the method prevents or reduces the likelihood of an inflammatory disorder, e.g., in some embodiments, the method comprises administering to a subject in need thereof a macrolide of the invention in an amount sufficient to prevent or reduce the likelihood of an inflammatory disorder. In some embodiments, the subject is at risk for an inflammatory disorder.

In another aspect, the invention provides a method of treating an inflammatory disorder in vitro comprising contacting an effective amount of a macrolide of the invention with an inflammatory cell culture.

The term "inflammatory disorder" refers to those diseases, disorders or conditions characterized by the following symptoms: pain (dolor), resulting from the production of toxicants and stimulation of nerves), fever (burning), resulting from vasodilation), redness (red), resulting from vasodilation and increased blood flow), swelling (tumor), resulting from excessive inflow and outflow of fluid limited) and/or loss of function (functional disease), which may be partial or complete, temporary or permanent. Inflammation exhibits a variety of forms, and includes, but is not limited to, acute inflammation, mucositis, atrophic inflammation, catarrhal inflammation, chronic inflammation, sclerosing inflammation, diffuse inflammation, disseminated inflammation, exudative inflammation, fibrous inflammation, fibrosing inflammation, focal inflammation, granulomatous inflammation, proliferative inflammation, hypertrophic inflammation, interstitial inflammation, metastatic inflammation, necrotic inflammation, occlusive inflammation, parenchymal inflammation, plastic inflammation (plactic), productive inflammation, proliferative inflammation, pseudomembranous inflammation, purulent inflammation, sclerogenic inflammation, serous fibrinous inflammation (serotic), serous inflammation, simple inflammation, specific inflammation, subacute inflammation, purulent inflammation, toxic inflammation, traumatic inflammation, and/or ulcerative inflammation.

Exemplary inflammatory disorders include, but are not limited to, inflammation associated with: acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), chronic pulmonary inflammatory syndrome (e.g., diffuse panbronchiolitis, cystic fibrosis, asthma, bronchiectasis, chronic obstructive pulmonary disease), arteritis (e.g., polyarteritis, temporal arteritis, polyarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, and Reiter's arthritis), ankylosing spondylitis, amyloidosis, amyotrophic lateral sclerosis, autoimmune disease, allergic disease or reaction, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, dermatomyositis (dermatomyositis), and inflammatory bowel disease, Diverticulitis, diabetes (e.g., type I diabetes, type 2 diabetes), skin conditions (e.g., psoriasis, eczema, burns, dermatitis, itch (pruritus)), endometriosis, Guillain-Barre syndrome (Guillain-Barre syndrome), infections, ischemic heart disease, Kawasaki disease (Kawasaki disease), glomerulonephritis, gingivitis, hypersensitivity, headache (e.g., migraine, tension headache), ileus (e.g., ileus during post-operative ileus and sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (bladder pain syndrome), gastrointestinal disorders (e.g., selected from peptic ulcer, crohn's disease, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, colitis) Gastritis, diarrhea, gastroesophageal reflux disease (GORD or its synonym GERD), Inflammatory Bowel Disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, beckett's syndrome, indeterminate colitis, and Inflammatory Bowel Syndrome (IBS)), lupus, multiple sclerosis, maculopathy, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcer, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, chronic inflammation associated with radiation injury of the cranium, chronic inflammation associated with radiation injury of the head, chronic inflammation associated with chronic inflammation of the head, chronic inflammation associated with inflammatory bowel disease, chronic inflammation of the head disease, chronic head disease, and head disease, Inflammatory diseases of the pelvis, reperfusion injury, crohn's disease, rheumatic fever, systemic lupus erythematosus, scleroderma, scierodoma, sarcoidosis, spondyloarthritis (spondyloarthophies), Sjogren's syndrome, thyroiditis, transplant rejection, tendonitis, trauma or injury (e.g., chilblain, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo, and Wegener's granulomatosis.

In some embodiments, the inflammatory disorder is an acute inflammatory disorder (e.g., inflammation resulting from infection). In some embodiments, the inflammatory disorder is a chronic inflammatory disorder. In some embodiments, the inflammatory disorder is inflammation associated with cancer.

Diastereoselective aldol process

During the construction of the west half (a), it was found that pseudoephedrine glycinamide undergoes highly selective addition to aldehydes and ketones, yielding a product with high diastereoselectivity in a single step. See, e.g., scheme W1. This reaction is believed to be broadly applicable to the use of other chiral adjuvants such as pseudoephedrine glycinamide in combination with a wide range of aldehydes and ketones.

Scheme W1.

Wherein:

R²⁵is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or a nitrogen protecting group;

R²⁶and R²⁷Each independently is optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl;

P²is hydrogen, optionally substituted alkyl or an oxygen protecting group; and

R²⁹is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

R⁸Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

or wherein R is⁸And R²⁹May together form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl ring;

G¹is-OR¹²or-NR¹³R¹⁴；

R¹²Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group; and

R¹³and R¹⁴Each independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocychcCyclyl, optionally substituted aryl, optionally substituted heteroaryl or a nitrogen protecting group, or R¹³And R¹⁴The binding forms a cyclic moiety.

In some embodiments, R²⁵Is optionally substituted C_1-6An alkyl group. In some embodiments, R²⁵Is unsubstituted C_1-6An alkyl group. In some embodiments, R²⁵Is methyl. In some embodiments, R²⁵Is ethyl. In some embodiments, R²⁵Is a nitrogen protecting group.

In some embodiments, R ²⁶And R²⁷Each independently is an optionally substituted alkyl group. In some embodiments, R²⁶And R²⁷At least one of which is independently optionally substituted C_1-6An alkyl group. In some embodiments, R²⁶And R²⁷At least one of which is an unsubstituted alkyl group. In some embodiments, R²⁶And R²⁷At least one of which is methyl. In some embodiments, R²⁶And R²⁷At least one of which is ethyl.

In some embodiments, R²⁶And R²⁷Each independently is an optionally substituted aryl group. In some embodiments, R²⁶And R²⁷Is independently an optionally substituted aryl group. In some embodiments, R²⁶And R²⁷At least one of which is independently an optionally substituted phenyl group. In some embodiments, R²⁶And R²⁷Is independently unsubstituted phenyl. In some embodiments, R²⁶And R²⁷Are both optionally substituted phenyl groups. In some embodiments, R²⁶And R²⁷Are both unsubstituted phenyl groups. In some embodiments, R²⁶Is optionally substituted C_1-6Alkyl and R²⁷Is an optionally substituted aryl group. In some embodiments, R²⁶Is unsubstituted C_1-6Alkyl and R²⁷Is optionally substituted phenyl. In some embodiments, R²⁶Is methyl and R²⁷Is phenyl.

In some casesIn embodiments, R²⁶And R²⁷Each independently is an optionally substituted heteroaryl group, e.g., pyridyl. In some embodiments, R²⁶And R²⁷Is an optionally substituted heteroaryl group. In some embodiments, R²⁶And R²⁷Are both optionally substituted heteroaryl. In some embodiments, R²⁶Is optionally substituted C_1-6Alkyl and R²⁷Is an optionally substituted heteroaryl group.

G as used herein¹is-OR¹²or-NR¹⁴R¹³Wherein R is¹²、R¹³And R¹⁴As defined above. In some embodiments, G¹is-NH₂. In some embodiments, G¹is-OH.

In some embodiments, P²Is hydrogen. In some embodiments, P²Is optionally substituted alkyl, e.g. C_1-6An alkyl group. In some embodiments, P²Is unsubstituted C_1-6An alkyl group. In some embodiments, P²Is an oxygen protecting group.

In some embodiments, R⁸And R²⁹Is different. In some embodiments, R²⁹Is in a ratio of R⁸Bulky (sterically) groups.

In some embodiments, R⁸And R²⁹At least one of which is optionally substituted alkyl, e.g. C_1-10An alkyl group. In some embodiments, R⁸And R²⁹At least one of which is unsubstituted C_1-10An alkyl group. In some embodiments, R ⁸And R²⁹At least one of which is substituted C_1-10An alkyl group.

In some embodiments, R⁸Is hydrogen. In some embodiments, R⁸Is hydrogen and R²⁹Is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R⁸Is hydrogen and R²⁹Is optionally substituted alkyl, e.g. C_1-10An alkyl group. In some embodiments, R⁸Is hydrogen and R²⁹Is an optionally substituted aryl group, for example, phenyl.

In some embodiments, R⁸Is an optionally substituted alkyl group, for example, methyl. In some embodiments, R⁸Is optionally substituted alkyl and R²⁹Is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R⁸Is optionally substituted alkyl and R²⁹Is optionally substituted alkyl, e.g. C_1-10An alkyl group. In some embodiments, R⁸Is optionally substituted alkyl and R²⁹Is an optionally substituted aryl group, for example, phenyl.

In some embodiments, R ⁸And R²⁹Together form an optionally substituted carbocyclic ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R⁸And R²⁹Together form an optionally substituted heterocyclyl ring, for example, oxetane, azetidine, tetrahydrofuran, pyrrolidine, pyran, dioxolane, piperidine, piperazine, or morpholine.

In some embodiments, the compound of formula (A-1) has the formula:

in some embodiments, the organic base is present in the aldol reaction of scheme W1. In some embodiments, the organic base is a group IA or IIA hydroxide or alkoxide, organolithium, organosodium, or organomagnesium. In some embodiments, the base is an organolithium. In some embodiments, the base is LDA. In some embodiments, the base is LiHMDS. In some embodiments, the base is NaHMDS. In some embodiments, a group IA or group IIA halide salt is present in the aldol reaction of scheme W1. In some embodiments, a group IA or group IIA halide salt is present with an organic base in the aldol reaction of scheme W1. In some embodiments, the halide salt is a lithium halide. In some embodiments, the halide salt is LiCl.

The diastereoselective aldol reaction can provide up to four diastereomeric products while forming two new stereogenic centers, as depicted in scheme W1. These products are generally rich in the stereoisomer of formula A-20, which is more than all other stereoisomers. In some embodiments, the aldol reaction of scheme W1 provides a ratio of the stereoisomer of formula a-20 to all other stereoisomers in a range from about 1:1 to about 100: 1. In some embodiments, the aldol reaction of scheme W1 provides a ratio of the stereoisomer of formula a-20 to all other stereoisomers of from about 1:1 to about 10: 1. In some embodiments, the aldol reaction of scheme W1 provides a ratio of the stereoisomer of formula a-20 to all other stereoisomers of from about 5:1 to about 10: 1. In some embodiments, the aldol reaction of scheme W1 provides a ratio of the stereoisomer of formula a-20 to all other stereoisomers of from about 10:1 to about 100: 1. In some embodiments, the aldol reaction of scheme W1 provides a ratio of the stereoisomer of formula a-20 to all other stereoisomers of from about 30:1 to about 100: 1. In some embodiments, the aldol reaction of scheme W1 provides a ratio of the stereoisomer of formula a-20 to all other stereoisomers of from about 50:1 to about 100: 1. In some embodiments, the aldol reaction of scheme W1 provides a ratio of the stereoisomer of formula a-20 to all other stereoisomers of from about 80:1 to about 100: 1. In some embodiments, the aldol reaction of scheme W1 provides a ratio of the stereoisomer of formula a-20 to all other stereoisomers of from about 90:1 to about 100: 1.

The aldol reaction product formula (a-20) can undergo further conversion, adding different functional groups, as shown in scheme W2. R as used herein³⁰Is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heterocycylAryl, hydroxy, substituted hydroxy, mercapto, substituted mercapto, amino or substituted amino. In some embodiments, R³⁰Is an optionally substituted alkyl group. In some embodiments, R³⁰Is a hydroxyl group. In some embodiments, R³⁰Is a substituted hydroxyl group. In some embodiments, R³⁰Is an amino group. In some embodiments, R³⁰Is a substituted amino group. In some embodiments, the compound of formula (A-20) is treated with an organometallic complex having a carbon-metal bond to provide the compound of formula (A-21) in the form of a ketone, wherein the metal is Li, Na, K, Mg, or Zn. In some embodiments, the organometallic complex is an organolithium. In some embodiments, the organometallic complex is an alkyl lithium (e.g., methyl lithium, ethyl lithium). In some embodiments, the organometallic complex is a grignard reagent (e.g., MeMgCl, EtMgCl, MeMgBr).

Scheme W2.

In some embodiments, heating the compound of formula (A-20) under proton-rich conditions provides the compound of formula (A-22) in the form of a carboxylic acid or ester, as shown in W3.

Scheme W3.

The term "proton-rich conditions" as used herein refers to a mixture of a protic or aprotic solvent with a proton source. Exemplary protic solvents include, but are not limited to, H₂O, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, and the like. The proton source may be an inorganic acid or an organic acid. Exemplary inorganic acids include, but are not limited to, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, and phosphoric acid. Exemplary organic acids include, but are not limited to, sulfonic acid (methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid), acetic acid, malic acid, fumaric acid, succinic acidCitric acid, benzoic acid, gluconic acid, lactic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, oxalic acid and maleic acid. In some embodiments, the proton-rich conditions are an aprotic solvent and a solvent for sulfuric acid.

R as used herein³¹Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl. In some embodiments, R ³¹Is optionally substituted alkyl, e.g. C_1-6An alkyl group. In some embodiments, R³¹Is unsubstituted C_1-6An alkyl group. In some embodiments, R³¹Is methyl, ethyl or propyl. In some embodiments, R³¹Is substituted C_1-6An alkyl group. In some embodiments, R³¹Is hydrogen.

In some embodiments, the compound of formula (a-20) is treated with a reducing agent to provide a compound of formula (a-23), which is an aldehyde as shown in W4. Examples of the reducing agent used in the scheme W4 include metal hydrides. In some embodiments, the reducing agent is lithium aluminum hydride, lithium borohydride, sodium borohydride, diisobutylaluminum hydride, or bis (2-methoxyethoxy) aluminum hydride. The amount of the reducing agent to be used may be selected within a range from equal to the compound of formula (A-20) to an excess amount relative to the compound of formula (A-20), as required.

Scheme W4

In some embodiments, the compound of formula (A-20) may be treated with a reducing agent to provide a compound of formula (A-24), which is the alcohol shown in scheme W5. Examples of the reducing agent used in the scheme W5 include metal hydrides. In some embodiments, the reducing agent is lithium aminoborohydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, diisobutylaluminum hydride, or bis (2-methoxyethoxy) aluminum hydride. The amount of the reducing agent to be used may be selected within a range from equal to the compound of formula (A-20) to an excess amount relative to the compound of formula (A-20), as required. In some embodiments, the reaction of scheme W4 is carried out in an inert gas such as nitrogen or argon.

Scheme W5.

In some embodiments, the compound of formula (A-20) may be treated with a reducing agent to provide a compound of formula (A-25), which is an amine as shown in scheme W6. Examples of the reducing agent used in the scheme W6 include metal hydrides. In some embodiments, the reducing agent is lithium aminoborohydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, diisobutylaluminum hydride, or bis (2-methoxyethoxy) aluminum hydride. The amount of the reducing agent to be used may be selected within a range from equal to the compound of formula (A-20) to an excess amount relative to the compound of formula (A-20), as required. In some embodiments, the reaction of scheme W4 is carried out in an inert gas such as nitrogen or argon.

Scheme W6

In some embodiments, compounds of formula (A-21) or formula (A-26) are treated with a phosphine to provide compounds of formula (A-27) or formula (A-28), respectively, shown in scheme W7. In some embodiments, an organic amine is present in the reaction of scheme W7. In some embodiments, the organic amine is a tertiary amine. In some embodiments, the tertiary amine is Et₂ ⁱPrN。

Scheme W7.

Construction of Western halves

The construction of the west moiety (a) (shown below, drawn in two different ways) used in the preparation of the macrolides of the invention involves the use of the inventive diastereoselective aldol process described herein. However, the synthesis of the west half using this aldol process described below is one of many methods for preparing the west half and should not limit the overall invention.

In some embodiments, the synthesis of the west half begins with treatment of (A-1) or a salt thereof with a base and then contacting with a compound of formula (A-2) or a salt thereof to yield an aldol product of formula (A-3) or a salt thereof, as shown in scheme W-8, scheme W-8.

Wherein R is⁸、R⁷、R²⁵、R²⁶、R²⁷、G¹、G³And P³As defined herein.

In some embodiments, the base is LiHMDS. In some embodiments, the base is LDA. In some embodiments, the reaction further comprises an additive such as LiCl.

In some embodiments, G¹is-NH₂The reaction yields an aldol product as shown in scheme W-9 or a salt thereof.

Scheme W-9.

In some embodiments, G¹is-NH₂And G³is-O-, the reaction affords an aldol product as shown in scheme W-10 or a salt thereof.

Scheme W-10.

In some embodiments, G¹to-OH, the reaction affords an aldol product as shown in scheme W-11 or a salt thereof.

Scheme W-11.

In some embodiments, G¹is-OH and G³is-O-, the reaction affords an aldol product as shown in scheme W-12 or a salt thereof.

Scheme W-12.

In some embodiments, wherein G¹is-OR¹²、–NHR¹³、–NHR¹⁴or-NR¹³R¹⁴And R¹²、R¹³And R¹⁴Protecting the free hydroxyl group of formula (A-3) or a salt thereof for a non-hydrogen group as described herein to provide a compound of formula (A-4) or a salt thereof, as shown in scheme W-13, wherein R ¹¹As defined herein.

Scheme W-13.

Or, wherein G¹is-NH₂、–NHR¹³or-NHR¹⁴First protecting the amino group and then protecting the alcohol to give a compound of formula (A-4) or a salt thereof, wherein G¹is-NHR¹³、–NHR¹⁴or-NR¹³R¹⁴As shown in scheme W-14.

Scheme W-14.

Or, in some embodiments, wherein G¹is-NH₂、–NHR¹³、–NHR¹⁴or-OH, amino and hydroxyl groups are simultaneously protected in the form of a cyclic carbamate or cyclic carbonate or a salt thereof, for example,after treatment with phosgene, as shown in scheme W-15.

Scheme W-15.

In some embodiments, with nucleophilic R^1aReagent treatment of a compound of formula (A-4) (wherein R¹¹And G¹As defined herein and may or may not be combined into a carbonate or carbamate) of a nucleophilic R, as defined herein)^1aThe reagent is, for example, R^1aM, where M is an anion, Li, Na, K, or MgX (where X is a halogen) to give a cleavage product of formula (A-5) or a salt thereof, as shown in scheme W-16. The resulting compounds are suitable tools for further diversification, e.g. reduction of the ketone moiety to give an alcohol, followed by conversion to a Leaving Group (LG), optionally followed by conversion to a nitro moiety, amination to an amine or imine, or use of a nucleophilic R^1bNucleophilic attack of a ketone or imine moiety by a reagent, said nucleophilic R^1bThe reagent is, for example, R ^1bM, wherein M is an anion, Li, Na, K or MgX, wherein X is a halogen, to give a tertiary alcohol or amine, wherein R is^1a、R^1b、R⁸、R⁷、R²⁵、R²⁶、R²⁷、R¹³、R¹⁴、G³、P²And P³As defined herein.

Scheme W-16.

In some embodiments, the compound of formula (A-4) is reduced, wherein R¹¹And G¹As defined herein and may or may not be combined into a carbonate or carbamate, to give an alcohol or salt thereof, as shown in scheme W-17. The resulting compounds are suitable tools for further diversification, e.g. oxidation to aldehydes and conversion to leaving groups, which are optionally converted to nitro compounds or amines, where LG, R^1a、R^1b、R⁸、R⁷、R²⁵、R²⁶、R²⁷、G¹、G³、P²And P³As defined herein.

Scheme W-17.

In some embodiments, the aldehyde or ketone described in scheme W-16 can be converted to a substituted amine using the route described in scheme W-18. Formation of Ellman sulfenimide followed by addition derived from R^1b(e.g., a grignard reagent or an organolithium reagent) followed by removal of the ancillary group yields the desired substituted amine, which has a relative stereochemistry.

Scheme W-18.

In some embodiments, a compound of formula (A-4) (wherein R is¹¹And G¹As defined herein) or a salt thereof into an acid, ester, activated acid or acid halide, ketone, iodoethylene, epoxide, or 1 carbon-added ketone or aldehyde, as shown in scheme W-19, wherein X, R ^1a、R^Z3、LG、R⁸、R⁷、R²⁵、R²⁶、R²⁷、G¹、G³、P²And P³As defined herein.

Scheme W-19.

In some embodiments, the phosphonate or phosphoylide of the west segment can be prepared such that the west segment is attached to the eastern half carbonyl moiety through an unsaturated ketone linker (see scheme W-20). The ester group can be chain extended to an intermediate that effects the addition of a carbon nucleophile containing a reactive phosphorus moiety.

Scheme W-20

Construction of east half

The present application further describes the construction of the eastern half (B) for use in the preparation of the macrolides of the invention. However, the synthesis of the eastern half described below is one of many ways to prepare the eastern half and should not limit the overall invention.

The present application generally describes the eastern half (B) and includes a group of the formula L3:

to obtain the compounds of the formula:

whereinz2、Y²、L²、R^2a、R^2b、R¹⁸、R¹⁹、R²⁰、R²¹、R^5a、R^5b、G²And R⁹As defined herein.

It is generally understood that the east half encompasses, for example, the formula (L)³-i)、(L³-ii) and (L)³-iii) such functional groups and these functional groups may be present in the starting materials and may be processed at any stage of the synthesis of the east half component. For example, as described above and in the present application, by eliminating-OR³Radical and reduction or functionalization of the double bond will (L)³-i) conversion of the group to (L)³-ii) and (L) ³-iii)。

In some embodiments, the preparation of the eastern half comprises the use of G as defined herein²The reagent is loaded on the aldehyde (A-1) or a salt thereofIs equipped with G²The group, optionally in the presence of a base, to give a compound of formula (A-2) or a salt thereof, as shown in scheme E-1.

Scheme E-1.

Wherein L is³、R^2a、R^2bAnd z2 is as defined herein,

the G is²The reagent is a compound of the formula:

wherein R is⁶、R¹⁰、R^5aAnd R^5bAs defined herein;

x in each case^G2is-OR¹⁵、–SR¹⁵or-N (R)¹⁵)₂；

R in each case¹⁵Independently is silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or two R¹⁵The groups may together form an optionally substituted heteroaryl or heterocyclic ring;

p in each case³And P⁶Independently is a silyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted carbocyclyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an oxygen protecting group;

or two R¹⁵The radicals combine to form a compound of the formula-C (R)^16a)₂A radical, giving a radical G of the formula²:

Or P⁶And R¹⁵Combined to form the formula-Si (R)^16b)₂A radical, giving a radical G of the formula ²:

Wherein R in each case^16aIndependently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and

wherein R in each case^16bIndependently is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

with R⁹Group-protecting alcohols, in which R⁹As defined herein, the formula R is used⁹LG compounds, wherein LG is a leaving group as defined herein, or with the use of thioglycoside compounds R⁹-SAr, when R⁹Is a carbohydrate as defined herein and wherein Ar is optionally substituted aryl or optionally substituted heteroaryl to give a protected alcohol of formula (A-3) as shown in scheme E-2, wherein G is²、L³、R^2a、R^2b、R^5a、R^5bAnd z2 is as defined herein.

Scheme E-2.

P of (A-3)³Deprotection affords alcohol (A-4), which is a tool for further synthetic processing. See, e.g., scheme E-3. For example, an alcohol may be oxidized to an aldehyde or acid, which may be further converted to an ester or an activated acid or acid halide. The aldehyde can be converted to an amine by reductive amination, or with a nucleophilic R ^Z4Reagent(e.g., R)^Z4M, wherein M is an anion, Li, Na, K, or MgX, wherein X is a halogen) followed by oxidation to a ketone. The alcohol may also be converted to a leaving group as defined herein, which is subsequently converted to a nitro compound or an amine.

Scheme E-3.

As an alternative to the aldehyde (A-1), it is further contemplated to use an aldehyde of the formula (A-5) or a salt thereof, which can be converted into various compounds, analogously to the synthetic processing described in the preceding scheme. See, e.g., scheme E-4.

Scheme E-4.

Furthermore, as an alternative to the aldehydes (A-1) and (A-5), it is further contemplated to use alkenyl compounds of the formula (A-9) or salts thereof, which can be converted into various compounds, similar to the synthetic processes described in the preceding schemes. See, e.g., scheme E-5.

Scheme E-5.

Modifications can be made to aldehydes or ketones such as those described in scheme E-5 to produce substituted amines such as those described in scheme E-6. Formation of chiral tert-butylsulfinylimines followed by nucleophilic addition of R^Z4(e.g., a Grignard reagent or an organolithium reagent) to produce an intermediate having a stereochemical configuration, e.g., C-37 or C-38. Removal of the chiral auxiliary groups gives the desired amines C-39 and C-40, which are used for the subsequent macrocyclization reaction.

Scheme E-6.

Such as those described in scheme E-5The aldehydes can be further modified under the conditions shown in scheme E-7 to yield other useful intermediates for derivatization or macrocyclization. Phosphonium salts or phosphonate derivatives such as of the formula C-42 (wherein R is^P1、R^P2And R^P3Each independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl) can be used to chain extend by forming an alkene with a corresponding carbonyl-containing organic compound.

Scheme E-7.

To obtain larger ring sizes (e.g., 16-membered rings), the macrocyclic eastern half is expanded, which can be done as shown in this application (scheme E-8). Treatment of the aldehyde with an alkoxy phosphonium salt or phosphonate reagent provides vinyl ethers C-12 or C-13. Hydrolysis under acidic conditions gives the chain-extended aldehyde precursor C-14 or C-15.

Scheme E-8.

In some embodiments, wherein L is²Is CH₂The aldehyde intermediate of the halodontope moiety can be accomplished using the two-step sequence described in scheme E-9. Enol ethers C-16 or C-17, wherein PG is an oxygen protecting group as defined herein, can be prepared using a base and an oxygen protecting group reagent (e.g., trimethylsilyl trifluoromethanesulfonate or trimethylsilyl chloride). The intermediate silyl enol ether may be halogenated with a source of electrophilic halogen. In some embodiments, the electrophilic halogen is fluorine. In some embodiments, the halogenating agent is SelectFluor.

Scheme E-9.

Examples

The above and other aspects of the present invention will be further understood upon consideration of the following examples, which are intended to illustrate some specific embodiments of the present invention and are not intended to limit the scope as defined by the claims.

Macrolide binding and resistance

Macrolide antibiotics (such as the exemplary macrolide shown in fig. 1) inhibit peptide synthesis by blocking the transport of nascent peptides through the exit channel in bacterial ribosomes. All 13-to 16-membered macrolide antibiotics bind to almost the same macrolide (or azalide) conformer in which the hydrophobic face of the molecule (containing several methyl groups and one ethyl group) engages with the walls of the peptidyl exit channel and the hydrophilic face of the molecule (containing four C-O and C ═ O groups) is exposed to the hydrophobic interior of the channel (fig. 2, surrounding the periphery of the indicated solithromycinA sphere). See, e.g., Bulkley et al, proc.natl.acad.sci.u.s.a.2010,107, 17158-17163; tu et al, Cell (Cambridge, MA, U.S.)2005,121, 257-; hansen et al, J.mol.biol.2003,330, 1061-1075; Llano-Sotelo et al, Antimicrob. Agents Chemother.2010,54, 4961-4970. The side chains of telithromycin and solithromycin are thought to participate in the pi-stacking interaction with the A752-U2609 base pair, enhancing binding to ribosomes, see, for example, Mankin, curr. Opin. Microbiol.2008,11, 414-421; Douthwaite et al, mol. Microbiol.2000,36, 183-192; Hansen et al, mol. Microbiol.1999,31, 623-631. the 3-aminophenyl substituent of solithromycin has been shown by X-ray crystallography to contact A752 and G via hydrogen bonds, which may explain in part the higher binding affinity of solithromycin than telithromycin, see, for example, Antelo-20. Solidamycin et al 10,54,4961-4970. The fluorine atom at C2 of solithromycin was in hydrophobic contact with C2611 and is believed to be responsible for the 4-to 16-fold increase in activity against multiple groups of gram-positive bacteria over non-fluorinated molecules. See, for example, Llano-Sotelo et al, Antimicrob. Agents Chemother.2010,54, 4961-4970.

Modification of the macrolide binding pocket is one of the major drug resistant forms of pathogenic bacteria. This may take the form of a base modification (e.g., dimethylation by a2058 of the erm gene), a base mutation (e.g., a2058G, a2059G, C2611G), or a more subtle change in the binding pocket resulting from the ribosome distal mutation (e.g., L4 ribosomal peptide modification). See, e.g., Leclercq et al, Antimicrob. Agents Chemother.1991,35, 1273-; leclercq et al, Antimicrob. Agents Chemother.1991,35, 1267-; weisblum, Antimicrob.AgentsChemother.1995,39, 577-cake 585; vester et al, Antimicrob.Agents Chemother.2001,45, 1-12; tu et al, Cell (Cambridge, MA, U.S.)2005,121, 257-. Semisynthetic modifications of macrolides (limited to only a few positions) have allowed for a large increase in binding by additional contact with the binding site. We believe that modifications to other positions that have not been explored provide greater opportunities for further antibiotic development.

Convergent synthesis method of the invention

Over the past decades, we have made significant progress in understanding the ribosome, whether it is structural or functional. The high resolution X-ray crystal structure of macrolide antibiotic-binding ribosomes of several archaea and, more recently, pathogenic bacteria has provided insight into the nature of macrolide binding. Very detailed models of erythromycin and other macrolide antibiotics bound to bacterial ribosomes (and especially those of pathogenic microorganisms such as E.coli) have been obtained by crystallographers only for the last three years. See, e.g., Dunkle et al, proc.natl.acad.sci.u.s.a. (2010)107: 17152-17157; Llano-Sotelo et al, Antimicrob. Agents Chemother (2010)54: 4961-4970. The basic information for rational drug design of the macrolide backbone, combined with biochemical and clinical data over half a century, has been quite abundant, which has made the design and synthesis of new antibiotic candidates of this type very timely, and we believe this is an excellent opportunity.

Although our understanding of the structural features that contribute to macrolide binding has gone to an unprecedented level, many are unknown because most of the positions of the macrolide backbone have never been modified due to the inherent limitations of semisynthesis. The synthetic route leading to the macrolide backbone of the present invention enables modification of multiple positions that are not feasible using semi-synthetic methods. We believe that the interaction with the hydrophobic binding pocket can be enhanced by a change in the alkyl substituent of the macrolide; the present application relates to hydrophobic groups such as alkyl, fluoro and/or fluoroalkyl groups. Modification of the C4-position of the macrolide enhances binding to modified ribosomes of drug-resistant strains, and the synthetic methods of the invention allow for facile changes to this and other positions. See, e.g., Tu et al, Cell (Cambridge, MA, U.S.) (2005)121: 257-; hansen et al, mol. cell (2002)10: 117-. The synthetic method of the invention allows very simple variation in the size of the macrocycle and in the composition of the heteroatoms. Changes in the deoxysugar amine residues were also achieved simply using the synthetic method of the present invention, allowing the development of several analogues that could potentially overcome the resistance associated with erm methylases, characterized by an adverse interaction between the sugar and dimethylated a 2058. See, e.g., Romero et al, Tetrahedron Lett (2005)46: 1483-; liang et al, Medicinal chemistry letters (2005)15: 1307-.

Several guidelines are followed in designing a total synthetic route to macrolide antibiotics. First, the method is based on the design of components and is convergent, such that it is possible to achieve multiplicative expansion of analogs by chemically altering each component. Second, chemical transformations can be selected to be scalable, so that sufficient quantities of any antibiotic candidate can be prepared for MIC screening, animal testing, and even final production.

The general heat-induced macrocyclic lactonization of dioxolones or beta-ketoesters proceeds via acylketene (acylketene) intermediates to the macrolides without elaborate protecting groups or coupling agents. Boeckman et al used the dioxolone process for the first time to prepare medium-sized macrolides. See, e.g., Boeckman, et al, J.Am.chem.Soc. (1989)111: 8286-8288. The beta-ketoester method was developed in detail by Witzeman. See, e.g., Witzeman, et al, J.org.chem. (1991)56: 1713-1718.

The results discussed in this application demonstrate that macrolactonization using dioxoles ketones or beta-ketoesters works very well with different backbone substitutions. The macrocyclized precursor is generated from two halves (the west half and the east half) of nearly equal complexity, which in turn are derived from variable building blocks. Our convergence building block strategy enables independent evolution of each component (synthetic route, structural composition).

We have synthesized over 50 new 15-membered azalide antibiotic candidates from the 5 east and 6 west halves of the macrolide backbone. All of these are novel chemical entities and none can be prepared by semisynthesis. Several of these candidates have been screened against a variety of pathogens such as staphylococcus aureus, streptococcus pneumoniae, escherichia coli and haemophilus influenzae, many of which are macrolide-resistant strains. Several of these new macrolides have been found to have better activity than azithromycin against both macrolide-sensitive and macrolide-resistant bacteria.

I. Synthetic eastern half