Lincosamides and uses thereof

Abstract

The present invention provides compounds for the treatment and prophylaxis of infectious diseases. The structure of the compound is a lincosamide analogue modified in amino octanose (northern) and amino acid (southern) regions. Also provided are methods of preparing the lincosamide compounds, pharmaceutical compositions containing the lincosamide compounds, and methods of treating infectious diseases using the disclosed lincosamide compounds.

Description

[0001] Related applications

[0002] This patent application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Patent Application USSN 63 / 332,993, filed on April 20, 2022, which is incorporated herein by reference in its entirety.

[0003] background

[0004] Emerging resistance to existing antibiotics is rapidly becoming a global crisis, particularly for infections originating from resistant Gram-negative bacteria. Pathogenic bacteria can transmit genes encoding antibiotic resistance both vertically (to their progeny) and horizontally (to neighboring bacteria of different lineages), so antibiotic resistance can evolve rapidly, particularly in hospital settings. See, e.g., Wright, Chem. Commun. (2011) 47:4055-4061. Each year in the United States, more than 99,000 people die from healthcare-associated infections, exceeding the toll from car accidents, HIV, and breast cancer combined, and resulting in an estimated $45 billion in U.S. healthcare costs. See, e.g., Klevens et al., Public Health Rep (2007) 122:160-166. The current crisis has been exacerbated by a reduction in research into the development of new antibiotics by most major pharmaceutical companies. See, e.g., Projan, Curr. Opin. Microbiol. (2003) 6:427-430. The current rate of introduction of new antibiotics is insufficient to combat growing resistance, and with the ease of international travel and increasing population density, the need for innovation in this area has never been greater.

[0005] Lincosamides are a class of antibiotics that prevent bacterial growth by interfering with protein synthesis. They bind to the 23S portion of the bacterial 50S ribosome subunit, causing premature dissociation of peptidyl-tRNA from the ribosome. Lincosamides do not interfere with protein synthesis in human cells (or other eukaryotic cells) because the structure of human ribosomes differs from that of bacterial ribosomes.

[0006] The first lincosamide to be discovered was lincomycin, but its use as an antibiotic has been largely replaced by the more potent clindamycin. Clindamycin also has some activity against parasitic protozoa and is used to treat toxoplasmosis and malaria. Lincosamides are typically used to treat staphylococcal and streptococcal infections, but have also shown promise against infections caused by Bacteroides fragilis and other anaerobic bacteria. They are used to treat toxic shock syndrome and are thought to directly block the production of the M protein, which causes severe inflammatory reactions.

[0007]

[0008] Target bacteria may develop resistance by altering the drug's binding site (similar to resistance to macrolides and streptogramins). The resistance mechanism is methylation of the 23S binding site. If this occurs, the bacteria become resistant to both macrolides and lincosamides. In rare cases, enzymatic inactivation of clindamycin has also been reported.

[0009] Lincosamides have also been associated with pseudomembranous colitis caused by Clostridium difficile (C. difficile). Pseudomembranous colitis is an inflammation of the colon associated with overgrowth of C. difficile. This overgrowth of C. difficile is often associated with recent use of lincosamide antibiotics. For example, clindamycin is the only lincosamide currently in clinical use that carries a black box warning due to its propensity to promote C. difficile-associated diarrhea (CDAD).

[0010] Therefore, the discovery and development of new antibiotics, especially new lincosamides, that are effective against drug-resistant bacteria represent a currently unmet medical need. Summary of the Invention

[0011] The main degradation pathway of clindamycin in vivo is that its methylthioglycoside forms relatively inactive clindamycin sulfoxide diastereomers through the " first pass " oxidation of liver cytochrome P450 enzyme. Generally speaking, reducing the metabolic degradation of antibiotics can improve their therapeutic index by achieving the same inhibitory effect with lower dosage. The present disclosure stems from the recognition that there is a significant unrealized potential to improve the therapeutic effect of lincosamides on MDR ESKAPE pathogens in vivo by targeted glycoside modification, and this argument has been supported by preliminary data. Specifically, the crystal structure analysis of the lincosamide analogs iboxamycin (iboxamycin) bound to bacterial ribosomes shows that limiting the formation of the macrocyclic part of the aminooctose (northern) region will promote the analogs to pre-arrange their preferred binding conformation, thereby reducing the entropy loss during binding, and increasing target engagement (target engagement).

[0012] Thus, compounds are disclosed as lincosamide analogs. These compounds have modified northern and amino acid (southern) regions. These compounds include novel heterocyclic moieties that restrict the northern region. The disclosed synthetic lincosamides exhibit potent activity against both Gram-positive and Gram-negative pathogens.

[0013] In one aspect, the present disclosure provides compounds of formula (I):

[0014]

[0015] and pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives or prodrugs thereof, wherein:

[0016] Each occurrence of P is independently hydrogen or a protecting group;

[0017] A is a substituted or unsubstituted heteroaliphatic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaralkyl group;

[0018] R 7 is hydrogen or unsubstituted alkyl;

[0019] R is a heterocyclic group;

[0020] Each occurrence of R 2 independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, -OR A 、-N(R A )2、-SR A 、-CN、-SCN、-C(=NR A )R A 、-C(=NR A )OR A 、-C(=NR A )N(R A )2, -C(=O)R A 、-C(=O)OR A 、-C(=O)N(R A )2、-NO2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )N(R A )2, -OC(=O)R A 、-OC(=O)OR A 、-OC(=O)N(R A )2、-NR A S(O)2R A 、-OS(O)2R A , or -S(O)2R A ; or two R 2The groups are linked to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;

[0021] t is 0-12; and

[0022] Each occurrence of R A R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0023] The disclosed compounds have antimicrobial activity and can be used to treat and / or prevent infectious diseases. Provided herein are pharmaceutical compositions of the compounds, kits containing the compounds and / or compositions, and methods of treatment using the compounds or their compositions. Infectious diseases treatable with the compounds of the invention include, but are not limited to, bacterial infections caused by Staphylococci, Streptococci, Enterococci, Acinetobacter, Clostridium, Bacteroides, Klebsiella, Escherichia coli, Pseudomonas, and Haemophilus species.

[0024] Also provided herein are methods of preparing the disclosed compounds. In certain embodiments, the disclosed compounds are prepared by a ring-closing metathesis reaction (eg, see Scheme 1).

[0025] The details of certain embodiments of the invention are set forth in the detailed description of certain embodiments below. Other features, objects and advantages of the invention will be apparent from the definitions, examples and claims.

[0026] Detailed Description of Certain Embodiments

[0027] The compounds disclosed herein include lincosamide analogs. Compared to known lincosamides (e.g., lincomycin and clindamycin), the disclosed compounds have increased structural diversity. These compounds have modified northern and amino acid (southern) regions, including novel heterocyclic moieties that restrict the northern region. The disclosed compounds have unexpected and potent activity against various microorganisms (including Gram-negative bacteria). Also disclosed are methods for preparing the disclosed compounds, pharmaceutical compositions comprising the compounds, uses of the compounds, and methods of using the compounds (e.g., for treating infectious diseases, preventing infectious diseases).

[0028] In one aspect, there is provided a compound of formula (I):

[0029]

[0030] and pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives or prodrugs thereof, wherein:

[0031] Each occurrence of P is independently hydrogen or a protecting group;

[0032] A is a substituted or unsubstituted heteroaliphatic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaralkyl group;

[0033] R is a heterocyclic group;

[0034] R 7 is hydrogen or unsubstituted alkyl;

[0035] Each occurrence of R 2 independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, -OR A 、-N(R A )2、-SR A 、-CN、-SCN、-C(=NR A )R A 、-C(=NR A )OR A 、-C(=NR A )N(R A )2, -C(=O)R A 、-C(=O)OR A 、-C(=O)N(R A )2、-NO2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )N(R A )2, -OC(=O)R A 、-OC(=O)OR A、-OC(=O)N(R A )2、-NR A S(O)2R A 、-OS(O)2R A , or -S(O)2R A ; or two R 2 The groups are linked to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring;

[0036] t is 0-12; and

[0037] Each occurrence of R A R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0038] Unless otherwise indicated, any formula described herein is also intended to include salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof. In certain embodiments, the provided compounds are salts of any formula described herein. In certain embodiments, the provided compounds are pharmaceutically acceptable salts of any formula described herein. In certain embodiments, the provided compounds are solvates of any formula described herein. In certain embodiments, the provided compounds are hydrates of any formula described herein. In certain embodiments, the provided compounds are polymorphs of any formula described herein. In certain embodiments, the provided compounds are cocrystals of any formula described herein. In certain embodiments, the provided compounds are tautomers of any formula described herein. In certain embodiments, the provided compounds are stereoisomers of any formula described herein. In certain embodiments, the provided compounds are isotopically labeled forms of any formula described herein. For example, compounds having the structures of the present invention but with hydrogen replaced by deuterium or tritium, 19 F 18 F replaces, or 12 C was 13 C or 14 Compounds substituted with C are within the scope of the present disclosure. In certain embodiments, provided compounds are deuterated forms of any formula or compound described herein.

[0039] In certain embodiments of the compounds of Formula (I), each occurrence of P is hydrogen.

[0040] Group R 7

[0041] As generally defined in this article, R 7 is hydrogen or unsubstituted alkyl.

[0042] In certain embodiments, R 7 is hydrogen or unsubstituted alkyl. In certain embodiments, R 7 is unsubstituted alkyl. In certain embodiments, R 7 For unsubstituted C 1-6 In certain embodiments, R 7 For unsubstituted C 1-4 In certain embodiments, R 7 For unsubstituted C 1-3 In certain embodiments, R 7 For unsubstituted C 1-2 In certain embodiments, R 7 In certain embodiments, R 7 In certain embodiments, R 7 For hydrogen.

[0043] Group A

[0044] As generally defined herein, A is a substituted or unsubstituted heteroaliphatic, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heteroaralkyl.

[0045] In certain embodiments, A is a substituted or unsubstituted heteroaliphatic.

[0046] In certain embodiments, A is a substituted or unsubstituted heterocyclyl.

[0047] In certain embodiments, A is a substituted or unsubstituted 4-8 membered monocyclic heterocyclyl, or a substituted or unsubstituted fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 4-8 membered monocyclic heterocyclyl, or a substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 5-8 membered monocyclic heterocyclyl, or a substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 5-8 membered monocyclic heterocyclyl, or a substituted or unsubstituted 9-11 membered fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl, or a substituted or unsubstituted 9-11 membered fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl, or a substituted or unsubstituted 9-10 membered fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl, or a substituted or unsubstituted 10-membered fused bicyclic heterocyclyl.

[0048] In certain embodiments, A is a substituted or unsubstituted 4-8 membered monocyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 5-8 membered monocyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 5-membered monocyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 6-membered monocyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 7-membered monocyclic heterocyclyl.

[0049] In certain embodiments, A is of the formula:

[0050]

[0051] in:

[0052] n is 1, 2, or 3;

[0053] R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaliphatic group, -C(=NR A )R A 、–C(=NR A )OR A 、–C(=NR A )N(R A )2, –C(=O)R A 、–C(=O)OR A 、–C(=O)N(R A )2, –S(O)2R A or nitrogen protecting groups;

[0054] Each occurrence of R 9 independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, -OR A 、-N(R A )2、-SR A 、-CN、-SCN、-C(=NR A )R A 、-C(=NR A )OR A 、-C(=NR A )N(R A )2, -C(=O)R A 、-C(=O)OR A 、-C(=O)N(R A )2、-NO2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )N(R A )2, -OC(=O)R A 、-OC(=O)OR A 、-OC(=O)N(R A )2、-NR A S(O)2R A 、-OS(O)2R A , or -S(O)2R A ;and

[0055] p is 0-4.

[0056] In certain embodiments, A is of the formula: In certain embodiments, A is of the formula: In certain embodiments, A is of the formula: In certain embodiments, A is of the formula:

[0057] In certain embodiments, A is of the formula: In certain embodiments, A is of the formula: In certain embodiments, A is of the formula: In certain embodiments, A is of the formula:

[0058] In certain embodiments, A is a substituted or unsubstituted fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 9-11 membered fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 9-10 membered fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 10-membered fused bicyclic heterocyclyl.

[0059] In certain embodiments, A is of the formula:

[0060]

[0061] in:

[0062] B is a carbocyclic group or a heterocyclic group;

[0063] R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaliphatic group, -C(=NR A )R A 、–C(=NR A )OR A 、–C(=NR A )N(R A )2, –C(=O)R A 、–C(=O)OR A 、–C(=O)N(R A )2, –S(O)2R A or nitrogen protecting groups;

[0064] Each occurrence of R 9 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, -OR A ,–N(R A )2. –SR A , –CN, –SCN, –C(=NR A )R A 、–C(=NR A )OR A 、–C(=NR A )N(R A )2, –C(=O)RA 、–C(=O)OR A 、–C(=O)N(R A )2, –NO2, –NR A C(=O)R A ,–NR A C(=O)OR A ,–NR A C(=O)N(R A )2. –NR A C(=NR A )N(R A )2, –OC(=O)R A 、–OC(=O)OR A 、–OC(=O)N(R A )2. –NR A S(O)2R A 、-OS(O)2R A , or -S(O)2R A ; or two R 9 The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; and

[0065] p is 0-4.

[0066] In certain embodiments, B is a cycloalkyl, cycloalkenyl, or heterocyclyl ring. In certain embodiments, B is a heterocyclyl ring. In certain embodiments, B is a 5-8 membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In certain embodiments, B is a 5-8 membered heterocyclyl ring. In certain embodiments, B is a 5-7 membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In certain embodiments, B is a 5-7 membered heterocyclyl ring. In certain embodiments, B is a 6-7 membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In certain embodiments, B is a 6-7 membered heterocyclyl ring. In certain embodiments, B is a 6-membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In certain embodiments, B is a 6-membered heterocyclyl ring. In certain embodiments, B is a 6-membered heterocyclyl ring. In certain embodiments, B is a 7-membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In certain embodiments, B is a 7-membered heterocyclyl ring.

[0067] In certain embodiments, A is of the formula:

[0068]

[0069] in:

[0070] X is O, S, or NR 9 or C(R 9 )2;

[0071] Y is O, S, N, or NR 9 、C(R9 2. CR 9 , CH2 or CH;

[0072] n is 0 or 1;

[0073] p is 0-4; and

[0074] Represents a single bond or a double bond.

[0075] In certain embodiments, X is O, S, NR 9 or C(R 9 )2. In certain embodiments, X is O, S or NR 9 In certain embodiments, X is O or S. In certain embodiments, X is O.

[0076] In certain embodiments, Y is O, S, NR 9 、C(R 9 2. CR 9 、CHR 9 , CH2 or CH. In certain embodiments, Y is O, NR 9 、C(R 9 2. CR 9 、CHR 9 , CH2 or CH. In certain embodiments, Y is NR 9 、C(R 9 2. CR 9 、CHR 9 , CH2 or CH. In certain embodiments, Y is C(R 9 2. CR 9 、CHR 9 , CH2 or CH. In certain embodiments, Y is C(R 9 2. CR 9 、CHR 9 , CH2 or CH. In certain embodiments, Y is C(R 9 2. CHR 9 or CH2. In certain embodiments, Y is C(R 9 ) 2. In certain embodiments, Y is CHR 9 In certain embodiments, Y is CH2. In certain embodiments, Y is CR 9 In certain embodiments, Y is CR 9 In certain embodiments, Y is CH.

[0077] In certain embodiments, n is 0. In certain embodiments, n is 1.

[0078] In certain embodiments, p is 0-3. In certain embodiments, p is 0-2. In certain embodiments, p is 0-1. In certain embodiments, p is 1-2. In certain embodiments, p is 0 or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2.

[0079] In certain embodiments, X is O; Y is NR 9 、C(R 9 2. CR 9 、CHR 9 , CH2 or CH; n is 1; and p is 0-2. In certain embodiments, X is O; Y is C(R 9 2. CR 9 、CHR 9 , CH2 or CH; n is 1; and p is 0-2. In certain embodiments, X is O; Y is CR 9 or CH; n is 1; and p is 1. In certain embodiments, X is O; Y is C(R 9 2. CHR 9 or CH2; n is 1; and p is 0-2.

[0080] In certain embodiments, A is of the formula:

[0081]

[0082] In certain embodiments, A is of the formula:

[0083]

[0084] In certain embodiments, A is of the formula:

[0085]

[0086] In certain embodiments, A is of the formula:

[0087]

[0088] In certain embodiments, A is of the formula:

[0089]

[0090] In certain embodiments, A is of the formula:

[0091]

[0092] In certain embodiments, A is of the formula:

[0093]

[0094] In certain embodiments, A is of the formula:

[0095]

[0096] In certain embodiments, A is of the formula:

[0097]

[0098] In certain embodiments, A is of the formula:

[0099]

[0100] In certain embodiments, A is of the formula:

[0101]

[0102] In certain embodiments, A is of the formula:

[0103]

[0104] In certain embodiments, A is of the formula:

[0105]

[0106] In certain embodiments, A is of the formula:

[0107]

[0108] In certain embodiments, A is of the formula:

[0109]

[0110] In certain embodiments, A is of the formula:

[0111]

[0112] In certain embodiments, A is of the formula:

[0113]

[0114] In certain embodiments, A is of the formula:

[0115]

[0116] In certain embodiments, A is of the formula:

[0117]

[0118] In certain embodiments, A is of the formula:

[0119]

[0120] In certain embodiments, A is of the formula:

[0121]

[0122] Group R 8

[0123] As generally defined in this article, R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaliphatic group, -C(=NR A )R A 、–C(=NR A )OR A 、–C(=NR A )N(R A )2, –C(=O)R A 、–C(=O)OR A 、–C(=O)N(R A )2、-S(O)2R A or nitrogen protecting groups.

[0124] In certain embodiments, R 8 is hydrogen, substituted or unsubstituted alkyl, or –C(=O)R A In certain embodiments, R 8 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 8 is hydrogen or unsubstituted alkyl. In certain embodiments, R 8 is hydrogen or unsubstituted C 1-6 In certain embodiments, R 8 is hydrogen or unsubstituted C 1-4 In certain embodiments, R 8 is hydrogen or unsubstituted C 1-3 In certain embodiments, R 8 is hydrogen or unsubstituted C 1-2 In certain embodiments, R 8 In certain embodiments, R 8 In certain embodiments, R 8 For hydrogen.

[0125] In certain embodiments, R 8 For unsubstituted C 1-6 In certain embodiments, R 8 For unsubstituted C 1-4 In certain embodiments, R 8For unsubstituted C 1-3 In certain embodiments, R 8 For unsubstituted C 1-2 In certain embodiments, R 8 In certain embodiments, R 8 It is a methyl group.

[0126] Group R 9

[0127] As generally defined in this article, each occurrence of R 9 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, -OR A ,–N(R A )2. –SR A , –CN, –SCN, –C(=NR A )R A 、–C(=NR A )OR A 、–C(=NR A )N(R A )2, –C(=O)R A 、–C(=O)OR A 、–C(=O)N(R A )2, –NO2, –NR A C(=O)R A ,–NR A C(=O)OR A ,–NR A C(=O)N(R A )2. –NR A C(=NR A )N(R A )2, –OC(=O)R A 、–OC(=O)OR A 、–OC(=O)N(R A )2. –NR A S(O)2R A 、-OS(O)2R A , or -S(O)2R A ; or two R 9 The groups are connected to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring. 9In certain embodiments, R 9 A substituent is an (R) stereocenter (ie, the carbon to which it is attached has the (R) configuration).

[0128] In certain embodiments, R 9 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, –OR A or –N(R A )2; or two R 9 The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring.

[0129] In certain embodiments, R 9 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, -C(=O)OR A 、–C(=O)N(R A )2、–C(=NR A )N(R A )2. –OR A or –N(R A )2; or two R 9 The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring.

[0130] In certain embodiments, R 9 is halogen, substituted or unsubstituted alkenyl, substituted alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; or two R 9 The groups are linked to form a substituted or unsubstituted carbocyclyl ring.

[0131] In certain embodiments, R 9 is halogen, unsubstituted vinyl, substituted or unsubstituted phenylethynyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted phenethyl; or two R 9 The groups are linked to form an unsubstituted cycloalkyl ring.

[0132] In certain embodiments, R 9 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. 9is a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl. 9 is substituted or unsubstituted phenyl or substituted or unsubstituted phenethyl.

[0133] In certain embodiments, R 9 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heteroalkyl. 9 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, or unsubstituted heteroalkyl. 9 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted carbocyclic group.

[0134] In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 It is -CH=CH2.

[0135] In certain embodiments, R 9 is a substituted or unsubstituted carbocyclyl. In certain embodiments, R 9 In certain embodiments, R 9 For unsubstituted C 3-6 In certain embodiments, R 9 For unsubstituted C 5-6 In certain embodiments, R 9 is an unsubstituted cyclopentyl. In certain embodiments, R 9 is an unsubstituted cyclohexyl group.

[0136] In certain embodiments, R 9 is a substituted or unsubstituted alkyl group. In certain embodiments, R 9 is substituted or unsubstituted C 1-6 In certain embodiments, R 9 C 1-6 In certain embodiments, R 9 Halogen, alkenyl, C 3-6 Cycloalkyl or –OR A Substituted C 1-6 In certain embodiments, R 9 Halogen, alkenyl, C 3-6 Cycloalkyl, heterocyclic, –N(R A )2. –SO2R A OR A Substituted C1-6 In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 for In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 for In certain embodiments, R 9 In certain embodiments, R 9 is -CH2CH2CH2N(CH3)2. In certain embodiments, R 9 is -CH2C(CH3)2OH. In certain embodiments, R 9 In certain embodiments, R 9 -CH2CH=CH2, -CH2CH2F, -CH2CHF2, Or -CH2CH2CH2OCH3. In certain embodiments, R 9 -CH2CH=CH2, -CH2CH2F, -CH2CHF2, -CH2CF2CH3, -CH2CH2CH2F, -CH2CH2CF2H, -CH2CH2CH2Cl, -CH2CH2CH2OCH3, -CH2CH2CH2OH, -CH2C(CH3)2OH, -CH2CH2CH2SO2CH3, CH2CH2CH2NH2, -CH2CH2CH2N(CH3)2, or

[0137] In certain embodiments, R 9 For unsubstituted C 1-6 In certain embodiments, R 9is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, or -C(CH3)3. In certain embodiments, R 9 In certain embodiments, R 9 is -CH3. In certain embodiments, R 9 In certain embodiments, R 9 In certain embodiments, R 9 is -CH(CH3)2. In certain embodiments, R 9 is -C(CH3)3. In certain embodiments, R 9 It is -CH2CH(CH3)2.

[0138] Ring R

[0139] As described herein, R is a heterocyclyl. In certain embodiments, R is a 6-14 membered heterocyclyl. In certain embodiments, R is an 8-12 membered heterocyclyl. In certain embodiments, R is a 9-12 membered heterocyclyl. In certain embodiments, R is a 9-11 membered heterocyclyl. In certain embodiments, R is an 11-membered heterocyclyl. R is a 10-membered heterocyclyl.

[0140] In certain embodiments, R comprises at least one unsaturated bond in its ring. In certain embodiments, R comprises at least one double bond (e.g., carbon-carbon or carbon-nitrogen). In certain embodiments, R comprises at least one unsaturated carbon-carbon bond in its ring. In certain embodiments, the unsaturated carbon-carbon bond is a double bond (i.e., an alkenyl bond). In certain embodiments, the unsaturated carbon-carbon bond is a triple bond (i.e., an alkynyl bond). In certain embodiments, R comprises at least one heteroatom in addition to oxygen in its ring. In certain embodiments, R comprises at least one heteroatom in addition to oxygen in its ring, wherein the heteroatom is nitrogen, oxygen, or sulfur. In certain embodiments, R comprises at least one heteroatom in addition to oxygen in its ring, wherein the heteroatom is nitrogen. In certain embodiments, R comprises at least one heteroatom in addition to oxygen in its ring, wherein the heteroatom is oxygen. In certain embodiments, R comprises at least one heteroatom in addition to oxygen in its ring, wherein the heteroatom is sulfur. In certain embodiments, R comprises at least one sulfur atom in its ring. In certain embodiments, R comprises a sulfur atom in its ring.

[0141] In certain embodiments, R is a heterocyclyl group of the formula:

[0142]

[0143] Where: R 1 -NR 2 -, -O-, or -S-. In certain embodiments, R 1 -NR 2 -. In certain embodiments, R 1 In certain embodiments, R 1 For -S-.

[0144] In certain embodiments, R is a heterocyclyl group of the formula:

[0145]

[0146] In certain embodiments, R is a heterocyclyl group of the formula:

[0147]

[0148] Where: R 1a -NR 2 -, -O-, or -S-; each R 1 Independently bond, -CR 2 R 2 -、CR 2 ,C,N,-NR 2 -, -O-, or -S-; and q is 3-6. In certain embodiments, R 1 -NR 2 -. In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1a -NR 2 -. In certain embodiments, R 1a In certain embodiments, R 1a For -S-.

[0149] In certain embodiments, R is a heterocyclyl group of the formula:

[0150]

[0151] Among them: Each R 1 Independently bond, -CR 2 R 2 -、CR 2 ,C,N,-NR 2 -, -O-, or -S-; and q is 3-6. In certain embodiments, each R 1 Independently -CR 2 R2 -、CR 2 ,C,N,-NR 2 In certain embodiments, each R 1 Independently -CR 2 R 2 -、CR 2、 N, -NR 2 In certain embodiments, each R 1 Independently -CR 2 R 2 -、CR 2 , C, N, or -NR 2 -. In certain embodiments, each R 1 Independently -CR 2 R 2 -、CR 2 , N, or -NR 2 -. In certain embodiments, each R 1 Independently -CR 2 R 2 -、CR 2 , C, or -O-. In certain embodiments, each R 1 Independently -CR 2 R 2 -、CR 2 , or -O-. In certain embodiments, each R 1 Independently -CR 2 R 2 -、CR 2 or C. In certain embodiments, each R 1 Independently -CR 2 R 2 - or CR 2 In certain embodiments, each R 1 Independently -CR 2 R 2 - or CR 2 In certain embodiments, each R 1 Independently -CR 2 R 2 - or CR 2 ; and q is 3. In certain embodiments, each R 1 Independently -CR 2 R 2 - or CR 2 ; and q is 4. In certain embodiments, each R 1 Independently -CR 2 R 2 - or CR 2; and q is 5. In certain embodiments, each R 1 Independently -CR 2 R 2 - or CR 2 ; and q is 6.

[0152] In certain embodiments, R is a heterocyclyl group of the formula:

[0153]

[0154] Among them: Each R 1 Independently a bond or -CR 2 R 2 -;and Represents a single bond or a double bond.

[0155] In certain embodiments, R is a heterocyclyl group of the formula:

[0156]

[0157] Among them: Each R 1 Independently a bond or -CR 2 R 2 -.

[0158] In certain embodiments, R is a heterocyclyl group of the formula:

[0159]

[0160] Among them: Each R 1 Independently a bond or -CR 2 R 2 -;and Represents a single bond or a double bond.

[0161] In certain embodiments, R is a heterocyclyl group of the formula:

[0162]

[0163] Among them: Each R 1 Independently a bond or -CR 2 R 2 -.

[0164] In certain embodiments, R is a heterocyclyl group of the formula:

[0165]

[0166] Among them: Each R 1 Independently a bond or -CR 2 R 2 -;and In certain embodiments, R is a heterocyclic group of the formula:

[0167]

[0168] Among them: Each R 1 Independently a bond or -CR 2 R 2 -.

[0169] In certain embodiments, R is a heterocyclyl group of the formula:

[0170]

[0171] In certain embodiments, R is a heterocyclyl group of the formula:

[0172]

[0173] In certain embodiments, R is a heterocyclyl group of the formula:

[0174]

[0175] In certain embodiments, R is a heterocyclyl group of the formula:

[0176]

[0177] In certain embodiments, R is a heterocyclyl group of the formula:

[0178]

[0179] In certain embodiments, R is a heterocyclyl group of the formula:

[0180]

[0181] In certain embodiments, R is a heterocyclyl group of the formula:

[0182]

[0183] In certain embodiments, R is a heterocyclyl group of the formula:

[0184]

[0185] In certain embodiments, R is a heterocyclyl group of the formula:

[0186]

[0187] In certain embodiments, R is a heterocyclyl group of the formula:

[0188]

[0189] In certain embodiments, R is a heterocyclyl group of the formula:

[0190]

[0191] In certain embodiments, R is a heterocyclyl group of the formula:

[0192]

[0193] In certain embodiments, R is a heterocyclyl group of the formula:

[0194]

[0195] In certain embodiments, R is a heterocyclyl group of the formula:

[0196]

[0197] In certain embodiments, R is a heterocyclyl group of the formula:

[0198]

[0199] In certain embodiments, R is a heterocyclyl group of the formula:

[0200]

[0201] In certain embodiments, R is a heterocyclyl group of the formula:

[0202]

[0203] In certain embodiments, R is a heterocyclyl group of the formula:

[0204]

[0205] In certain embodiments, R is a heterocyclyl group of the formula:

[0206]

[0207] In certain embodiments, R is a heterocyclyl group of the formula:

[0208]

[0209] In certain embodiments, R is a heterocyclyl group of the formula:

[0210]

[0211] In certain embodiments, R is a heterocyclyl group of the formula:

[0212]

[0213] In certain embodiments, R is a heterocyclyl group of the formula:

[0214]

[0215] In certain embodiments, R is a heterocyclyl group of the formula:

[0216]

[0217] In certain embodiments, R is a heterocyclyl group of the formula:

[0218]

[0219] In certain embodiments, R is a heterocyclyl group of the formula:

[0220]

[0221] In certain embodiments, R is a heterocyclyl group of the formula:

[0222]

[0223] In certain embodiments, R is a heterocyclyl group of the formula:

[0224]

[0225] In certain embodiments, R is a heterocyclyl group of the formula:

[0226]

[0227] In certain embodiments, R is a heterocyclyl group of the formula:

[0228]

[0229] In certain embodiments, R is a heterocyclyl group of the formula:

[0230]

[0231] where R 2 is substituted or unsubstituted alkyl or substituted or unsubstituted heteroaryl. In certain embodiments, R 2 is substituted alkyl or substituted heteroaryl. In certain embodiments, R 2 is a haloalkyl or substituted triazolyl group. In certain embodiments, R 2 is a triazolyl group substituted with fluoromethyl or 2,4-difluorophenyl.

[0232] In certain embodiments, R is a heterocyclyl group of the formula:

[0233]

[0234] In certain embodiments, R is a heterocyclyl group of the formula:

[0235]

[0236] where R 2 is substituted or unsubstituted alkyl or substituted or unsubstituted heteroaryl. In certain embodiments, R 2 is substituted alkyl or substituted heteroaryl. In certain embodiments, R 2 is a haloalkyl or substituted triazolyl group. In certain embodiments, R 2 is a triazolyl group substituted with fluoromethyl or 2,4-difluorophenyl.

[0237] In certain embodiments, R is a heterocyclyl group of the formula:

[0238]

[0239] In certain embodiments, R is a heterocyclyl group of the formula:

[0240]

[0241] In certain embodiments, R is a heterocyclyl group of the formula:

[0242]

[0243] In certain embodiments, R is a heterocyclyl group of the formula:

[0244]

[0245] In certain embodiments, R is a heterocyclyl group of the formula:

[0246]

[0247] In certain embodiments, R is a heterocyclyl group of the formula:

[0248]

[0249] In certain embodiments, R is a heterocyclyl group of the formula:

[0250]

[0251] In certain embodiments, both R 2 The groups are linked to form a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heteroaryl ring. 2 The groups are linked to form a substituted or unsubstituted benzene ring.

[0252] In certain embodiments, R is a heterocyclyl group of the formula:

[0253]

[0254] In certain embodiments, both R 2 The groups are linked to form a substituted or unsubstituted carbocyclyl ring, or a substituted or unsubstituted heterocyclyl ring. 2 The groups are each -OH.

[0255] In certain embodiments, R is a heterocyclyl group of the formula:

[0256]

[0257] Wherein: X is -O-, -NR 2 -, or -CR 2 R 2 -.

[0258] In certain embodiments, R is a heterocyclyl group of the formula:

[0259]

[0260] wherein R is optionally replaced by 1-4 independent R 2 Group substitution.

[0261] In certain embodiments, R is a heterocyclyl group of the formula:

[0262]

[0263] wherein R is optionally replaced by 1-4 independent R 2 Group substitution.

[0264] In certain embodiments, R is a heterocyclyl group of the formula:

[0265]

[0266] wherein R is optionally replaced by 1-4 independent R 2 Group substitution.

[0267] In certain embodiments, R is a heterocyclyl group of the formula:

[0268]

[0269] In certain embodiments, R is a heterocyclyl group of the formula:

[0270]

[0271] In certain embodiments, R is a heterocyclyl group of the formula:

[0272]

[0273] In certain embodiments, R is a heterocyclyl group of the formula:

[0274]

[0275] In certain embodiments, R is a heterocyclyl group of the formula:

[0276]

[0277] where R 2 In certain embodiments, R 2 For fluorine.

[0278] In certain embodiments, R is a heterocyclyl group of the formula:

[0279]

[0280] In certain embodiments, R is a heterocyclyl group of the formula:

[0281] where R 2 In certain embodiments, R 2 For fluorine.

[0282] In certain embodiments, R is a heterocyclyl group of the formula:

[0283]

[0284] wherein R is optionally replaced by 1-4 independent R 2 Group substitution.

[0285] In certain embodiments, R is a heterocyclyl group of the formula:

[0286]

[0287] In certain embodiments, R is a heterocyclyl group of the formula:

[0288]

[0289] Group R 2 and t

[0290] As described in this article, each occurrence of R 2independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, -OR A 、-N(R A )2、-SR A 、-CN、-SCN、-C(=NR A )R A 、-C(=NR A )OR A 、-C(=NR A )N(R A )2, -C(=O)R A 、-C(=O)OR A 、-C(=O)N(R A )2、-NO2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )N(R A )2, -OC(=O)R A 、-OC(=O)OR A 、-OC(=O)N(R A )2、-NR A S(O)2R A 、-OS(O)2R A , or -S(O)2R A ; or two R 2 The groups are linked to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0291] In certain embodiments, each occurrence of R 2 are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, a nitrogen protecting group when attached to a nitrogen atom, -OR A 、-N(R A )2、-SR A , or -CN; or two R 2The groups are linked to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0292] In certain embodiments, each occurrence of R 2 are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A 、-N(R A )2、-SR A , or -CN; or two R 2 The groups are linked to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

[0293] In certain embodiments, each occurrence of R 2 are independently hydrogen, halogen, substituted or unsubstituted alkyl, -OR A 、-N(R A )2, or -SR A ; or two R 2 The groups are linked to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heterocyclyl ring.

[0294] In certain embodiments, each occurrence of R 2 are independently halogen, substituted or unsubstituted alkyl, or -OR A ; or two R 2 The groups are linked to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heterocyclyl ring.

[0295] In certain embodiments, each occurrence of R 2 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, each occurrence of R 2 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted heteroaryl. In certain embodiments, each occurrence of R 2 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, each occurrence of R 2 is independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl. In certain embodiments, each occurrence of R 2are independently halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl.

[0296] In certain embodiments, each occurrence of R 2 Independently where R 20 is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -OR A 、-N(R A )2, or -SR A ; X is N or CH; and R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0297] In certain embodiments, each occurrence of R 2 Independently where R 20 is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -OR A 、-N(R A )2, or -SR A ; X is N or CH; and R 10 For hydrogen,

[0298]

[0299] In certain embodiments, each occurrence of R 2 are independently hydrogen, fluorine, fluoromethyl, difluoromethyl, methyl, -OH, -CH2NH2, -CH2OH, -CH2OAc, -C≡CH,

[0300] where R 20 is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -OR A 、-N(R A )2, or -SR A ; X is N or CH; and R 10 For hydrogen,

[0301] In certain embodiments, each occurrence of R 2 are independently hydrogen, -OH, -CH2NH2, -CH2OH, -CH2OAc, -C≡CH, fluoro, fluoromethyl, difluoromethyl, or methyl.

[0302] In certain embodiments, R2 In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 for In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 It is a methyl group.

[0303] In certain embodiments, each occurrence of R 2 is independently fluoro, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl. In certain embodiments, each occurrence of R 2 is independently fluoro, substituted or unsubstituted alkyl, or substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, each occurrence of R 2 is independently fluoro, haloalkyl, unsubstituted alkyl, or substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, each occurrence of R 2 are independently fluorine, C 1-6 Haloalkyl, unsubstituted C 1-6 In certain embodiments, each occurrence of R 2 are independently fluorine, C 1-4 Haloalkyl, unsubstituted C 1-4In certain embodiments, each occurrence of R 2 are independently fluorine, C 1-3 Haloalkyl, unsubstituted C 1-3 In certain embodiments, each occurrence of R 2 are independently fluorine, C 1-2 Haloalkyl, unsubstituted C 1-2 In certain embodiments, each occurrence of R 2 is independently fluoro, fluoromethyl, methyl, or substituted or unsubstituted triazolyl. In certain embodiments, each occurrence of R 2 is independently fluoro, fluoromethyl, methyl or substituted triazolyl. In certain embodiments, each occurrence of R 2 are independently fluoro, fluoromethyl, methyl, or

[0304] In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2 In certain embodiments, each occurrence of R 2 is substituted or unsubstituted triazolyl or methyl. In certain embodiments, each occurrence of R 2 is substituted triazolyl or methyl. In certain embodiments, each occurrence of R 2 Methyl or

[0305] In certain embodiments, each occurrence of R 2 are independently halogen, substituted or unsubstituted alkyl, or -OR A In certain embodiments, each occurrence of R 2 are independently fluorine, substituted or unsubstituted alkyl, or -OR A In certain embodiments, each occurrence of R 2 is independently fluoro, substituted or unsubstituted alkyl, or -OH. In certain embodiments, each occurrence of R 2 is independently fluoro, unsubstituted alkyl, or -OH. In certain embodiments, each occurrence of R 2 are independently fluorine, unsubstituted C 1-6 In certain embodiments, each occurrence of R 2 are independently fluorine, unsubstituted C 1-4 In certain embodiments, each occurrence of R 2 are independently fluorine, unsubstituted C 1-3In certain embodiments, each occurrence of R 2 are independently fluorine, unsubstituted C 1-2 In certain embodiments, each occurrence of R 2 is independently fluoro, methyl, or -OH.

[0306] In certain embodiments, each occurrence of R 2 is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, each occurrence of R 2 is independently hydrogen or unsubstituted alkyl. In certain embodiments, each occurrence of R 2 are independently hydrogen or unsubstituted C 1-6 In certain embodiments, each occurrence of R 2 are independently hydrogen or unsubstituted C 1-4 In certain embodiments, each occurrence of R 2 are independently hydrogen or unsubstituted C 1-3 In certain embodiments, each occurrence of R 2 are independently hydrogen or unsubstituted C 1-2 In certain embodiments, each occurrence of R 2 are independently hydrogen or methyl.

[0307] In certain embodiments, each occurrence of R 2 is independently substituted or unsubstituted alkyl. In certain embodiments, each occurrence of R 2 is independently unsubstituted alkyl. In certain embodiments, each occurrence of R 2 are independently unsubstituted C 1-6 In certain embodiments, each occurrence of R 2 are independently unsubstituted C 1-4 In certain embodiments, each occurrence of R 2 are independently unsubstituted C 1-3 In certain embodiments, each occurrence of R 2 are independently unsubstituted C 1-2 In certain embodiments, each occurrence of R 2 are independently methyl.

[0308] As described herein, t is an integer from 0 to 12. In certain embodiments, t is from 0 to 6. In certain embodiments, t is from 1 to 6. In certain embodiments, t is from 0 to 4. In certain embodiments, t is from 1 to 4. In certain embodiments, t is from 0 to 2. In certain embodiments, t is 1 or 2. In certain embodiments, t is 0 or 1. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 4. In certain embodiments, t is 5. In certain embodiments, t is 6. In certain embodiments, t is 7. In certain embodiments, t is 8. In certain embodiments, t is 9. In certain embodiments, t is 10. In certain embodiments, t is 11. In certain embodiments, t is 12.

[0309] Embodiments of formula (I)

[0310] In certain embodiments, the compound of formula (I) is a compound of formula (Ia):

[0311]

[0312] or a pharmaceutically acceptable salt thereof, wherein A, P, R, R 2 、R 7 and t are as defined herein.

[0313] In certain embodiments, the compound of formula (I) is a compound of formula (Ib):

[0314]

[0315] or a pharmaceutically acceptable salt thereof, wherein R 1 -NR 2 -, -O-, or -S-; and A, P, R, R 2 、R 7 and t are as defined herein.

[0316] In certain embodiments, the compound of formula (I) is a compound of formula (Ic):

[0317]

[0318] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 、R 7 and t are as defined herein.

[0319] In certain embodiments, the compound of formula (I) is a compound of formula (Id):

[0320]

[0321] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently bond, -CR 2 R 2 -、CR 2 ,C,N,-NR 2 -, -O- or S; q is 3-6; and A, P, R 2 and R 7 As defined herein.

[0322] In certain embodiments, the compound of formula (I) is a compound of formula (Ie):

[0323]

[0324] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; represents a single bond or a double bond; and A, P, R 2 and R 7 As defined herein.

[0325] In certain embodiments, the compound of formula (I) is a compound of formula (Ie-1):

[0326]

[0327] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0328] In certain embodiments, the compound of formula (I) is a compound of formula (If):

[0329]

[0330] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0331] In certain embodiments, the compound of formula (I) is a compound of formula (If-1):

[0332]

[0333] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0334] In certain embodiments, the compound of formula (I) is a compound of formula (If-2):

[0335]

[0336] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0337] In certain embodiments, the compound of formula (I) is a compound of formula (If-3):

[0338]

[0339] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0340] In certain embodiments, the compound of formula (I) is a compound of formula (If-4):

[0341]

[0342] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0343] In certain embodiments, the compound of formula (I) is a compound of formula (If-5):

[0344]

[0345] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R7 As defined herein.

[0346] In certain embodiments, the compound of formula (I) is a compound of formula (Ig):

[0347]

[0348] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0349] In certain embodiments, the compound of formula (I) is a compound of formula (Ig-1):

[0350]

[0351] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0352] In certain embodiments, the compound of formula (I) is a compound of formula (Ig-2):

[0353]

[0354] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0355] In certain embodiments, the compound of formula (I) is a compound of formula (Ig-3):

[0356]

[0357] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0358] In certain embodiments, the compound of formula (I) is a compound of formula (Ig-4):

[0359]

[0360] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0361] In certain embodiments, the compound of formula (I) is a compound of formula (Ig-5):

[0362]

[0363] or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently a bond or -CR 2 R 2 -; and A, P, R 2 and R 7 As defined herein.

[0364] In certain embodiments, the compound of formula (I) is a compound of formula (Ih):

[0365]

[0366] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein.

[0367] In certain embodiments, the compound of formula (I) is a compound of formula (Ih-1):

[0368]

[0369] or a pharmaceutically acceptable salt thereof, wherein A, P and R 7 As defined herein.

[0370] In certain embodiments, the compound of formula (I) is a compound of formula (Ih-2):

[0371]

[0372] or a pharmaceutically acceptable salt thereof, wherein A, P and R 7 As defined herein.

[0373] In certain embodiments, the compound of formula (I) is a compound of formula (Ii):

[0374]

[0375] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein. In certain embodiments, the compound of formula (I) is a compound of formula (Ii-1):

[0376]

[0377] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein. In certain embodiments, the compound of formula (I) is a compound of formula (Ii-2):

[0378]

[0379] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein. In certain embodiments, the compound of formula (I) is a compound of formula (Ii-3):

[0380]

[0381] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein. In certain embodiments, the compound of formula (I) is a compound of formula (Ii-4):

[0382]

[0383] or a pharmaceutically acceptable salt thereof, wherein A, P and R 7 As defined herein.

[0384] In certain embodiments, the compound of formula (I) is a compound of formula (Ii-5):

[0385]

[0386] or a pharmaceutically acceptable salt thereof, wherein A, P and R 7 As defined herein.

[0387] In certain embodiments, the compound of formula (I) is a compound of formula (Ii-6):

[0388]

[0389] or a pharmaceutically acceptable salt thereof, wherein A, P and R 7 As defined herein.

[0390] In certain embodiments, the compound of formula (I) is a compound of formula (Ii-7):

[0391]

[0392] or a pharmaceutically acceptable salt thereof, wherein A, P and R 7 As defined herein.

[0393] In certain embodiments, the compound of formula (I) is a compound of formula (Ii-8):

[0394]

[0395] or a pharmaceutically acceptable salt thereof, wherein A is as defined herein.

[0396] In certain embodiments, the compound of formula (I) is a compound of formula (Ij):

[0397]

[0398] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein.

[0399] In certain embodiments, the compound of formula (I) is a compound of formula (Ij-1):

[0400]

[0401] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein.

[0402] In certain embodiments, the compound of formula (I) is a compound of formula (Ij-2):

[0403]

[0404] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein.

[0405] In certain embodiments, the compound of formula (I) is a compound of formula (Ij-3):

[0406]

[0407] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein.

[0408] In certain embodiments, the compound of formula (I) is a compound of formula (Ij-4):

[0409]

[0410] or a pharmaceutically acceptable salt thereof, wherein A, P and R 7 As defined herein.

[0411] In certain embodiments, the compound of formula (I) is a compound of formula (Ij-5):

[0412]

[0413] or a pharmaceutically acceptable salt thereof, wherein A, P and R 7 As defined herein.

[0414] In certain embodiments, the compound of formula (I) is a compound of formula (Ij-6):

[0415]

[0416] or a pharmaceutically acceptable salt thereof, wherein A, P and R 7 As defined herein.

[0417] In certain embodiments, the compound of formula (I) is a compound of formula (Ik):

[0418]

[0419] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein.

[0420] In certain embodiments, the compound of formula (I) is a compound of formula (Ik-1):

[0421]

[0422] or a pharmaceutically acceptable salt thereof, wherein A, P and R 7 As defined herein.

[0423] In certain embodiments, the compound of formula (I) is a compound of formula (II):

[0424]

[0425] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein.

[0426] In certain embodiments, the compound of formula (I) is a compound of formula (Il-1):

[0427]

[0428] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein.

[0429] In certain embodiments, the compound of formula (I) is a compound of formula (I1-2):

[0430]

[0431] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein. In certain embodiments of the compound of formula (I1-2), R 2 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroaryl. In certain embodiments of the compound of formula (I1-2), R 2 is substituted alkyl or substituted heteroaryl. In certain embodiments of the compound of formula (I1-2), R 2 Is a haloalkyl or substituted triazolyl. In certain embodiments of the compound of formula (Il-2), R 2 is a triazolyl group substituted with fluoromethyl or 2,4-difluorophenyl.

[0432] In certain embodiments, the compound of formula (I) is a compound of formula (I1-3):

[0433]

[0434] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein. In certain embodiments of the compound of formula (I1-3), R 2 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroaryl. In certain embodiments of the compound of formula (I1-3), R 2 is substituted alkyl or substituted heteroaryl. In certain embodiments of the compound of formula (I1-3), R 2 Is a haloalkyl or substituted triazolyl. In certain embodiments of the compound of formula (I1-3), R 2 is a triazolyl group substituted with fluoromethyl or 2,4-difluorophenyl.

[0435] In certain embodiments, the compound of formula (I) is a compound of formula (I1-4):

[0436]

[0437] or a pharmaceutically acceptable salt thereof, wherein A and R 2As defined herein. In certain embodiments of the compound of formula (I1-4), R 2 is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroaryl. In certain embodiments of the compound of formula (I1-4), R 2 is substituted alkyl or substituted heteroaryl. In certain embodiments of the compound of formula (I1-4), R 2 Is a haloalkyl or substituted triazolyl. In certain embodiments of the compound of formula (I1-4), R 2 is a triazolyl group substituted with fluoromethyl or 2,4-difluorophenyl.

[0438] In certain embodiments, the compound of formula (I) is a compound of formula (Im):

[0439]

[0440] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein.

[0441] In certain embodiments, the compound of formula (I) is a compound of formula (Im-1):

[0442]

[0443] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein.

[0444] In certain embodiments, the compound of formula (I) is a compound of formula (Im-2):

[0445]

[0446] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein.

[0447] In certain embodiments, the compound of formula (I) is a compound of formula (Im-3):

[0448]

[0449] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein. In certain embodiments of the compound of formula (Im-3), R 2 In certain embodiments of the compound of formula (Im-3), R 2 For fluorine.

[0450] In certain embodiments, the compound of formula (I) is a compound of formula (Im-4):

[0451]

[0452] or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 and R 7 As defined herein. In certain embodiments of the compound of formula (Im-4), R 2 In certain embodiments of the compound of formula (Im-4), R 2 For fluorine.

[0453] In certain embodiments, the compound of formula (I) is a compound of formula (Im-5):

[0454]

[0455] or a pharmaceutically acceptable salt thereof, wherein A and R 2 As defined herein. In certain embodiments of the compound of formula (Im-5), R 2 In certain embodiments of the compound of formula (Im-5), R 2 For fluorine.

[0456] In certain embodiments, the compound of formula (I) is a compound of formula (In):

[0457]

[0458] or a pharmaceutically acceptable salt thereof, wherein A, R 2 and R 7 As defined herein.

[0459] In certain embodiments, the compound of formula (I) is a compound of formula (In-1):

[0460]

[0461] or a pharmaceutically acceptable salt thereof, wherein A and R 2 As defined herein.

[0462] In certain embodiments, the compound of formula (I) is a compound of formula (In-2):

[0463]

[0464] or a pharmaceutically acceptable salt thereof, wherein B, R 2 、R 8 、R 9 and p are as defined herein.

[0465] In certain embodiments, the compound of formula (I) is a compound of formula (In-3):

[0466]

[0467] or a pharmaceutically acceptable salt thereof, wherein R 2 、R 8 、R 9 , X, Y, n and p are as defined herein.

[0468] In certain embodiments, the compound of formula (I) is a compound of formula (In-4):

[0469]

[0470] or a pharmaceutically acceptable salt thereof, wherein R 2 、R 8 、R 9 , Y and p are as defined herein.

[0471] In certain embodiments, the compound of formula (I) is a compound of formula (In-5):

[0472]

[0473] or a pharmaceutically acceptable salt thereof, wherein R 2 、R 8 、R 9 , Y and p are as defined herein.

[0474] In certain embodiments, the compound of formula (I) is a compound of formula (In-6):

[0475]

[0476] or a pharmaceutically acceptable salt thereof, wherein R 2 、R 8 、R 9 , Y and p are as defined herein.

[0477] In certain embodiments, the compound of formula (I) is a compound of formula (In-7):

[0478]

[0479] or a pharmaceutically acceptable salt thereof, wherein R 2 、R 8 and R 9 As defined herein.

[0480] In certain embodiments, the compound of formula (I) is a compound of formula (In-8):

[0481]

[0482] or a pharmaceutically acceptable salt thereof, wherein R 2 、R 8 and R 9 As defined herein.

[0483] In certain embodiments, the compound of formula (I) is a compound of formula (In-9):

[0484]

[0485] or a pharmaceutically acceptable salt thereof, wherein R 2 、R 8 and R 9 As defined herein.

[0486] In certain embodiments, the compound of formula (I) is a compound of formula (In-10):

[0487] or a pharmaceutically acceptable salt thereof, wherein R 2 、R 8 and R 9 As defined herein.

[0488] In certain embodiments, the compound of formula (I) is a compound of formula (In-11):

[0489] or a pharmaceutically acceptable salt thereof, wherein R 2 and R 9 As defined herein.

[0490] In certain embodiments, the compound of formula (I) is a compound of formula (In-12):

[0491] or a pharmaceutically acceptable salt thereof, wherein R 2 and R 9 As defined herein.

[0492] In certain embodiments, the compound of formula (I) is a compound of formula (In-13):

[0493] or a pharmaceutically acceptable salt thereof, wherein R 2 and R 9 As defined herein.

[0494] In certain embodiments, the compound of formula (I) is a compound of formula (In-14):

[0495] or a pharmaceutically acceptable salt thereof, wherein R 2 As defined herein.

[0496] In certain embodiments, the compound of formula (I) is a compound of any of the following formulas:

[0497]

[0498]

[0499] and pharmaceutically acceptable salts thereof.

[0500] In certain embodiments, the compound of formula (I) is a compound of the formula:

[0501]

[0502] or a pharmaceutically acceptable salt thereof.

[0503] In certain embodiments, the compound of formula (I) is a compound of the formula:

[0504]

[0505] or a pharmaceutically acceptable salt thereof, wherein each R 11 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group or nitrogen protecting group, or two R 11 The groups are connected to form a substituted or unsubstituted heterocyclyl ring. In certain embodiments, -N(R 11 )2 is

[0506] In certain embodiments, the compound of formula (I) is a compound of the formula:

[0507]

[0508] or a pharmaceutically acceptable salt thereof.

[0509] In certain embodiments, the compound of formula (I) is a compound of the formula:

[0510]

[0511] or a pharmaceutically acceptable salt thereof, wherein each R 11 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, nitrogen protecting group, or two R 11 The groups are connected to form a substituted or unsubstituted heterocyclyl ring. In certain embodiments, -N(R11 )2 is

[0512] In certain embodiments, the compound of formula (I) is a compound of the formula:

[0513]

[0514] or a pharmaceutically acceptable salt thereof, wherein R 20 is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -OR A 、-N(R A )2, or -SR A ; and R 10 For hydrogen,

[0515] In certain embodiments, the compound of formula (I) is a compound of the formula:

[0516]

[0517] or a pharmaceutically acceptable salt thereof, wherein X is N or CH; and R 10 For hydrogen,

[0518] Exemplary Compounds Exemplary compounds of Formula (I) include, but are not limited to, the compounds listed in Table 1.

[0519] Table 1. Exemplary compounds of formula (I)

[0520]

[0521]

[0522] Exemplary compounds of formula (I) include, but are not limited to, the compounds listed in Table 2.

[0523] Table 2. Exemplary compounds of formula (I)

[0524]

[0525]

[0526] Exemplary compounds of formula (I) include, but are not limited to, the compounds listed in Table 3.

[0527] Table 3. Exemplary compounds of formula (I)

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536] Preparation of compounds of formula (I)

[0537] The following describes exemplary methods that can be used to prepare the compounds of the present disclosure, but should not be considered as limiting. The compounds herein can be prepared by other synthetic methods known in the art, and the procedures described herein can be modified or combined with other known methods.

[0538] In another aspect, the compounds of the present disclosure are prepared by a process comprising ring-closing metathesis of a compound of formula (A) or (A1), as shown in Scheme 1.

[0539] Solution 1.

[0540]

[0541] For all intermediates, A, P, R 1 、R 2 and R 7 As defined herein for compounds of formula (I), unless otherwise stated.

[0542] In certain embodiments, the ring-closing metathesis reaction is achieved by using a transition metal catalyst. In certain embodiments, the transition metal catalyst is a tungsten (W), molybdenum (Mo) or ruthenium (Ru) catalyst. In certain embodiments, the catalyst is a ruthenium catalyst.

[0543] For examples of olefin metathesis reagents, catalysts, and reaction conditions that can be used in the present process, see, for example, Schrodi, Y.; Pederson, RL Aldrichimica Acta 2007, 40, 45; Adv. Synth. Catal. 2007, 349, 1-268; Grubbs, RH Tetrahedron 2004, 60, 7117; Handbook of Metathesis; Grubbs, RH, Ed.; Wiley-VCH: Weinheim, 2003; Vols.1–3; Trnka, TM; Grubbs, RHAcc. Chem. Res. 2001, 34, 18; Fürstner, A. An gew.Chem.,Int.Ed.2000,39,3012;Schuster,M.;Blechert,S.Angew.Chem.,Int.Ed.1997,36,2036;Ritter,T.etal.Organometallics 2006,25,5740;Chatterjee,AKet al.J.Am.Chem.Soc.2000,122,3783;Chatterjee,AK;Grubbs,RHOrg.Lett.1999,1,1751;Murelli,RP;Snapper,MLOrg.Lett.2007,9,1749;Stewart,ICet al.Org.Lett.2007,9,1589;Ung,T.etal.Organometallics 2004,23,5399;Benitez,D.;Goddard,WA,III.J.Am.Chem.Soc.2005,127,12218;Love,JAet al. Angew. Chem., Int. Ed. 2002, 41, 4035; Sanford, MS et al. Organometallics 2001, 20, 5314; Choi, T.-L.; Grubbs, RH Angew. Chem. 2003, 115, 1785; Ritter, T. et al. Organometallics 2006, 25, 5740; and references cited therein; each of which is incorporated herein by reference.

[0544] In certain embodiments, the metathesis catalyst is a Grubbs catalyst. In certain embodiments, the Grubbs catalyst has the formula:

[0545]

[0546] Benzylenebis-(tricyclohexylphosphine)-dichlororuthenium (X=Cl); Benzylenebis-(tricyclohexylphosphine)-dibromoruthenium (X=Br); Benzylenebis-(tricyclohexylphosphine)-diiodoruthenium (X=I);

[0547]

[0548] 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tricyclohexylphosphine)ruthenium (X=Cl; R=cyclohexyl); 1,3-(bis(mesityl)-2-imidazolidinylidene)dibromo-(phenylmethylene)(tricyclohexylphosphine)ruthenium (X=Br; R=cyclohexyl); 1,3-(bis(mesityl)-2-imidazolidinylidene)diiodo-(phenylmethylene)(tricyclohexylphosphine)ruthenium (X=I; R=cyclohexyl); 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(triphenylphosphine)ruthenium (X=Cl; R=phenyl); 1,3-(bis(methyl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tribenzylphosphine)ruthenium (X=Cl; R=benzyl);

[0549]

[0550]

[0551] In certain embodiments, the metathesis catalyst is a second generation Grubbs catalyst (Grubbs II), which has the formula:

[0552]

[0553] In certain embodiments, the metathesis catalyst is a Grubbs-Hoveyda catalyst. In certain embodiments, the Grubbs-Hoveyda catalyst has the formula:

[0554]

[0555] In certain embodiments, the method further comprises coupling a compound of formula (B) with a compound of formula (C) to form a compound of formula (A), or coupling a compound of formula (B1) with a compound of formula (C) to form a compound of formula (A1), as shown in Scheme 2 below.

[0556] Option 2.

[0557]

[0558]

[0559] In certain embodiments, the formation of the amide bond is promoted by an amide coupling agent (e.g., 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), hydroxybenzotriazole (HOBt), etc., or a combination thereof). In certain embodiments, the amide coupling agent (e.g., HATU, EDC, HOBt) reacts with the compound of formula (C). In certain embodiments, the amide coupling agent (e.g., HATU, EDC, HOBt) reacts with the compound of formula (C) prior to amide coupling with the compound of formula (B) or (B1). In certain embodiments, the amide coupling agent is HATU.

[0560] In certain embodiments, the method comprises adding up to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 equivalents of an amide coupling agent. In certain embodiments, the method comprises carrying out the coupling reaction at room temperature, ambient temperature, or elevated temperature. In certain embodiments, the method comprises carrying out the coupling reaction at 20-60°C, 20-50°C, 20-40°C, 20-30°C, 20-25°C, or 25-30°C.

[0561] In certain embodiments, additional reagents may be added to the amide bond forming reaction. In certain embodiments, additional reagents may promote amide coupling by protecting the free hydroxyl groups of the compound of formula (B) or (B1). In certain embodiments, the additional reagent is a silylating agent. In certain embodiments, the silylating agent reacts with the free hydroxyl groups of the compound of formula (B) or (B1) to form a silyl protecting group in situ during the reaction. In certain embodiments, additional reagents are added to the compound of formula (B) or (B1) before amide coupling. In certain embodiments, the additional reagent is N, O-bis(trimethylsilyl)trifluoroacetamide. In certain embodiments, the method comprises adding up to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0 or more equivalents of a silylating agent.

[0562] In another aspect, the compounds of the present disclosure are prepared by ring-closing metathesis of a compound of formula (B) to form a compound of formula (E), or ring-closing metathesis of a compound of formula (B1) to form a compound of formula (E1), as shown in Scheme 3.

[0563] In certain embodiments, ring-closing metathesis is achieved using any of the catalysts and conditions described herein.

[0564] Option 3.

[0565]

[0566] For all intermediates, unless otherwise stated, A, P, R 1 、R 2 and R 7 are as defined herein for compounds of formula (I). In certain embodiments, R 7 is a substituted or unsubstituted acetyl group. In certain embodiments, R 7 It is trifluoroacetyl.

[0567] In certain embodiments, the method further comprises coupling a compound of formula (E) with a compound of formula (C) to form a compound of formula (I), or coupling a compound of formula (E1) with a compound of formula (C) to form a compound of formula (I), as shown in Scheme 4 below.

[0568] Solution 4.

[0569]

[0570]

[0571] In certain embodiments, the formation of the amide bond is promoted by an amide coupling agent (e.g., 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), hydroxybenzotriazole (HOBt), etc., or a combination thereof). In certain embodiments, the amide coupling agent (e.g., HATU, EDC, HOBt) reacts with the compound of formula (C). In certain embodiments, the amide coupling agent (e.g., HATU, EDC, HOBt) reacts with the compound of formula (C) prior to amide coupling with the compound of formula (E) or (E1). In certain embodiments, the amide coupling agent is HATU.

[0572] In certain embodiments, the method comprises adding up to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 equivalents of an amide coupling agent. In certain embodiments, the method comprises carrying out the coupling reaction at room temperature, ambient temperature, or elevated temperature. In certain embodiments, the method comprises carrying out the coupling reaction at 20-60°C, 20-50°C, 20-40°C, 20-30°C, 20-25°C, or 25-30°C.

[0573] In certain embodiments, additional reagents are added to the amide bond forming reaction. In certain embodiments, additional reagents can promote amide coupling by protecting the free hydroxyl groups of the compound of formula (E) or (E1). In certain embodiments, additional reagents are silylating agents. In certain embodiments, silylating agents react with the free hydroxyl groups of the compound of formula (E) or (E1) to form a silyl protecting group in situ during the reaction. In certain embodiments, additional reagents are added to the compound of formula (E) or (E1) before amide coupling. In certain embodiments, additional reagents are N, O-bis(trimethylsilyl)trifluoroacetamide. In certain embodiments, the method comprises adding up to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0 or more equivalents of a silylating agent.

[0574] Pharmaceutical compositions and administration

[0575] The present disclosure provides a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0576] Pharmaceutically acceptable excipients include any or all solvents, diluents or other liquid vehicles, dispersants, suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like, as appropriate to the specific dosage form desired. General considerations in formulating and / or preparing pharmaceutical composition formulations 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).

[0577] The pharmaceutical compositions herein can be prepared by any method known in the pharmaceutical art. Generally, the preparation method includes the step of combining the compound of the present invention with a carrier and / or one or more other auxiliary agents (accessory ingredients), and then, if necessary and / or desired, shaping and / or packaging the product into a desired single dose unit or multiple dose units.

[0578] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, 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 containing a predetermined amount of a compound of the present disclosure. The amount of the compound is generally equal to the dose of the compound to be administered to a subject and / or a convenient fraction of that dose, for example, one-half or one-third of that dose.

[0579] The relative amounts of the compound, pharmaceutically acceptable excipients, and / or any other ingredients in the pharmaceutical compositions of the present invention will vary depending on the characteristics, size, and / or condition of the subject being treated, and also on the route by which the composition is to be administered. For example, the composition may include 0.1% to 100% (w / w) of the compound.

[0580] The pharmaceutically acceptable excipient for the preparation of the pharmaceutical composition provided by the application comprises an inert diluent, a dispersant and / or a granulating agent, a surfactant and / or an emulsifying agent, a disintegrating agent, a binding agent, a preservative, a buffer, a lubricant and / or an oil. Excipients such as cocoa butter and suppository wax, coloring agents, coating agents, sweeteners, flavoring agents and spices may also be present in the composition.

[0581] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound, the liquid dosage form may also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, and mixtures thereof. In addition to inert diluents, oral compositions may include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and fragrances. In a specific embodiment for parenteral administration, the conjugate of the invention is mixed with a solubilizing agent, and mixtures thereof.

[0582] Injectable formulations, for example, sterile injectable aqueous or oily suspensions can be prepared according to the prior art using suitable dispersants or wetting agents and suspending agents. Sterile injectable formulations can be sterile injectable solutions, suspensions, or emulsions in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable carriers and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media.

[0583] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound 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) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, some 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 glyceryl 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 form may comprise buffering agents.

[0584] The dosage form for topical and / or transdermal administration of the compounds of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and / or patches. Typically, the compound is mixed under aseptic conditions with a pharmaceutically acceptable carrier and / or any required preservative and / or buffer.

[0585] Although the description of the pharmaceutical compositions provided herein relates 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 animals of all kinds. Modification of pharmaceutical compositions suitable for administration to humans to render the compositions suitable for administration to various animals is also readily understood, and those skilled in the veterinary field can design and / or perform such modifications using ordinary experimentation.

[0586] The compounds provided herein are generally formulated in unit dosage form for ease of administration and uniformity of dosage. However, it will be understood that the total daily dosage of the compound will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for a particular subject or organism will depend on a number of factors, including the severity of the disease, disorder, condition, and disorder to be treated; the activity of the specific compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and excretion rate of the specific compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors well known in the medical field.

[0587] The compounds and compositions provided herein can be administered in any way, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal (interdermal), rectal, intravaginal, intraperitoneal, topical (as powder, ointment, cream and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation and / or inhalation; and / or as 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 medicament, 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 in a state of intolerance to oral administration, so intravenous, intramuscular and / or rectal administration are also preferred optional modes of administration.

[0588] An effective amount can be included in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In some embodiments, when multiple doses are administered to a subject or administered to a tissue or cell, any two doses of the multiple doses include different or substantially the same amount of the compound herein. In some embodiments, when multiple doses are administered to a subject or administered to a tissue or cell, the frequency of administering multiple doses to the subject or administering multiple doses to the tissue or cell is three times a day, twice a day, once a day, once every other day, once every three days, once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the doses herein (e.g., a single dose or any of the multiple doses) independently include 0.1 μg to 1 μg, 0.001 mg to 0.01 mg, 0.01 mg to 0.1 mg, 0.1 mg to 1 mg, 1 mg to 3 mg, 3 mg to 10 mg, 10 mg to 30 mg, 30 mg to 100 mg, 100 mg to 300 mg, 300 mg to 1,000 mg, or 1 g to 10 g (inclusive) of a compound herein.

[0589] It will be understood that the compounds or compositions herein can be administered in combination with one or more other therapeutic agents. The compounds or compositions can be administered simultaneously with one or more other therapeutic agents, before or after one or more other therapeutic agents. Typically, each drug can be administered with a dosage and / or schedule determined for the drug. It is further understood that the other therapeutic agents used in the combination can also be administered together in a single composition or separately in different compositions. The specific combination adopted in the dosing regimen will take into account the compatibility of the invented compound with the other therapeutic agents and / or the desired therapeutic effect to be achieved. In general, it is contemplated that the other therapeutic agents used in the combination will be used at a level not exceeding that when they are used alone. In certain embodiments, the level used in the combination will be lower than the level they are used alone.

[0590] Exemplary additional therapeutically active agents include, but are not limited to, antibiotics, antivirals, anesthetics, anticoagulants, enzyme inhibitors, steroids, steroidal or nonsteroidal anti-inflammatory drugs, antihistamines, immunosuppressants, antigens, vaccines, antibodies, decongestants, sedatives, opioids, pain relievers, analgesics, antipyretics, 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 under the Code of Federal Regulations (CFR)), therapeutically active agents, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0591] In some embodiments, the other therapeutically active agent is an antibiotic. Exemplary antibiotics include, but are not limited to, penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g., cephalexin), compounds (e.g., erythromycin, clarithromycin, azithromycin, troleandomycin), fluoroquinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin), sulfonamides (e.g., trimethoprim), tetracyclines (e.g., tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycycline, chlortetracycline, oxytetracycline, minocycline, 6-deoxytetracycline, lymecycline, meclocycline, methacycline, rolicycline, and glycylcycline antibiotics (e.g., tigecycline), aminoglycosides (e.g., gentamicin, tobramycin, paromomycin), aminocyclines (e.g., spectinomycin), chloramphenicol, sparmycin, and quinupristin / dalfopristin (Syndercid TM ).

[0592] The present invention also includes kits (e.g., pharmaceutical packaging). The provided kits can include the invented pharmaceutical composition or compound and a container (e.g., a vial, an ampoule, a bottle, a syringe and / or a dispersible package or other suitable container). In certain embodiments, the provided kits can also optionally include a second container comprising a pharmaceutical excipient for diluting or suspending the invented pharmaceutical composition or compound. In certain embodiments, the invented pharmaceutical composition or compound provided in the container and the second container are combined to form a unit dosage form.

[0593] Treatment and usage

[0594] The present disclosure contemplates the use of the compounds of the present invention to treat infectious diseases, such as fungal, bacterial, viral and / or parasitic infections. Lincosamides are well known to have antibacterial activity.

[0595] Therefore, as generally described herein, methods for treating infectious diseases are provided, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Such methods can be performed in vivo (i.e., by administering to a subject). Treatments used herein include therapeutic treatments and prophylactic treatments.

[0596] In certain embodiments, the effective amount is a therapeutically effective amount. For example, in some embodiments, the method slows the progression of an infectious disease in a subject. In certain embodiments, the method improves the condition of a subject suffering from an infectious disease. In certain embodiments, the subject is suspected of having an infectious disease or actually has an infectious disease.

[0597] In some embodiments, the effective amount is a prophylactic effective amount. For example, in some embodiments, the method prevents or reduces the possibility of an infectious disease, for example, in some embodiments, the method includes administering to a subject in need thereof a compound of the present disclosure in an amount sufficient to prevent or reduce the possibility of an infectious disease. In some embodiments, the subject has a risk of contracting an infectious disease (e.g., has been exposed to another subject suspected of having an infectious disease or indeed having an infectious disease, or has been exposed to or is believed to have been exposed to a pathogen).

[0598] In one aspect, a method for killing a microorganism (e.g., a fungus, bacteria, virus, parasite) is provided, comprising contacting the microorganism with an effective amount of a compound of the present disclosure. The compound can contact the microorganism in vivo (e.g., in a subject in need thereof) or in vitro.

[0599] In another aspect, a method for inhibiting the growth of a microorganism (e.g., fungus, bacteria, virus, parasite) is provided, comprising contacting the microorganism with an effective amount of a compound of the invention. The compound can contact the microorganism in vivo (e.g., in a subject in need thereof) or in vitro.

[0600] In another aspect, provided herein is an in vitro method for inhibiting the growth of a pathogen comprising contacting an effective amount of a compound of the present invention with a pathogen (eg, bacteria, virus, fungus, or parasite) in cell culture.

[0601] On the other hand, an in vitro method for inhibiting pathogen growth is provided, comprising contacting a pathogen (e.g., a bacterium, virus, fungus, or parasite) with an effective amount of a compound of the present disclosure. On the other hand, a method for inhibiting protein synthesis with an effective amount of a compound of the present disclosure is provided (e.g., by binding to the 23s portion of the 50S subunit of the bacterial ribosome and causing premature dissociation of peptidyl-tRNA from the ribosome to interfere with protein synthesis). In certain embodiments, inhibiting protein synthesis comprises inhibiting the ribosomes of bacteria with an effective amount of a compound of the present disclosure. Protein synthesis can be inhibited in vivo or in vitro.

[0602] As used herein, "infectious disease" and "microbial infection" are used interchangeably and refer to infection by a pathogen, such as a fungus, bacteria, virus, or parasite. In certain embodiments, the infectious disease is caused by a fungus, bacteria, or parasite. In some embodiments, the infectious disease is caused by a pathogen that is resistant to other treatments. In some embodiments, the infectious disease is caused by a pathogen that is multidrug-resistant or drug-resistant, for example, an infectious disease is caused by a pathogen that neither grows nor dies in the presence of another treatment or that does not grow or die as a result of another treatment.

[0603] In certain embodiments, the infectious disease is a bacterial infection. For example, in certain embodiments, the present application provides a method for treating a bacterial infection, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0604] In certain embodiments, the compound has a mean inhibitory concentration (MIC) against a specific bacteria of less than or equal to 50 μg / mL, less than or equal to 25 μg / mL, less than or equal to 20 μg / mL, less than or equal to 10 μg / mL, less than or equal to 5 μg / mL, less than or equal to 1 μg / mL, less than or equal to 0.5 μg / mL, or less than or equal to 0.25 μg / mL.

[0605] In certain embodiments, the bacteria are sensitive (e.g., responsive) or resistant to known commercial compounds, such as azithromycin, lincomycin, clindamycin, telithromycin, erythromycin, spiramycin, and the like. In certain embodiments, the bacteria are resistant to known compounds. For example, in certain embodiments, the bacteria are lincomycin-resistant or clindamycin-resistant.

[0606] In certain embodiments, the bacterial infection is resistant to other antibiotic (e.g., non-compound) therapies. For example, in certain embodiments, the pathogen has vancomycin resistance (VR). In certain embodiments, the pathogen has methicillin resistance (MR), for example, in certain embodiments, the bacterial infection is methicillin-resistant Staphylococcus aureus infection (MRSA infection). In certain embodiments, the pathogen has quinolone resistance (QR). In certain embodiments, the pathogen has fluoroquinolone resistance (FR).

[0607] Exemplary bacterial interferences include, but are not limited to, the following bacterial infections: Gram-positive bacteria (e.g., phylum Actinobacteria, phylum Firmicutes, or phylum Tenericutes); Gram-negative bacteria (e.g., phylum Aquificae, phylum Deinococcus–Thermus, phylum Fibrobacteres / chlorobi / Bacteroidetes (FCB)), phylum Fusobacteria, phylum Gemmatimonadest, phylum Ntrospirae, phylum Planctomycetes / Verrucomicrobia / Chlamydiae (PVC)), phylum Proteobacteria, phylum Spirochaetes, or phylum Synergistetes); or other bacteria (e.g., phylum Acidobacteria, phylum Chlroflexi, phylum Chrystiogenetes, phylum Cyanobacteria, phylum Deferrubacteres, phylum Dictyoglomi, phylum Thermodesulfobacteria, or phylum Thermotogae).

[0608] In certain embodiments, the bacterial infection is a Gram-positive bacterial infection.

[0609] In certain embodiments, the Gram-positive bacteria are bacteria of the phylum Firmicutes.

[0610] In certain embodiments, the bacterium is a member of the phylum Firmicutes and the genus Enterococcus, i.e., the bacterial infection is an enterococcal infection. Exemplary Enterococcus bacteria include, but are not limited to, E. avium, E. durans, E. faecalis, E. faecium, E. gallinarum, E. solitarius, E. casseliflavus, and E. raffinosus.

[0611] In certain embodiments, the bacteria is a member of the phylum Firmicutes and the genus Staphylococcus, i.e., the bacterial infection is a Staphylococcus infection. Exemplary Staphylococcus bacteria include, but are not limited to, S. arlettae, S. aureus, S. auricularis, S. capitis, S. caprae, S. carnous, S. chromogenes, S. cohii, S. condimenti, S. croceolyticus, S. delphini, S. devri esei, Staphylococcus epidermidis (S.epidermis), Staphylococcus equorum (S.equorum), Staphylococcus felis (S.felis), S.fluroettii, Staphylococcus gallinarum (S.gallinarum), Staphylococcus haemolyticus (S.haemolyticus), Staphylococcus hominis (S.hominis), Staphylococcus hyicus (S.hyicus), Staphylococcus intermedius (S.intermedius), Staphylococcus kloosii (S.kloosii), S.leei, Staphylococcus lenus (S.lenus), In some embodiments, the staphylococcal infection is a Staphylococcus aureus infection.

[0612] In certain embodiments, the Staphylococcus aureus has an efflux (e.g., mef, msr) genotype. Bacteria with an efflux genotype actively pump drugs out of the cell through efflux pumps.

[0613] In certain embodiments, the Staphylococcus aureus has a methylase (e.g., erm) genotype. In certain embodiments, erm is a bacterial gene encoding erythromycin ribosomal methylase, which methylates a single adenine in 23S rRNA, which is itself a component of 50S rRNA.

[0614] In certain embodiments, the bacteria is a member of the phylum Firmicutes and the genus Bacillus, i.e., the bacterial infection is a Bacillus infection. Exemplary Bacillus bacteria include, but are not limited to, B. alcalophilus, B. alvei, B. aminovorans, B. amyloliquefaciens, B. aneurinolyticus, B. anthracis, B. aquaemaris, B. atrophaeus, B. boroniphilus, B. brevis, B. thermolyticus, B. Bacillus caldolyticus, Bacillus centrosporus, Bacillus cereus, Bacillus circulans, Bacillus coagulans, Bacillus firmus, Bacillus flavothermus, Bacillus fusiformis, Bacillus globigii, B. infernus, Bacillus larvae, Bacillus laterosporus, Bacillus spp. orus), Bacillus lentus, Bacillus licheniformis, Bacillus megaterium, Bacillus mesentericus, Bacillus mucilaginosus, Bacillus mycoides, Bacillus natto, Bacillus pantothenticus, Bacillus polymyxa, Bacillus pseudoanthracis, Bacillus pumilus, Bacillus schlegelii, B. sphaericus, B. sporothermodurans, B. stearothermophilus, B. subtilis, B. thermoglucosidasius, B. thuringiensis, B. vulgatis, and B. weihenstephanensis. In certain embodiments, the Bacillus infection is a Bacillus subtilis infection.In certain embodiments, the Bacillus subtilis has an efflux (e.g., mef, msr) genotype. In certain embodiments, the Bacillus subtilis has a methylase (e.g., erm) genotype.

[0615] In certain embodiments, the bacteria is a member of the Firmicutes and Streptococcus. That is, the bacterial infection is a streptococcal infection. Exemplary Streptococcus bacteria include, but are not limited to, S. agalactiae, S. anginosus, S. bovis, S. canis, S. constellatus, S. dysgalactiae, S. equinus, S. iniae, S. intermedius, S. mitis, S. mutans, S. oralis, S. parasanguinis, S. spp. anguinis), S.peroris, S.pneumoniae, S.pyogenes (S.pyogenes), S.ratti, S.salivarius, S.thermophilus, S.sanguinis, S.sobrinus, S.suis, S.uberis, S.vestibularis, S.viridans, and S.zooepidemicus. In certain embodiments, the streptococcal infection is a S.pyogenes infection. In certain embodiments, the streptococcal infection is a S.pneumoniae infection. In certain embodiments, the S.pneumoniae has an efflux (e.g., mef, msr) genotype. In certain embodiments, the S.pneumoniae has a methylase (e.g., erm) genotype.

[0616] In certain embodiments, the bacteria are members of the phylum Firmicutes and the genus Clostridium, i.e., the bacterial infection is a clostridial infection. Examples of Clostridium bacteria include, but are not limited to, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, and Clostridium sordellii.

[0617] In certain embodiments, the compounds of the present disclosure are safer alternatives to clindamycin because the incidence of pseudomembranous colitis is reduced. In certain embodiments, the compounds of the present disclosure have increased activity against Clostridium difficile (C. difficile) compared to clindamycin. In certain embodiments, the mean inhibitory concentration (MIC) of the compound against Clostridium difficile is less than or equal to 50 μg / mL, less than or equal to 25 μg / mL, less than or equal to 20 μg / mL, less than or equal to 10 μg / mL, less than or equal to 5 μg / mL, less than or equal to 1 μg / mL, less than or equal to 0.5 μg / mL, or less than or equal to 0.25 μg / mL.

[0618] In certain embodiments, the bacterial infection is a Gram-negative bacterial infection.

[0619] In certain embodiments, the gram-negative bacteria are bacteria of the phylum Proteobacteria and the genus Escherichia. That is, the bacterial infection is an Escherichia infection. Exemplary Escherichia bacteria include, but are not limited to, Escherichia albertii, Escherichia blattae, Escherichia coli, Escherichia fergusonii, Escherichia hermannii, and Escherichia vulneris. In certain embodiments, the Escherichia infection is an Escherichia coli infection.

[0620] In certain embodiments, gram-negative bacteria are bacteria of the phylum Proteobacteria and the genus Haemophilus. That is, bacterial infection is Haemophilus infection. Exemplary Haemophilus bacteria include but are not limited to Haemophilus aegyptius (H.aegyptius), Haemophilus aphrophilus (H.aphrophilus), Pasteurella avium (H.avium), Haemophilus ducreyi (H.ducreyi), H.felis, Haemophilus haemolyticus (H.haemolyticus), Haemophilus influenzae (H.influenzae), Haemophilus parainfluenzae (H.parainfluenzae), Haemophilus pararabbitus (H.paracuniculus), Haemophilus parahaemolyticus (H.parahaemolyticus), H.pittmaniae, Haemophilus segnis (Haemophilus segnis) and Haemophilus somnus (H.somnus). In certain embodiments, Haemophilus infection is Haemophilus influenzae infection.

[0621] In certain embodiments, gram-negative bacteria are the antibacterials of Proteobacteria and Acinetobacter. That is, bacterial infection is Acinetobacter infection. Exemplary Acinetobacter includes but is not limited to Acinetobacter baumannii (A.baumanii), Acinetobacter haemolyticus and Acinetobacter lwoffii. In certain embodiments, Acinetobacter infection is Acinetobacter baumannii infection.

[0622] In certain embodiments, gram-negative bacteria are bacteria of the phylum Proteobacteria and the genus Klebsiella. That is, the bacterial infection is a Klebsiella infection. Exemplary Klebsiella include, but are not limited to: Klebsiella granulomatis (K.granulomatis), Klebsiella oxytoca (K.oxytoca), Klebsiella michiganensis (K.michiganensis), Klebsiella pneumoniae (K.pneumoniae), Klebsiella quasipneumoniae (K.quasipneumoniae) and Klebsiella variicola (K.variicola). In certain embodiments, the Klebsiella infection is a Klebsiella pneumoniae infection.

[0623] In certain embodiments, gram-negative bacteria are bacteria of the phylum Proteobacteria and Pseudomonas. That is, bacterial infection is Pseudomonas infection. Exemplary Pseudomonas bacteria include but are not limited to Pseudomonas aeruginosa (P.aeruginosa), Pseudomonas oryzihabitans (P.oryzihabitans), P.plecoglissicida, Pseudomonas syringae (P.syringae), Pseudomonas putida (P.putida) and Pseudomonas fluorescens (P.fluorscens). In certain embodiments, Pseudomonas infection is Pseudomonas aeruginosa infection.

[0624] In certain embodiments, the gram-negative bacteria are bacteria of the phylum Bacteroidetes and genus Bacteroides. That is, the bacterial infection is a Bacteroides infection. Exemplary Bacteroides bacteria include, but are not limited to, Bacteroides fragilis (B. fragilis), Bacteroides distasonis (B. distasonis), Bacteroides ovatus, Bacteroides thetaiotaomicron, and Bacteroides vulgaris. In certain embodiments, the Bacteroides infection is a Bacteroides fragilis infection.

[0625] In certain embodiments, the bacterial infection treated is a staphylococcal infection, a streptococcal infection, an enterococcal infection, an acinetobacter infection, a clostridial infection, a bacteriodes infection, an escherichia coli infection, a pseudomonas infection, a neisseria infection, a klebsiella infection or a haemophilus infection. In certain embodiments, the bacterial infection treated is a staphylococcal infection, a streptococcal infection, an enterococcal infection, an acinetobacter infection, an escherichia coli infection, a pseudomonas infection or a klebsiella infection.

[0626] In certain embodiments, the bacterial infection is a dental infection, an abdominal infection, an abscess, pelvic inflammatory disease, or an anaerobic infection.

[0627] In certain embodiments, the compounds are useful in treating acne, toxic shock syndrome, malaria, and reducing the risk of premature birth in women with bacterial vaginosis. In certain embodiments, the compounds are useful in treating methicillin-resistant Staphylococcus aureus.

[0628] In certain embodiments, the bacteria are atypical bacteria, ie, neither Gram-positive nor Gram-negative.

[0629] In certain embodiments, the infectious disease is a parasitic infection. Therefore, in certain embodiments, the present application provides a method for treating a parasitic infection, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0630] In certain embodiments, the compound has an IC of less than 50 uM, less than 25 uM, less than 20 uM, less than 10 uM, less than 5 uM, or less than 1 uM against a particular parasite. 50 (uM).

[0631] Exemplary parasites include, but are not limited to, Trypanosoma spp. (e.g., Trypanosoma cruzi, Trypanosoma brucei), Leishmania spp., Giardia spp., Trichomonas spp., Entamoeba spp., Naegleria spp., Acanthamoeba spp., Schistosoma spp., Plasmodium spp. (e.g., P. flaciparum), Crytosporidium spp., Isospora spp., Balantidium spp., Pneumocystis spp. spp.), Babesia, Loa Loa, Ascaris lumbricoides, Dirofilaria immitis, and Toxoplasma ssp. (e.g., T. gondii).

[0632] As generally described herein, the present invention further relates to a method for treating an inflammatory condition comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof. The method can be performed in vivo (i.e., by administration to a subject) or in vitro (e.g., in contact with a pathogen, tissue, or cell culture). The treatment used herein includes therapeutic and prophylactic treatments.

[0633] In certain embodiments, the effective amount is a therapeutically effective amount. For example, in certain embodiments, the method slows the progression of an inflammatory condition in a subject. In certain embodiments, the method improves the condition of a subject suffering from an inflammatory condition. In certain embodiments, the subject is suspected of having an inflammatory condition or does have an inflammatory condition.

[0634] In certain embodiments, the effective amount is a prophylactic effective amount. For example, in certain embodiments, the method prevents or reduces the likelihood of an inflammatory condition. For example, in certain embodiments, the method comprises administering to a subject in need thereof an amount of a compound of the invention sufficient to prevent or reduce the likelihood of an inflammatory condition. In certain embodiments, the subject is at risk for an inflammatory condition.

[0635] The term "inflammatory condition" refers to those diseases, disorders or conditions characterized by the following symptoms: pain (dolor, resulting from the production of toxins and irritation of nerves), heat (burning, resulting from vasodilation), redness (rubor, resulting from vasodilation and increased blood flow), swelling (tumor, resulting from excessive influx and restricted outflow of fluids) and / or loss of function (loss of function, which may be partial or complete, temporary or permanent). Inflammation manifests itself in many forms and includes, but is not limited to, acute inflammation, adhesive inflammation, atrophic inflammation, catarrhal inflammation, chronic inflammation, sclerotic inflammation, diffuse inflammation, disseminated inflammation, exudative inflammation, fibrous inflammation, fibroplastic inflammation, focal inflammation, granulomatous inflammation, proliferative inflammation, hypertrophic inflammation, interstitial inflammation, metastatic inflammation, necrotizing inflammation, occlusive inflammation, parenchymal inflammation, plastic inflammation, productive inflammation, proliferative inflammation, pseudomembranous inflammation, suppurative inflammation, sclerosing inflammation, seroplastic inflammation, serous inflammation, simple inflammation, specific inflammation, subacute inflammation, suppurative inflammation, toxic inflammation, traumatic inflammation and / or ulcerative inflammation.

[0636] In certain embodiments, the inflammatory disorder is an acute inflammatory disorder (e.g., inflammation caused by infection). In certain embodiments, the inflammatory disorder is a chronic inflammatory disorder. In certain embodiments, the inflammatory disorder is inflammation associated with cancer.

[0637] definition

[0638] Chemical terms

[0639] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are confirmed to conform to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover) and specific functional groups are generally defined as therein. In addition, the general principles of organic chemistry and specific functional moieties and reactivity are as described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0640] The compounds 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 of the present invention 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 may be separated from the mixture 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., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention also encompasses the compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0641] In the formula, is a single bond, where the stereochemistry of the directly attached moiety is not specified (e.g., cis or trans olefin), --- is absent or a single bond, and It is a single bond or a double bond.

[0642] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, except for the replacement of hydrogen by deuterium or tritium, may be represented by 18 F Replacement 19 F or use 13 C or 14 C Substitution 12 C is within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0643] When a numerical range is listed, it is intended to include every value and sub-range within that range. For example, "C 1–6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 、C1-5 、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 4-5 and C 5-6 alkyl.

[0644] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0645] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group ("C 1–10 In certain embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1–9 In certain embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1–8 In certain embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1–7 In certain embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1–6 In certain embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1–5 In certain embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1–4 In certain embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1–3 In certain embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1–2 In certain embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In certain embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2–6 C 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted (“substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, an alkyl group is an unsubstituted C 1-10 Alkyl (such as unsubstituted C 1-6 Alkyl, for example, -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, for example, unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is substituted C 1-10 Alkyl (such as substituted C 1-6 Alkyl, e.g., -CF3, Bn).

[0646] The term "haloalkyl" is a substituted alkyl group in which one or more hydrogen atoms are independently replaced by a halogen, e.g., fluorine, bromine, chlorine, or iodine. In certain embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 Examples of haloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0647] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, which heteroatom is within the parent chain (i.e., inserted between adjacent carbon atoms) and / or is placed at one or more terminal positions of the parent chain. In certain embodiments, heteroalkyl refers to a saturated group ("heteroalkyl") having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain.1–10 In certain embodiments, a heteroalkyl group is a saturated group having from 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1–9 In certain embodiments, a heteroalkyl group is a saturated group having from 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–8 In certain embodiments, a heteroalkyl group is a saturated group having from 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1–7 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1–6 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroalkyl”). 1–5 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroalkyl”). 1–4 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1–3 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroalkyl”). 1–2 In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroC1 alkyl"). 2–6 Unless otherwise specified, each instance of heteroalkyl is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted (“substituted heteroalkyl”) with one or more substituents. In certain embodiments, heteroalkyl is an unsubstituted heteroC 1–10 In certain embodiments, heteroalkyl is substituted heteroC 1–10 alkyl.

[0648] The term "alkenyl" 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 certain embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2–9 In certain embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2–8 In certain embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2–7 In certain embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2–6 In certain embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2–5 In certain embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2–4 In certain embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2–3 In certain embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butene) or terminal (such as in 1-butene). C 2–4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2–6 Examples of the alkenyl group include the aforementioned C 2–4 In some embodiments, alkenyl is an unsubstituted C 1-4, C 1-6, C 1-8, C 1-9, C 2-10, C 3-11, C 3-12, C 3-13, C 3-14, C 3-16, C 3-17, C 3-18, C 3-19, C 4-20, C 5-31, C 4-32, C 4-33, C 4-34, C 4-35, C 4-36, C 4-37, C 4-38, C 4-44, C 4-45, C 4-50, C 4-6, C 4-7, C 4-8, C 4-9, C 4-10, C 4-11, C 4-12, C 4-13, C 4-14, C 4-15, C 4-16, 2–10 In certain embodiments, alkenyl is a substituted C 2–10 In alkenyl, the stereochemistry of the C=C double bond is not specified (e.g., -CH=CHCH3 or ) can be an (E)- or (Z)-double bond.

[0649] The term "heteroalkenyl" refers to an alkenyl group 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 is placed at one or more terminal positions of the parent chain. In certain 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 ("heteroalkenyl"). 2–10 In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1 or more heteroatoms (“heteroC 2–9 In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms (“heteroC 2–8 In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms ("heteroC alkenyl"). 2–7 In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms (“heteroC 2–6In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC alkenyl"). 2–5 In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC alkenyl"). 2–4 In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2–3 In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC alkenyl"). 2–6 Unless otherwise specified, each instance of heteroalkenyl is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, heteroalkenyl is an unsubstituted heteroC 2–10 In certain embodiments, heteroalkenyl is substituted heteroC 2–10 Alkenyl.

[0650] The term "alkynyl" refers to a straight or branched chain hydrocarbon group ("C 2–10 In certain embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2–9 In certain embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2–8 In certain embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2–7 In certain embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2–6 In certain embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2–5 In certain embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2–4 In certain embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2–3 In certain embodiments, an alkynyl group has 2 carbon atoms (a "C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2–4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2–6 Examples of the alkynyl group include the aforementioned C 2–4Alkynyl and pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, an alkynyl group is an unsubstituted C 2–10 In certain embodiments, the alkynyl group is a substituted C 2–10 Alkynyl.

[0651] The term "heteroalkynyl" refers to an alkynyl group 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 is placed at one or more terminal positions of the parent chain. In certain embodiments, heteroalkynyl refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroalkynyl"). 2–10 In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroC 2–9 In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroC 2–8 In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroC 2–7 In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroC 2–6 In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2–5 In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2–4 In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2–3 In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2–6 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 certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2–10 In certain embodiments, heteroalkynyl is substituted heteroC 2–10 Alkynyl.

[0652] The term "carbocyclyl" or "carbocyclic" refers to a non-aromatic ring system having 3 to 14 ring carbon atoms ("C 3–14 In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3–10 In certain embodiments, a carbocyclyl group has 3 to 9 ring carbon atoms ("C 3–9 In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3–8 In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3–7 In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3–6 In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4–6 In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C 5–6 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5–10 Carbocyclyl"). Exemplary C 3–6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3–8 Carbocyclic groups include but are not limited to the aforementioned C 3–6 Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3–10 Carbocyclic groups include but are not limited to the aforementioned C 3–8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10) and the like. As illustrated in the preceding examples, in certain embodiments, carbocyclyl is monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged, or spirocyclic ring system such as a bicyclic ring system ("bicyclic carbocyclyl") or a tricyclic ring system ("tricyclic carbocyclyl")) and may be saturated or may contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems as defined above fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in this case, the carbon number still refers to the number of carbons in the carbocyclyl ring system. Unless otherwise indicated, the carbocyclyl in each case is independently unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl is an unsubstituted C 3–14 In certain embodiments, the carbocyclyl group is a substituted C 3–14 Carbocyclic group.

[0653] In certain embodiments, a "carbocyclyl" is a monocyclic, saturated carbocyclyl ("C 3–14 In certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3–10 In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3–8 In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3–6 In certain embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4–6 In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5–6 In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5–10 Cycloalkyl”). C 5–6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3–6 Examples of the cycloalkyl group include the aforementioned C 5–6 Cycloalkyl as well as cyclopropyl (C3) and cyclobutyl (C4). 3–8 Examples of the cycloalkyl group include the aforementioned C 3–6 Cycloalkyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted (“substituted cycloalkyl”) with one or more substituents. In certain embodiments, cycloalkyl is unsubstituted C 3–14 In certain embodiments, the cycloalkyl group is a substituted C 3–14 Cycloalkyl.

[0654] "Carbocyclylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a carbocyclyl group, wherein the point of attachment is on the alkyl portion.

[0655] The term "heterocyclyl" or "heterocyclic" 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 heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, as valence permits. A heterocyclyl group may be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl")), and may be saturated or may 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 carbocyclyl groups, where the point of attachment is on the carbocyclyl ring or on the heterocyclyl ring, or includes 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 the 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, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. In certain embodiments, heterocyclyl is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, heterocyclyl is a substituted 3-14 membered heterocyclyl.

[0656] In certain embodiments, a heterocyclyl group 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 certain embodiments, a heterocyclyl group 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 certain embodiments, a heterocyclyl group 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 certain embodiments, a 5-6 membered heterocyclyl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5-6 membered heterocyclyl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5-6 membered heterocyclyl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0657] Examples of 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiirane. Examples of 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thiirane. Examples of 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrole-2,5-dione. Examples of 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Examples of 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary groups of 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithio-cyclohexane, and dioxane. Exemplary 6-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazacyclohexane. Exemplary groups of 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary groups of 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthylimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrole yl, 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]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0658] "Heterocycloalkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heterocyclyl, wherein the point of attachment is on the alkyl portion.

[0659] The term "aryl" refers to a group having 6-14 ring carbon atoms and zero heteroatoms in a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared π electrons in the cyclic array) ("C 6-14 In certain embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms ("C 10 In certain embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aryl ring, and in this 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 certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 Aryl.

[0660] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, where the point of attachment is on the alkyl portion.

[0661] The term "heteroaryl" refers to a radical 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 π electrons in the 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 can be a carbon or nitrogen atom, as valence permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, 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 a heteroaryl ring as defined above is fused to 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. For polycyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring bearing the heteroatom (e.g., 2-indolyl) or on the ring containing no heteroatoms (e.g., 5-indolyl).

[0662] In certain 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 certain 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 certain 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 certain embodiments, a 5-6 membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5-6 membered heteroaryl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, a heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In certain embodiments, a heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0663] 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, aza Oxalic acid thia Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, 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.

[0664] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

[0665] Adding the prefix / suffix "-ene" to a group indicates that the group is a divalent radical, for example, alkylene is a divalent radical of alkyl, alkenylene is a divalent radical of alkenyl, alkynylene is a divalent radical of alkynyl, heteroalkylene is a divalent radical of heteroalkyl, heteroalkenylene is a divalent radical of heteroalkenyl, heteroalkynylene is a divalent radical of heteroalkynyl, carbocyclylene is a divalent radical of carbocyclyl, heterocyclylene is a divalent radical of heterocyclyl, arylene is a divalent radical of aryl, and heteroarylene is a divalent radical of heteroaryl.

[0666] Unless otherwise clear, group is optionally substituted.Term " optionally substituted " refers to be substituted or unsubstituted.In certain embodiments, alkyl, alkenyl, alkynyl, assorted alkyl, assorted alkenyl, assorted alkynyl, carbocyclic radical, heterocyclic radical, aryl and heteroaryl group are optionally substituted. "Optionally substituted " refers to that group can be substituted or not substituted (for example, " substituted " or " unsubstituted " alkyl, " substituted " or " unsubstituted " alkenyl, " substituted " or " unsubstituted " alkynyl, " substituted " or " unsubstituted " assorted alkyl, " substituted " or " unsubstituted " assorted alkenyl, " substituted " or " unsubstituted " assorted alkynyl, " substituted " or " unsubstituted " assorted alkyl, " substituted " or " unsubstituted " assorted alkenyl, " substituted " or " unsubstituted " assorted alkynyl, " substituted " or " unsubstituted " carbocyclic radical, " substituted " or " unsubstituted " heterocyclic radical, " substituted " or " unsubstituted " aryl or " substituted " or " unsubstituted " heteroaryl). Typically, the term "substituted" means that at least one hydrogen on a group is replaced by a permissible substituent, for example, a substituent is a substituent that produces a stable compound after substitution, for example, a compound that does not spontaneously undergo transformation (such as rearrangement, cyclization, elimination or other reactions). 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 substituent at each position may be the same or different. The term "substituted" is intended to include substitution with all permissible substituents of an organic compound, and includes any substituent herein that forms a stable compound. The present invention is intended to include any and all combinations that result in stable compounds. For the purposes of the present invention, a heteroatom (such as nitrogen) may have a hydrogen substituent and / or any suitable substituent herein, as long as the valence of the heteroatom is satisfied and a stable portion is formed. The present invention is not intended to be limited in any way by the exemplary substituents herein.

[0667] 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 bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=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 bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R 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

[0668] -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(Rbb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=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 1-10 Alkyl, C 1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, hetero C 1-10 Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl 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 5 R dd group;

[0669] Or the two geminal hydrogens on the carbon atom are replaced by the following groups: =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb , or = NOR cc ;

[0670] R aa Each instance of is independently selected from C 1-10 Alkyl, C 1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, hetero C 1-10 Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14Aryl, and 5-14 membered heteroaryl, or two R aa The groups are connected 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 group is independently substituted with 0, 1, 2, 3, 4 or 5 R dd group;

[0671] R bb Each instance of is independently 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 1-10 Alkyl, C 1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, hetero C 1-10 Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R bb The groups are connected 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 group is independently substituted with 0, 1, 2, 3, 4 or 5 R dd group;

[0672] R cc Each instance of is independently selected from hydrogen, C 1-10 Alkyl, C1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, hetero C 1-10 Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R cc The groups are connected 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 group is independently substituted with 0, 1, 2, 3, 4 or 5 R dd group;

[0673] R dd Each instance of is independently 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 ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=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 ff C(=NRff )N(R ff )2、-NR ff SO2R 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 1-6 Alkyl, C 1-6 Perhalogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hetero C 1-6 Alkyl, hetero C 2-6 Alkenyl, hetero C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 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 5 R gg group, or two geminal R dd Substituents may be linked to form =O or =S;

[0674] R ee Each instance of is independently selected from C 1-6 Alkyl, C 1-6 Perhalogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hetero C 1-6 Alkyl, hetero C 2-6 Alkenyl, hetero C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 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 5 R gg group;

[0675] R ff Each instance of is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Perhalogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hetero C 1-6 Alkyl, hetero C 2-6 Alkenyl, hetero C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, or two R ff The groups are connected to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted with 0, 1, 2, 3, 4 or 5 R gg group; and

[0676] R gg Each instance of is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X -、- NH(C 1-6 Alkyl)2 + X -、- NH2(C 1-6 alkyl) + X -、- NH3 + X -、- N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhalogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hetero C 1-6 Alkyl, hetero C 2-6 Alkenyl, hetero C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10Aryl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl; or two geminal R gg Substituents may be linked to form =O or =S; wherein X - For the counter ion.

[0677] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0678] The term "hydroxy" or "hydroxyl" refers to the group -OH. The term "substituted hydroxy" or "substituted hydroxy" refers, by extension, to a hydroxy group in which the oxygen atom directly attached to the parent molecule is replaced by 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 )2 and -OP(=O)(NR bb )2, where R aa , R bb and R cc As defined herein.

[0679] The term "amino" refers to the group -NH2. The term "substituted amino" refers, by extension, to monosubstituted amino, disubstituted amino, or trisubstituted amino. In certain embodiments, "substituted amino" is monosubstituted amino or disubstituted amino.

[0680] The term "monosubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is replaced by one hydrogen and one non-hydrogen group, and includes groups selected from the group consisting of: -NH(Rbb ),-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 )2 and -NHP(=O)(NR bb )2, where R aa 、R bb and R cc As defined herein, and wherein the group -NH(R bb ) of R bb Not hydrogen.

[0681] The term "disubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted by two non-hydrogen groups and includes groups selected from the group consisting of: -N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-NR bb SO2R aa 、-NR bb P(=O)(OR cc )2 and -NR bb P(=O)(NR bb )2, where R aa 、R bb and R cc As defined herein, provided that the nitrogen atom directly attached to the parent molecule is not replaced by hydrogen.

[0682] The term "trisubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted by three groups and includes groups selected from the group consisting of: -N(R bb )3 and -N(R bb )3 + X -， where R bb and X - As defined herein.

[0683] The term "sulfonyl" refers to a group selected from -SO2N(R bb )2, -SO2Raa and-SO2OR aa A group in which R aa and R bb As defined herein.

[0684] The term "sulfinyl" refers to the group -S(=O)R aa , where R aa As defined herein.

[0685] The term "acyl" refers to a group having the following general formula: -C(=O)R X1 、-C(=O)OR X1 、-C(=O)-OC(=O)R X1 、-C(=O)SR X1 、-C(=O)N(R X1 )2, -C(=S)R X1 、-C(=S)N(R X1 )2、-C(=S)S(R X1 ),-C(=NR X1 )R X1 、-C(=NR X1 )OR X1 、-C(=NR X1 )SR X1 and -C(=NR X1 )N(R X1 )2, where R X1 is hydrogen; halogen; substituted or unsubstituted hydroxy; substituted or unsubstituted mercapto; substituted or unsubstituted amino; substituted or unsubstituted acyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted or two R X1The groups together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thio, cyano, isocyano, amino, azido, nitro, hydroxy, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthio, heteroaliphaticthio, alkylthio, heteroalkylthio, arylthio, heteroarylthio, acyloxy, and the like, each of which may or may not be further substituted).

[0686] The term "silyl" refers to the group -Si(R aa )3, where R aa As defined herein.

[0687] The term "oxo" refers to the group =0, and the term "thio" refers to the group =S.

[0688] The nitrogen atoms may be substituted or unsubstituted, as valence 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 1-10 Alkyl, C 1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, hetero C 1-10 Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R groups connected to the N atom cc The groups are combined 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 group is independently substituted with 0, 1, 2, 3, 4 or 5 R dd group, and wherein R aa 、R bb 、R cc and R dd As defined above.

[0689] In certain 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 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, hetero C 1-10 Alkyl, hetero C 2-10 Alkenyl, hetero C 2-10 Alkynyl, C 3-10Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 aryl 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 5 R dd group, and wherein R aa 、R bb 、R cc and R dd As defined herein. Nitrogen protecting groups are well known in the art and include those disclosed in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0690] For example, a nitrogen protecting group such as an amide group (e.g., -C(=O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, picolinamide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, N-butanilide, (N′-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0691] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthenyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate ( Carbamic acid 1-(4-biphenylyl)ethyl ester (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethyl ester (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl ester (Pyoc), 2-(N,N-dicyclohexylcarbamoylamino)ethyl ester, tert-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), ethylene carbamate oc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylthioethyl carbamate -methylsulfonylethyl ester, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthienyl carbamate (Mtpc), 2,4-dimethylthienyl carbamate (Bmpc), 2-phosphinoethyl carbamate (Peoc), 2-triphenylphosphinoisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylformamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furylmethyl carbamate, 2- Iodoethyl ester, isobornyl carbamate, isobutyl carbamate, isonicotinoyl carbamate, p-(p′-methoxyphenylazo)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-trimethylbenzyl carbamate.

[0692] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2R aa ) include, but are 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), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylmethylsulfonamide.

[0693] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N′-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-tetramethyldisilazide adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one , 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 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-pyrrolidin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N- 2,7-Dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-pyridylmethylamino N′-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexyleneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexene)

[0014] The present invention also includes but is not limited to the following: 1,2-dinitrobenzenesulfonamide, 2,4 ...

[0694] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxy protecting group"). Oxygen protecting groups include, but are not limited to, -R aa 、-N(Rbb )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 )2 and -P(=O)(NR bb )2, where R aa , R bb and R cc As defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, which is incorporated herein by reference.

[0695] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, 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, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)phenyl)-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)phenyl)-4-methoxypiperidin-4-yl 1-Methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylhydrogen selenyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-diphenylcycloheptyl (di benzosuberyl), triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, bis(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4′-bromophenylacetyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl) Tonyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl (dimethylthexylsilyl), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl (tri-p-xylylsilyl), triphenylsilyl, diphenylmethylsilyl alkyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate / salt (levulinoyldithioacetal), pivalate, adamantate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mikon) esters), 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-(triphenylphosphino)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, tert-butyl carbonate (BOC or 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, methyl dithiocarbonate Esters, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 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, dimethylphosphinosulfinyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate and toluenesulfonate (Ts).

[0696] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also known as a "thiol 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 )2 and -P(=O)(NR bb )2, where R aa 、R bb and R cc As defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, which is incorporated herein by reference.

[0697] As used herein, "leaving group" (LG) is a term of art and refers to a molecular fragment that leaves with a pair of electrons in a heterolytic bond cleavage, wherein the molecular fragment is an anion or a neutral molecule. As used herein, a leaving group can be an atom or group that can be displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halides (e.g., chloride, bromide, iodide), -ORaa (when attached to a carbonyl group, wherein Raa is as defined herein), -O(C=O)RLG, or -O(SO)2RLG (e.g., tosyl, methylsulfonyl, phenylsulfonyl), wherein RLG is an optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some cases, the leaving group is a halogen. In certain embodiments, the leaving group is I.

[0698] As used herein, the phrase "at least one instance" refers to 1, 2, 3, 4 or more instances, 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 instances (including the end values).

[0699] A "non-hydrogen group" refers to any group other than hydrogen as defined for a particular variable.

[0700] The term "carbohydrate" or "sugar" refers to aldehyde or ketone derivatives of polyols. Carbohydrates include compounds with relatively small molecules (such as sugars) as well as large molecules or polymers (such as starch, glycogen and cellulose polysaccharides). The term "sugar" refers to monosaccharides, disaccharides or polysaccharides. Monosaccharides are the simplest carbohydrates because they cannot be hydrolyzed into smaller carbohydrates. Most monosaccharides can be represented by the general formula C y H 2y O y (For example, C6H 12 O6 (hexose such as glucose)), where y is an integer equal to or greater than 3. Some polyols not represented by the above general formula can also be considered as monosaccharides. For example, deoxyribose is a sugar of formula C5H 10O4 and is a monosaccharide. Monosaccharides are typically composed of 5 or 6 carbon atoms and are referred to as pentoses and hexoses, respectively. If a monosaccharide contains an aldehyde, it is called an aldose; if it contains a ketone, it is called a ketose. Monosaccharides can also be composed of three, four, or seven carbon atoms in the form of aldoses or ketoses, referred to as trioses, tetroses, and heptoses, respectively. Glyceraldehyde and dihydroxyacetone are considered aldotrioses and ketotrioses, respectively. Examples of aldotrioses include erythrose and threose; ketotrioses include erythrulose. Aldopentoses include ribose, arabinose, xylose, and lyxose; and ketopentoses include ribulose, arabinose, xylulose, and lyxulose. Examples of aldohexoses include glucose (e.g., dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose; and ketohexoses include fructose, psicose, sorbose, and tagatose. Heptulose includes sedoheptulose. Except for the first and last carbons, each carbon atom of a monosaccharide with a hydroxyl group (-OH) is asymmetric, making the carbon atom a stereocenter with two possible configurations (R or S). Due to this asymmetry, any given monosaccharide chemical formula may have many isomers. For example, the aldohexose D-glucose has the formula C6H 12 O6, except for two of its six carbon atoms, all are stereo centers, making D-glucose 16 (i.e., 2 4The assignment of D or L is based on the orientation of the asymmetric carbon farthest from the carbonyl group: in the standard Fischer projection, if the hydroxyl group is on the right, the molecule is a D sugar, otherwise it is an L sugar. The aldehyde or ketone group of a linear monosaccharide will react reversibly with the hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocycle with an oxygen bridge between the two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and exist in equilibrium with the linear form. In the process of converting from the linear form to the cyclic form, the carbon atom containing the carbonyl oxygen (called the terminal carbon) becomes a stereocenter with two possible configurations: the oxygen atom can be located above or below the plane of the ring. The resulting possible pair of stereoisomers is called anomers. In the α anomer, the -OH substituent on the terminal carbon is located on the opposite side (trans) of the ring and the -CH2OH side branch. Wherein -CH2OH substituent and terminal hydroxyl group on the same side (cis) of the ring plane of the alternative form is called β anomer.Carbohydrate comprising two or more connected monosaccharide units is respectively referred to as disaccharide or polysaccharide (for example, trisaccharide).Two or more monosaccharide units are combined together by the covalent bond known as the glycosidic bond formed by dehydration reaction, resulting in the loss of hydrogen atoms from one monosaccharide and the loss of hydroxyl from another.Exemplary disaccharides include sucrose, lactulose, lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose, laminaribiose, gentiobiose, mannobiose, melibiose, nigerose or rutinose.Exemplary trisaccharides include but are not limited to isomaltotriose, nigerose, maltotriose, melezitose, maltotriulose, raffinose and kestose.Term carbohydrate also includes other natural or synthetic stereoisomers of carbohydrate herein.

[0701] These and other exemplary substituents are described in more detail in the "Detailed Description," "Examples," and "Claims" sections. The present invention is not limited in any way to the exemplary substituents listed above.

[0702] Other definitions

[0703] As used herein, the term "salt" refers to any and all salts and encompasses pharmaceutically acceptable salts.

[0704] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals, within reasonable medical judgment, and does not have excessive toxicity, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (which is incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of an amino group with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, and an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or are salts formed by using other methods known in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Other pharmaceutically acceptable salts include salts formed using counterions (e.g., halide ions, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates) with non-toxic ammonium, quaternary ammonium, and amine cations, as appropriate.

[0705] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds herein may be prepared, for example, in crystalline form and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0706] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, a hydrate of a compound can be represented, for example, by the general formula R·x H2O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O).

[0707] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds caused by the formal migration of at least one hydrogen atom and at least one change in valence (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on a variety of factors, including temperature, solvent, and pH. Tautomerization (i.e., a reaction that provides a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerizations.

[0708] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0709] Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of one another are termed "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and can be described using the R- and S-sequencing rules of Cahn and Prelog, or by the following method, in which the molecule is rotated in the plane of polarized light and designated as right- or left-handed (i.e., (+) or (-)-isomer, respectively). A chiral compound can exist as a single enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture".

[0710] The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, photoelectric properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors can lead to one crystalline form being dominant. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0711] The term "prodrug" refers to a compound that has a cleavable group and becomes a compound of the present invention by solvent decomposition or under physiological conditions, which is pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, etc. Other derivatives of the compounds of the present invention are active in their acid or acid derivative forms, but generally provide advantages in terms of solubility, tissue compatibility, or delayed release in mammalian organisms in acid-sensitive forms (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners in the art, for example, esters prepared by the reaction of the parent acid with a suitable alcohol, or amides prepared by the reaction of the parent acid compound with a substituted or unsubstituted amine, or anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups on the compounds of the present invention are specific prodrugs. In some cases, it is desirable to prepare double ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C8 12 Substituted aryl and C7-C 12 Aryl alkyl esters may be preferred.

[0712] The terms "composition" and "formulation" are used interchangeably.

[0713] A "subject" to which administration is contemplated is a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) and / or other non-human animals. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a commercially relevant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or a dog), or a bird (e.g., a commercially relevant bird, such as a chicken, a duck, a goose, or a turkey). In certain embodiments, the non-human animal is a fish, a reptile, or an amphibian. The non-human animal can be male or female at any stage of development. The non-human animal can be a transgenic or genetically engineered animal. "Disease," "disorder," and "condition" are used interchangeably herein.

[0714] The terms "administering," "administering," or "administering" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound of the present application, or a composition thereof, into or onto a subject.

[0715] As used herein, and unless otherwise indicated, the term "treatment" refers to actions that occur while a subject is suffering from a particular infectious disease or inflammatory condition, which reduces the severity of the infectious disease or inflammatory condition, or arrests or slows the progression of the infectious disease or inflammatory condition ("therapeutic treatment"), and also refers to actions that occur before a subject becomes suffering from a particular infectious disease or inflammatory condition ("prophylactic treatment").

[0716] In general, an "effective amount" of a compound is an amount sufficient to elicit a desired biological response. Those skilled in the art will appreciate that the effective amount of a compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition to be treated, the route of administration, and the age, health, and condition of the subject. An effective amount includes both therapeutic and prophylactic treatments.

[0717] Unless otherwise indicated, a "therapeutically effective amount" of a compound as used herein is an amount of the compound sufficient to provide a therapeutic benefit in treating an infectious disease or inflammatory condition, or sufficient to delay or minimize one or more symptoms associated with an infectious disease or inflammatory condition. A therapeutically effective amount of a compound refers to an 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 condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of an infectious disease or inflammatory condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0718] As used herein and unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent an infectious disease or inflammatory condition, or one or more symptoms associated with an infectious disease or inflammatory condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapeutic agents, that provides a prophylactic benefit in preventing an infectious disease or inflammatory condition. The term "prophylactically effective amount" can include an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent. Example

[0719] In order to more fully understand the invention herein, the following examples are set forth.The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting the scope thereof.

[0720] Synthesis of lincosamide analogs

[0721] General Experimental Procedures: Unless otherwise noted, all reactions were performed under positive nitrogen pressure in flame-dried round-bottom flasks fitted with rubber septa. Air- and moisture-sensitive liquids were transferred via syringe or stainless steel cannula. Unless otherwise noted, organic solutions were concentrated by rotary evaporation (house vacuum, approximately 25-40 torr) at ambient temperature. Analytical thin-layer chromatography (TLC) was performed using glass plates (0.25 mm, 1 / 4 in) pre-coated with silica gel. The thin layer chromatography plate was developed by ultraviolet irradiation and then stained with aqueous sulfuric acid solution of ceric ammonium molybdate (CAM), aqueous ethanol-sulfuric acid solution of 2,4-dinitrophenylhydrazine (DNP), or aqueous sodium hydroxide-potassium carbonate solution of potassium permanganate (KMnO4), followed by brief heating with a heat gun. Flash column chromatography was performed as described by Still et al. (Still, WC; Khan, M.; Mitra A. J. Org. Chem. 1978, 43, 2923-2925), using silica gel ( 15-40μM, EMD MilliporeCorp.).

[0722] Materials: Commercially available reagents and solvents were used.

[0723] Instrument: Proton magnetic resonance ( 1 H NMR spectra were recorded on a Bruker 400 (400 MHz) NMR spectrometer at 23° C. Proton chemical shifts are expressed in parts per million (ppm, delta scale) and are referenced to the residual tritium (CHCl) in the NMR solvent. 3，δ7.26; CD3OD, δ3.31). Data are expressed as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, pent = quintet, m = multiple and / or multiple resonance, br = broad, app = apparent), integral and coupling constant (J), in Hertz (Hz). Carbon nuclear magnetic resonance spectrum ( 13 C NMR) were recorded on a Bruker 400 (101 MHz) NMR spectrometer at 23°C. Carbon chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to the carbon resonance of the NMR solvent (CDCl3, δ 77.16; CD3OD, δ 49.00). 13 Multiplicity is reported only when the C signal is coupled to a magnetically active nucleus (e.g. 19 F). Fluorine NMR spectrum ( 19 FNMR) were recorded on a Bruker 400 (376 MHz) NMR spectrometer at 23°C. Infrared (IR) spectra were obtained using a Bruker ALPHA FT-IR spectrometer. Data are presented as follows: Absorption frequency (cm -1 ), absorption intensity (s = strong, m = medium, w = weak, br = broad). High-resolution mass spectra were obtained by electrospray ionization (ESI) at the Harvard University Mass Spectrometry Facility using a Thermo QExactive Plus Orbitrap mass spectrometer or at the Harvard Laukien-Purcell Instrument Center using a Bruker Compact qTOF mass spectrometer. High-performance liquid chromatography purification was performed using an Agilent Technologies 1200 Series preparative HPLC system.

[0724] Synthesis of FSA1507013, FSA1507066, FSA1507068, FSA1508001, and FSA1508003

[0725]

[0726] (2R,3S,4S,5R,6R)-2-((Benzoyloxy)methyl)-6-(but-3-en-1-ylthio)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate: 4-Bromo-1-butene (2.48 mL, 24.5 mmol, 1.5 equiv) was added to a solution of (2R,3S,4S,5R,6R)-2-((Benzoyloxy)methyl)-6-mercaptotetrahydro-2H-pyran-3,4,5-triyl tribenzoate (prepared according to the following: Doyle, et al., Org. Lett. 2017, 19, 5802–5805) (10.0 g, 16.3 mmol, 1.0 equiv) dissolved in distilled THF (60 mL). The solution was cooled to 0 ° C and DBU (3.65 mL, 24.5 mmol, 1.5 equivalents) was added, and a white precipitate was immediately formed. The reaction mixture was stirred for 10 minutes and concentrated under reduced pressure. Purification by flash column chromatography (10-20% ethyl acetate / hexane) gave the product (3.0 g, 4.50 mmol, 28% yield) as a white foam. 1 HNMR(400MHz, CDCl3)δ8.15–8.06(m,2H),8.00(ddd,J=17.3,8.3,1.4Hz,4H),7.85–7.73(m ,2H),7.69–7.59(m,1H),7.60–7.43(m,4H),7.46–7.35(m,5H),7.33–7.19(m,2H),6.09–5.9 7(m,2H),5.90–5.84(m,2H),5.69(ddt,J=16.9,10.2,6.6Hz,1H),5.11–4.90(m,3H),4.61( dd,J=11.5,7.5Hz,1H),4.46(dd,J=11.5,5.2Hz,1H),2.84–2.53(m,2H),2.53–2.19(m,2H). 13 C NMR (101MHz, CDCl3) δ166.16,165.84,165.66,165.53,136.19,133.75,133.61,133.36,133.35,130.10,130.07,129.87,129.85,129.61,129. 24,129.17,129.14,128.80,128.60,128.57,128.40,116.47,82.78,69 .25,69.08,69.06,67.54,62.87,33.78,29.37.HRMS(ESI+,m / z):[M+Na] + Calculated value C 38 H 34O9S, 689.1816; measured value 689.1814.

[0727]

[0728] (2R,3R,4S,5S,6R)-2-(But-3-en-1-ylsulfanyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate: Dichlorotetrakis(1,1-dimethylethyl)di-μ-hydroxyditin (0.43 g, 0.752 mmol, 0.17 equiv.) (prepared according to the following: Ni, M. et al., Carb. Res. 2020, 498, 108172.) was added to (2R,3S,4S,5R,6R)-2-((benzoyloxy)methyl)-6-(but-3-en-1-ylsulfanyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (2.95 g, 4.42 mmol, 1.0 equiv.) dissolved in a mixture of anhydrous MeOH (30 mL) and anhydrous THF (9 mL). The reaction mixture was stirred at 65°C overnight (16 hours) and concentrated under reduced pressure. Purification by flash column chromatography (10-25% ethyl acetate in hexanes) gave the product (2.0 g, 3.25 mmol, 74% yield) as a white foam. 1 H NMR (400MHz, CDCl3) δ8.11 (dd, J=8.2, 1.4Hz, 2H), 7.99 (dd, J=8.3, 1.4Hz, 2H), 7.81 (dd, J= 8.2,1.4Hz,2H),7.64(t,J=7.4Hz,1H),7.52(dt,J=9.4,7.5Hz,3H),7.41(dt,J=15.6,7.5Hz ,3H),7.23(m,2H),5.99(d,J=5.1Hz,1H),5.93–5.72(m,4H),5.17–4.98(m,2H),4.73(t,J=6 .8Hz,1H),3.91–3.73(m,1H),3.66(dd,J=11.7,6.8Hz,1H),2.82–2.56(m,2H),2.37(m,2H). 13 C NMR (101MHz, CDCl3) δ166.73,165.81,165.36,136.18,133.83,133.51,133.28,130.05,129.95,129.70,129.05,128. 90,128.71,128.50,128.33,116.46,82.86,69.85,69.55,69.18,69.00,60.78,33.70,29.46.HRMS(ESI+,m / z):[M+H] +Calculated value C 31 H 30 O8S, 563.1734; measured value 563.1728.

[0729]

[0730] (2R,3R,4S,5R,6S)-2-(But-3-en-1-ylthio)-6-formyltetrahydro-2H-pyran-3,4,5-triyl tribenzoate: To a solution of (2R,3R,4S,5S,6R)-2-(but-3-en-1-ylthio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (2.30 g, 4.09 mmol, 1.00 equiv) in dichloromethane (25 mL) was added Dess-Martin periodinane (2.61 g, 6.14 mmol, 1.50 equiv) and the resulting white suspension was stirred for 1 hour. The reaction mixture was diluted with diethyl ether (100 mL) and treated with saturated aqueous sodium bicarbonate (37.5 mL) followed by aqueous sodium thiosulfate (50 wt%, 37.5 mL). The resulting bilayer mixture was stirred vigorously at 23°C for 1 hour, and the layers were separated. The aqueous layer was extracted with diethyl ether (3 x 15 mL), and the combined organic extracts were washed sequentially with saturated aqueous sodium bicarbonate solution (37.5 mL) and brine (37.5 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated to afford the product (2.27 g, 4.05 mmol, 99% yield) as a white foam, which was used in the subsequent sulfinimine condensation reaction without further purification.

[0731]

[0732]

[0149] (2R,3R,4S,5S,6R)-2-(But-3-en-1-ylthio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate: To a mixture of (2R,3R,4S,5R,6S)-2-(but-3-en-1-ylthio)-6-formyltetrahydro-2H-pyran-3,4,5-triyl tribenzoate (2.27 g, 4.05 mmol, 1.00 equiv), (R)-(+)-2-methyl-2-propanesulfenamide (983 mg, 8.10 mmol, 2.00 equiv) and anhydrous copper(II) sulfate (970 mg, 6.08 mmol, 1.50 equiv) was added anhydrous toluene (13.5 mL). The resulting suspension was heated to 40 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite, washed (3 × 30 mL CH2Cl2). The combined organic extracts were concentrated and purified by flash column chromatography (10-50% ethyl acetate / hexane) to give the product (1.88 g, 2.83 mmol, 70% yield) as a white foam. 1 H NMR (400MHz, CDCl3) δ8.04(d,J=2.2Hz,1H),7.98(dd,J=6.9,1.5Hz,3H),7.78(dd,J=8.4,1.4H z,2H),7.64–7.55(m,1H),7.57–7.48(m,1H),7.45(t,J=7.6Hz,3H),7.39(dd,J=8.4,7.2Hz,2H ),7.26(d,J=2.2Hz,3H),6.30(dd,J=3.0,1.5Hz,1H),6.14(d,J=4.9Hz,1H),5.89–5.71(m,3H) ,5.53(t,J=1.8Hz,1H),5.09–4.98(m,2H),2.82–2.63(m,2H),2.42–2.34(m,2H),0.99(s,9H). 13 C NMR (101MHz, CDCl3) δ165.68,165.45,165.30,164.66,135.93,133.59,133.54,133.25,129.95,129.89,129.75,129.14,129.00, 128.96,128.61,128.50,128.28,116.72,83.46,71.38,69.45,69.05,68.59,57.11,33.69,29.76,22.08.HRMS(ESI+,m / z):[M+H] + Calculated value C 35 H 37NO8S2, 664.2033; measured value 664.2023.

[0733]

[0734] (2R,3R,4S,5R,6R)-2-((R)-1-aminobut-3-en-1-yl)-6-(but-3-en-1-ylthio)tetrahydro-2H-pyran-3,4,5-triol: To a solution of (2R,3R,4S,5S,6R)-2-(but-3-en-1-ylthio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (0.689 g, 1.04 mmol, 1.00 equiv) in THF (4 mL) was added allylmagnesium bromide (0.92 M in THF, 3.39 mL, 3.12 mmol, 3.00 equiv) at –78 °C. The mixture was stirred at -78 °C for 1 hour. The solution was warmed to room temperature and 0.5 M NaOMe (10 mL, 5.00 mmol, 4.81 equiv) in MeOH was added. After stirring for 1 hour, 4 M HCl (2.5 mL, 10.0 mmol, 9.60 equiv) in 1,4-dioxane was added and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (10-20% methanol / DCM containing 0.5% saturated aqueous NH4OH) to give the product as a yellow oil (0.20 g, 0.691 mmol, 67% yield over 3 steps). 1 H NMR (400MHz, MeOD) δ5.92–5.81(m,2H),5.42(d,J=5.5Hz,1H),5.23–5.15(m,2H),5.12–4.99(m,2H),4.13–4.05(m,2H),3.99(d d,J=6.9,1.5Hz,1H),3.57(dd,J=10.2,3.4Hz,1H),3.27–3.22(m,1H),2.72–2.48(m,3H),2.46–2.33(m,2H),2.30–2.18(m,1H). 13 CNMR(101MHz,MeOD)δ136.69,133.93,117.70,114.91,86.67,70.97,70.52,68.91,67.98,50.81,36.18,33.69,29.34.HRMS(ESI+,m / z):[M+H] + Calculated value C 13 H 23NO4S, 290.1421; measured value 290.1423.

[0735]

[0736] N-((R)-1-((2R,3R,4S,5R,6R)-6-(but-3-en-1-ylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)but-3-en-1-yl)-2,2,2-trifluoroacetamide: To a solution of (2R,3R,4S,5R,6R)-2-((R)-1-aminobut-3-en-1-yl)-6-(but-3-en-1-ylthio)tetrahydro-2H-pyran-3,4,5-triol (0.20 g, 0.691 mmol, 1.00 equiv) in MeOH (15 mL) was added methyl trifluoroacetate (90 uL, 0.898 mmol, 1.30 equiv) and triethylamine (289 uL, 2.07 mmol, 3.00 equiv). After stirring at room temperature overnight (16 hours), the reaction mixture was concentrated under reduced pressure. The crude reaction mixture was extracted with ethyl acetate (20 mL) and washed with brine (3×10 mL) to give the product as a yellow oil (0.21 g, 0.545 mmol, 79% yield). 1H NMR (400MHz, MeOD) δ5.94–5.70(m,2H),5.41(d,J=5.7Hz,1H),5.12–4.99(m,4H),4.29(td,J=8.9,4.2Hz,1H),4.19(dd,J=8.4,1.3Hz,1H),4.09(dd ,J=10.2,5.6Hz,1H),3.88(dd,J=3.3,1.3Hz,1H),3.61–3.54(m,1H),2.71 –2.54(m,3H),2.39(tddt,J=8.1,6.6,5.1,1.4Hz,2H),2.29–2.20(m,1H). 13 C NMR(101MHz,MeOD)δ157.53,157.16,136.68,133.89,116.91,114.93,86.66,7 0.71,70.13,68.76,67.95,49.73,35.35,33.64,29.20.HRMS(ESI+,m / z):[M+H] + Calculated value C 15 H 22 F3NO5S,386.1244; measured value 386.1244.

[0737]

[0738]

[0266] 2,2,2-Trifluoro-N-((1R,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)acetamide: N-((R)-1-((2R,3R,4S,5R,6R)-6-(but-3-en-1-ylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)but-3-en-1-yl)-2,2,2-trifluoroacetamide (0.21 g, 0.545 mmol, 1.00 equiv) was dissolved in toluene (1360 mL) and the solution was heated to reflux. Freshly sublimed benzoquinone (23.6 mg, 0.218 mmol, 0.40 equiv) and Grubbs II catalyst (92.6 mg, 0.109 mmol, 0.20 equiv) were dissolved in toluene (5 mL) and added to the reaction mixture. After stirring at reflux for 20 minutes, the reaction mixture was quenched with DMSO (0.77 mL, 10.9 mmol, 20.0 equiv) and then cooled to room temperature. The reaction mixture was concentrated in vacuo, redissolved in ethyl acetate (15 mL) and brine (15 mL), and the layers were separated. The aqueous layer was washed with ethyl acetate (3 × 15 mL), and the combined organic extracts were dried over sodium sulfate and concentrated. After concentration under reduced pressure, the product was purified by flash column chromatography (5–10% methanol in DCM) to afford the product as a brown oil (75 mg, 0.21 mmol, 39% yield). 1 H NMR (400MHz, MeOD) δ5.67–5.51(m,2H),5.44(d,J=5.9Hz,1H),4.50(dd,J=11.1,1.0Hz ,1H),4.40(dt,J=11.1,3.3Hz,1H),4.02(dd,J=10.2,5.9Hz,1H),3.77(d,J=3.3Hz,1H ),3.44(dd,J=10.2,3.3Hz,1H),3.16(ddd,J=13.9,4.2,2.3Hz,1H),2.99(tdd,J=13.5 ,11.4,4.2Hz,1H),2.79–2.65(m,2H),2.20–2.13(m,1H),2.05(dt,J=13.5,3.7Hz,1H). 13 C NMR(101MHz,MeOD)δ157.49,157.12,133.39,124.10,117.53,114.67,88.97,7 1.64,68.61,68.51,67.75,47.96,32.88,27.13,27.09.HRMS(ESI+,m / z):[M+H] + Calculated value C 13 H 18F3NO5S,358.0931; measured value 358.0932.

[0739]

[0740]

[0266] (1R,8R,9R,10R,11S,12R,Z)-8-amino-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triol: To a solution of 2,2,2-trifluoro-N-((1R,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)acetamide (40 mg, 0.112 mmol, 1.00 equiv) in MeOH (5 mL) was added 20% w / v aqueous KOH (2 mL). The reaction mixture was stirred at room temperature overnight and purified by flash column chromatography (10-15% methanol / DCM containing 0.5% aqueous NH 3 ) to give the product (29 mg, 0.112 mmol, 99% yield) as a yellow oil. 1 H NMR(400MHz,MeOD)δ5.69(td,J=11.5,3.4Hz,1H),5.64–5.56(m,1H),5.44(d,J=5.8Hz,1 H),4.36(dd,J=10.4,1.1Hz,1H),4.02(dd,J=10.2,5.9Hz,1H),3.87(dd,J=3.4,1.1Hz,1 H),3.56–3.51(m,1H),3.48–3.43(m,1H),3.18–3.13(m,1H),3.04–2.94(m,1H),2.93–2. 83(m,1H),2.73(td,J=13.7,4.6Hz,1H),2.19(d,J=13.8Hz,1H),2.08(d,J=14.1Hz,1H). 13 C NMR(101MHz,MeOD)δ136.08,123.68,90.32,72.74,70.95,69.68,68.87,49.81,34.13,28.56,28.41.HRMS(ESI+,m / z):[M+H] + Calculated value C 11 H 19 NO4S, 262.1108; measured value 262.1107.

[0741]

[0742] (4S,5aS,8S,8aR)-4-isobutyl-8-(((1R,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-13-oxa-2-thiabicyclo[7.3.1]trideca-5-en-8-yl)carbamoyl)octahydro-2H-oxepinano[2,3-c]pyrrol-7-ium carboxylate (FSA1507013·HCOOH): (1R,8R,9R,10R,11S,12R,Z)-8-amino-13-oxa-2-thiabicyclo[7.3.1]trideca-5-en-8-yl)carbamoyl To a solution of 1-ene-10,11,12-triol (8.4 mg, 0.032 mmol, 1.00 equiv) dissolved in DMF (0.5 mL) was added (4S,5aS,8S,8aR)-7-(tert-butoxycarbonyl)-4-isobutyloctahydro-2H-oxepin-[2,3-c]pyrrole-8-carboxylic acid (13.2 mg, 0.039 mmol, 1.20 equiv), HATU (14.7 mg, 0.039 mmol, 1.20 equiv) and DIPEA (33.6 uL, 0.193 mmol, 6.00 equiv). The reaction mixture was stirred at room temperature overnight (16 h). After concentration under reduced pressure, 1 M HCl in MeOH (3 mL, 3.00 mmol, 93.8 equiv) was added and the reaction mixture was stirred for 1 h. Concentration under reduced pressure followed by purification by preparative HPLC (5-50% MeCN / H2O with 0.1% HCOOH over 30 min) afforded the product FSA1507013.HCOOH (5.0 mg, 0.0094 mmol, 29% yield over two steps) as a thin, clear film. 1 H NMR(400MHz,MeOD)δ8.35(s,2H),5.74–5.53(m,2H),5.44(d,J=5.9Hz,1H),4.34(d,J=5.3Hz,4H),4.01(td,J=10.3,4 .9Hz,2H),3.85–3.74(m,2H),3.59(dd,J=11.3,7.3Hz,1H),3.43(dd,J=10.2,3.4Hz,1H),3.16(ddd,J=14.1,4.2,2.3H z,1H),3.05–2.86(m,2H),2.78–2.61(m,2H),2.32(d,J=10.7Hz,1H),2.16(d,J=13.7Hz,1H),2.07(dd,J=13.3,4.9Hz, 1H),2.01(d,J=12.8Hz,1H),1.82–1.61(m,5H),1.19(td,J=6.8,3.6Hz,2H),1.01–0.93(m,1H),0.90(d,J=6.5Hz,6H).13 C NMR(101MHz,MeOD)δ166.62,166.15,133.07,124.72,88.93,79.62,71.62,69.26,68.54,67.92,67.81 ,60.43,46.68,42.09,35.66,35.17,34.74,32.92,27.14,24.89,21.77,21.53.HRMS(ESI+,m / z):[M+H] + Calculated value C 24 H 40 N2O6S, 485.2680; measured value 485.2687.

[0743]

[0744] (4S,5aS,8S,8aR)-4-isobutyl-7-methyl-8-(((1R,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)carbamoyl)octahydro-2H-oxepin[2,3-c]pyrrol-7-ium carboxylate (FSA) 1508003·HCOOH): Sodium cyanoborohydride (2.4 mg, 0.038 mmol, 10 equiv) was added to a solution of FSA1507013·HCOOH (2.0 mg, 0.0038 mmol, 1.0 equiv) in 37% w / w aqueous formaldehyde (15.4 mg, 0.114 mmol, 50 equiv) and stirred at ambient temperature for 45 minutes. The reaction mixture was quenched with saturated aqueous sodium carbonate (10 mL) and extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were dried over sodium sulfate. The mixture was concentrated under reduced pressure and then purified by preparative HPLC (5–50% MeCN / H2O containing 0.1% HCOOH for 30 minutes) to afford the product, FSA1508003·HCOOH (2.0 mg, 0.0037 mmol, 97% yield), as a thin, clear film. 11H NMR (600 MHz, CD3OD) δ 8.30 (br s, 1H), 5.66–5.56 (m, 2H), 5.44 (d, J = 5.9 Hz, 1H), 4.39 (t, J = 9.2 Hz, 1H), 4.36–4.27 (m, 2H), 4.02 (dd, J = 10.3, 6.0 Hz, 1H), 4.00–3.97 (m, 1H), 3.85 (d, J = 3.5 Hz, 1H), 3.87–3.74 (m, 2H), 3.48 (dd, J = 10.3, 6.3 Hz, 1H), 3.42 (dd, J = 10.2, 3.3 Hz, 1H), 3.15 (ddd, J = 14.1, 4.2, 2.3 Hz, 1H), 2.99 (qd, J = 13.7, 4.3 Hz, 1H), 2.74–2.62 (m, 6H), 2.30 (qdd, J = 11.7, 8.7, 2.4 Hz, 1H), 2.16 (d, J = 13.3 Hz, 1H), 2.03 (d, J = 12.6 Hz, 1H), 1.97 (d, J = 13.3 Hz, 1H), 1.75–1.61 (m, 4H), 1.24–1.12 (m, 2H), 0.94 (q, J = 11.7, 11.0 Hz, 1H), 0.89 (d, J = 2.0 Hz, 3H), 0.88 (d, J = 1.9 Hz, 3H). 13 13C NMR (101 MHz, CD3OD) δ 134.78, 125.79, 90.32, 81.52, 72.95, 72.73, 71.00, 70.03, 69.23, 69.02, 59.60, 49.05, 48.09, 45.04, 41.27, 37.71, 37.12, 35.47, 34.27, 28.62, 28.55, 26.30, 23.21, 22.91. HRMS (ESI+, m / z): [M + H] + Calculated for C 25 H 42 N2O6S, 499.2836; found 499.2834.

[0745]

[0746] (2R,3R,4S,5S,6R)-2-(but-3-en-1-ylthio)-6-((1R,2S)-1-(((R)-tert-butylsulfinyl)amino)-2-methylbut-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (S-AA) and (2R,3R,4S,5S,6R)-2-(but-3-en-1-ylthio)-6-((1R,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-methylbut-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate 4,5-Triyl tribenzoate (R-AA): To a solution of (2R,3R,4S,5S,6R)-2-(but-3-en-1-ylthio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (0.320 g, 0.483 mmol, 1.00 equiv) in THF (5 mL) was added crotonylzinc bromide (prepared according to: Krasovskiy, A.; Knochel, P. Synthesis 2006, 890-891) (0.20 M in THF, 7.2 mL, 1.44 mmol, 3.00 equiv) at -78°C and allowed to warm to room temperature overnight. The mixture was diluted with ethyl acetate (10 mL) and quenched with saturated aqueous ammonium chloride (20 mL). The layers were separated and the aqueous layer was further extracted with ethyl acetate (3 × 20 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography (10–40% ethyl acetate / hexanes) afforded the product R-AA (129.3 mg, 0.180 mmol, 37% yield) as the major first-eluting product and S-AA (64.7 mg, 0.090 mmol, 19% yield) as the minor second-eluting product, both as white foams.

[0747] R-AA: 1H NMR (400MHz, CDCl3) δ8.15–8.08(m,2H),8.00–7.93(m,2H),7.80–7.73(m,2H),7.66–7.57(m,1H),7.56–7.4 6(m,3H),7.44–7.34(m,3H),7.23(t,J=7.8Hz,2H),6.25–6.20(m,1H),6.08–5.92(m,2H),5.83–5.67(m,3H), 5.17(dt,J=10.5,1.5Hz,1H),5.11(dt,J=17.3,1.6Hz,1H),5.04–4.93(m,2H),4.71–4.62(m,1H),3.58–3.50 (m,2H),2.90(pent,J=6.9Hz,1H),2.78–2.62(m,2H),2.44–2.26(m,2H),1.14(s,9H),1.12(d,J=7.3Hz,3H). 13 CNMR(101MHz,CDCl3)δ165.96,165.44,165.22,138.72,136.14,133.56, 133.53,133.16,130.10,130.07,129.93,129.72,129.36,129.24,128.7 8,128.56,128.26,116.68,116.62,83.97,70.49,69.70,69.36,69.10,6 0.01,57.12,37.80,33.88,30.57,23.03,16.64.HRMS(ESI+,m / z):[M+H] + Calculated value C 39 H 45 NO8S2,720.2659; measured value 720.2655.

[0748] S-AA: 1H NMR (400MHz, CDCl3) δ8.15–8.06(m,2H),8.01–7.91(m,2H),7.85–7.72(m,2H),7.72–7.57(m,1H),7.55–7. 46(m,3H),7.44–7.34(m,3H),7.27–7.18(m,2H),6.20(d,J=3.2Hz,1H),6.04(d,J=5.8Hz,1H),5.89–5.71( m,3H),5.67(dd,J=10.8,3.2Hz,1H),5.22–5.11(m,2H),5.10–4.94(m,2H),4.74(d,J=6.9Hz,1H),3.71(d, J=5.9Hz,1H),3.60–3.51(m,1H),2.79–2.59(m,3H),2.46–2.29(m,2H),1.13(d,J=7.6Hz,3H),1.09(s,9H). 13 CNMR(101MHz,CDCl3)δ165.85,165.44,165.28,140.70,136.22,133.73, 133.54,133.22,130.11,130.07,129.87,129.51,129.27,129.24,128.8 5,128.57,128.32,116.70,116.14,83.91,69.71,69.13,68.96,68.92,6 0.07,56.82,39.98,33.90,30.39,22.94,16.05.HRMS(ESI+,m / z):[M+H] + Calculated value C 39 H 45 NO8S2,720.2659; measured value 720.2653.

[0749]

[0750]

[0147] (1R,7R,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate: (2R,3R,4S,5S,6R)-2-(but-3-en-1-ylthio)-6-((1R,2R)-1-(((R)-tert-butylsulfinyl)amino)-2-methylbut-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (129.3 mg, 0.180 mmol, 1.00 equiv) was dissolved in toluene (895 mL) and the solution was heated to reflux. Freshly sublimed benzoquinone (7.8 mg, 0.072 mmol, 0.40 equiv) and Grubbs II catalyst (30.6 mg, 0.036 mmol, 0.20 equiv) were dissolved in toluene (5 mL) and added to the reaction mixture. After stirring at reflux for 20 minutes, the reaction mixture was quenched with DMSO (0.25 mL, 3.6 mmol, 20.0 equiv) and then cooled to room temperature. The reaction mixture was concentrated in vacuo, redissolved in ethyl acetate (10 mL) and brine (10 mL), and the layers were separated. The aqueous layer was washed with ethyl acetate (3 × 10 mL), and the combined organic extracts were dried over sodium sulfate and concentrated. Purification by flash column chromatography (15–45% ethyl acetate / hexane) afforded the product as a pale yellow film (24 mg, 0.0347 mmol, 19% yield). NMR analysis revealed a 74:26 mixture of atropisomers. For clarity, only the peak corresponding to the major atropisomer is shown. 1 HNMR(400MHz, CDCl3)δ8.14–8.03(m,2H),8.00–7.91(m,2H),7.83–7.72(m,2H),7.66–7.57(m,1H),7.57–7.44(m,3H) ,7.43–7.33(m,3H),7.26–7.19(m,2H),6.21(d,J=2.9Hz,1H),6.04(d,J=5.5Hz,1H),5.75–5.61(m,3H),5.52(td,J=11 .7,3.6Hz,1H),4.77(d,J=10.5Hz,1H),3.48(ddd,J=10.4,7.0,3.4Hz,1H),3.34(d,J=7.2Hz,1H),3.28–3.06(m,2H),2 .96(qd,J=13.5,4.1Hz,1H),2.67(td,J=13.7,4.5Hz,1H),2.26(d,J=13.9Hz,1H),1.28(s,9H),1.11(d,J=6.8Hz,3H). 13C NMR (101MHz, CDCl3) δ166.01,165.54,165.06,133.55,133.36,133.06,131.93,130.86,130.11,130.08,129.97,129.87,129.57,129.2 9,128.70,128.60,128.22,85.39,70.43,70.33,69.31,68.67,59.54,57.49,33.84,32.28,28.10,23.12,17.60.HRMS(ESI+,m / z):[M+H] + Calculated value C 37 H 41 NO8S2, 692.2346; measured value 692.2337.

[0751]

[0752]

[0266] (1R,7S,8R,9R,10R,11S,12R,Z)-8-Amino-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triol: NaOMe in MeOH (0.5 M, 1.0 mL, 0.5 mmol, 14.4 equiv) was added to (1R,7R,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (24 mg, 0.0347 mmol, 1.00 equiv) and the resulting solution was stirred for 1 h. HCl / dioxane (4.0 M, 0.25 mL, 1.0 mmol, 28.8 equiv) was then added to the mixture, and the resulting white suspension was stirred for 1 hour. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (5–50% MeCN / H₂O containing 0.1% HCOOH over 30 minutes) to afford the product as a pale yellow film (7.3 mg, 0.0265 mmol, 76% yield over two steps). NMR indicated that the product was isolated as the free base, not as the formate salt. 1H NMR (400MHz, MeOD) δ5.64(td,J=11.7,3.7Hz,1H),5.47(d,J=5.9Hz,1H),5.31(td,J=11.1,1.8Hz,1H),4.45(dd,J=10.5,1.2Hz,1H) ,4.04(dd,J=10.2,5.9Hz,1H),3.92–3.85(m,1H),3.51(dd,J=10.4,3.3Hz,1H),3.47(dd,J=10.2,3.4Hz,1H),3.23(ddd,J=11.1,7.1 3.5Hz,1H),3.17(ddd,J=14.0,4.1,2.3Hz,1H),2.93(qd,J=13.2,4.1Hz,1 H),2.72(td,J=13.6,4.5Hz,1H),2.33–2.12(m,1H),1.16(d,J=7.1Hz,3H). 13 C NMR(101MHz,MeOD)δ134.66,129.25,90.23,72.51,70.68,69.52,68.78,55.20,33.88,30.84,29.06,16.94.HRMS(ESI+,m / z): [M+H] + Calculated value C 12 H 21 NO4S, 276.1264; measured value 276.1263.

[0753]

[0754] (4S,5aS,8S,8aR)-4-isobutyl-8-(((1R,7R,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)carbamoyl)octahydro-2H-oxepin[2,3-c]pyrrol-7-ium carboxylate (FSA1507066·HCOOH): (1R,7R,8R,9R,10R,11S,12R,Z)-8-amino-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)carbamoyl)octahydro-2H-oxepin[2,3-c]pyrrol-7-ium carboxylate was added to a 1% ethanol solution in DMF (0.5 mL). To the mixture of (4S,5aS,8S,8aR)-7-(tert-butoxycarbonyl)-4-isobutyloctahydro-2H-oxepin-[2,3-c]pyrrole-8-carboxylic acid (10.8 mg, 0.032 mmol, 1.20 equiv), HATU (12.0 mg, 0.032 mmol, 1.20 equiv) and DIPEA (27.7 uL, 0.159 mmol, 6.00 equiv) was added 13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triol (7.3 mg, 0.0265 mmol, 1.00 equiv). The reaction mixture was stirred at room temperature overnight (16 hours). After concentration under reduced pressure, 1M HCl in MeOH (1 mL, 1.00 mmol, 37.7 equiv) was added and the reaction mixture was stirred for 1 hour. Concentration under reduced pressure followed by purification by preparative HPLC (5-50% MeCN / H2O containing 0.1% HCOOH over 30 min) afforded the product FSA1507066.HCOOH (5.0 mg, 0.0092 mmol, 35% yield over two steps) as a thin, clear film. 1H NMR(400MHz,MeOD)δ8.45(br s,1H),5.50(td,J=11.6,3.5Hz,1H),5.44(d,J=5.9Hz,1H),5.38(td,J= 10.9,1.7Hz,1H),4.43–4.20(m,4H),4.06–3.95(m,2H),3.81(td,J=11. 6,11.0,3.7Hz,1H),3.75(d,J=3.3Hz,1H),3.58(dd,J=11.3,7.4Hz,1H),3.41(dd,J=10.2,3.4Hz,1H),3.15(ddd,J=13.9,4.0,2.2Hz,1H),3.06( ddd,J=10.7,7.1,3.3Hz,1H),2.98(dd,J=12.6,4.1Hz,1H),2.87(t,J=11.7Hz,1H),2.69(td,J=13.6,4.6Hz,1H),2.36–2.24(m,1H),2.23–2.15 (m,1H),2.00(d,J=12.4Hz,1H),1.90–1.58(m,4H),1.19(td,J=6.8,3.5 Hz,2H),1.03(d,J=6.9Hz,3H),1.02–0.92(m,1H),0.89(d,J=6.5Hz,6H). 13 C NMR(101MHz,MeOD)δ169.22,168.65,132.52,132.20,90.19,80.95,72.91,72.14,70.01,69.50,69.11,62.27,53.96 ,49.50,48.13,43.67,37.31,36.43,36.06,34.11,32.54,29.03,26.29,23.17,22.93,17.45.HRMS(ESI+,m / z):[M+H] + Calculated value C 25 H 42 N2O6S, 499.2836; measured value 499.2834.

[0755] FSA1507066·HCOOH was prepared and isolated as a single diastereomer. The C-7 methyl group was designated as the R-stereocenter. In addition, one of ordinary skill will recognize that compounds having either an R or S-stereocenter at the C-7 methyl group can be obtained by the synthetic routes described herein.

[0756]

[0757] (4S,5aS,8S,8aR)-4-Isobutyl-7-methyl-8-(((1R,7R,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)carbamoyl)octahydro-2H-oxepin[2,3-c]pyrrol-7-ium carboxylate (FSA1508001·HCOOH): Sodium cyanoborohydride (2.4 mg, 0.038 mmol, 10 equiv) was added to a solution of FSA1507066·HCOOH (2.1 mg, 0.0038 mmol, 1.0 equiv) in 37% w / w aqueous formaldehyde (15.4 mg, 0.114 mmol, 50 equiv) and stirred at ambient temperature for 45 minutes. The reaction mixture was quenched with saturated aqueous sodium carbonate (10 mL), extracted with CHCl (2 x 20 mL), and the combined organic layers dried over sodium sulfate. The mixture was concentrated under reduced pressure and then purified by preparative HPLC (5–50% MeCN / H2O containing 0.1% HCOOH for 30 minutes) to afford the product, FSA1508001·HCOOH (1.9 mg, 0.0034 mmol, 89% yield), as a thin, clear film. 1H NMR (400 MHz, MeOD) δ 8.29 (br s,1H),5.52(td,J=11.6,3.5Hz,1H),5.45(d,J=5.9Hz,1H),5.34(td,J=11.0, 1.9Hz,1H),4.37(dd,J=11.0,7.2Hz,1H),4.30–4.17(m,2H),4.02(dd,J=10.2, 5.9Hz,1H),4.02–3.95(m,1H),3.85(d,J=3.6Hz,1H),3.83–3.66(m,2H),3.48 –3.44(m,1H),3.41(dd,J=10.3,3.3Hz,1H),3.16(ddd,J=14.1,4.2,2.3Hz,1H) ,3.13–3.02(m,1H),2.97(qd,J=13.1,4.1Hz,1H),2.71(dd,J=13.7,4.6Hz,1H ),2.68–2.54(m,f4H),2.30(dtt,J=11.9,5.9,2.6Hz,1H),2.24–2.15(m,1H),1 .97(d,J=13.4Hz,1H),1.73–1.59(m,4H),1.19(hept,J=6.7Hz,2H),1.01(d,J= 6.8Hz,3H),0.97–0.90(m,1H),0.894(d,J=6.5Hz,3H),0.887(d,J=6.5Hz,3H). 13 C NMR(101MHz,MeOD)δ170.31,166.89,132.54,132.22,90.18,81.54,73.25,72.88,72.37,70.06,69.39,68.85,59.71,53 .49,48.11,45.13,41.51,37.73,37.22,35.36,34.07,32.26,29.07,26.29,23.22,22.91,17.54.HRMS(ESI+,m / z):[M+H] + Calculated value C 26 H 44 N2O6S, 513.2993; measured value 513.2992.

[0758] FSA1508001·HCOOH was prepared and isolated as a single diastereomer. The C-7 methyl group was designated as the R-stereocenter. In addition, one of ordinary skill will recognize that compounds having either an R or S-stereocenter at the C-7 methyl group can be obtained by the synthetic routes described herein.

[0759]

[0760]

[0147] (1R,7S,8R,9R,10S,11S,12R,E)-8-(((R)-tert-butylsulfinyl)amino)-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate: (2R,3R,4S,5S,6R)-2-(but-3-en-1-ylthio)-6-((1R,2S)-1-(((R)-tert-butylsulfinyl)amino)-2-methylbut-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (64.7 mg, 0.090 mmol, 1.00 equiv) was dissolved in toluene (445 mL) and the solution was heated to reflux. Freshly sublimed benzoquinone (3.9 mg, 0.036 mmol, 0.40 equiv) and Grubbs II catalyst (15.3 mg, 0.018 mmol, 0.20 equiv) were dissolved in toluene (5 mL) and added to the reaction mixture. After stirring at reflux for 20 minutes, the reaction mixture was quenched with DMSO (0.25 mL, 3.6 mmol, 40.0 equiv) and cooled to room temperature. The reaction mixture was concentrated in vacuo, redissolved in ethyl acetate (5 mL) and brine (5 mL), and the layers were separated. The aqueous layer was washed with ethyl acetate (3 × 5 mL), and the combined organic extracts were dried over sodium sulfate and concentrated. Purification by flash column chromatography (15–45% ethyl acetate / hexane) afforded the product as a pale yellow film (4 mg, 0.0058 mmol, 6% yield). NMR analysis revealed the product as a 66:34 mixture of atropisomers. For clarity, only the peak corresponding to the major atropisomer is shown. 1 HNMR(400MHz, CDCl3)δ8.14–8.03(m,2H),8.01–7.91(m,2H),7.84–7.72(m,2H),7.67–7.57(m,1H),7.5 3–7.46(m,3H),7.47–7.33(m,3H),7.25–7.19(m,2H),6.09–5.96(m,2H),5.78–5.56(m,3H),5.31(t,J= 12.9Hz,1H),4.87(d,J=10.5Hz,1H),3.92(d,J=4.9Hz,1H),3.34–3.18(m,2H),3.05(s,1H),2.68(d,J= 13.5Hz,1H),2.43(t,J=13.9Hz,1H),2.10(q,J=13.5,12.5Hz,1H),1.31(s,9H),1.26(d,J=9.8Hz,3H). 13C NMR (101MHz, CDCl3) δ166.19,165.94,165.53,133.71,133.55,133.28,133.07,131.90,130.14,130.11,130.06,129.97,129.82,129.2 6,128.79,128.60,128.36,88.29,70.34,69.82,69.50,69.45,57.38,56.61,38.20,37.95,35.69,22.89,18.94.HRMS(ESI+,m / z):[M+H] + Calculated value C 37 H 41 NO8S2, 692.2346; measured value 692.2338.

[0761]

[0762]

[0266] (1R,7S,8R,9R,10R,11S,12R,E)-10,11,12-Trihydroxy-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-8-amine (aminium) formate: NaOMe in MeOH (0.5 M, 1.0 mL, 0.5 mmol, 86.2 equiv) was added to (1R,7S,8R,9R,10S,11S,12R,E)-8-(((R)-tert-butylsulfinyl)amino)-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (4 mg, 0.0058 mmol, 1.00 equiv) and the resulting solution was stirred for 1 h. Then HCl / dioxane (4.0 M, 0.25 mL, 1.0 mmol, 172.4 equiv) was added to the mixture and the resulting white suspension was stirred for 1 hour. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (5-50% MeCN / H2O containing 0.1% HCOOH over 30 minutes) to afford the product (1.5 mg, 0.0047 mmol, 80% yield over two steps) as a light yellow film.

[0763] The product was found to exist as a 54:46 mixture of atropisomers, which is consistent with the method reported by Hu et al. (Hu, DX; Grice, P.; Ley, SVJ Org. Chem. 2012, 77, 5198-5202). For clarity, only the peak corresponding to the major atropisomer is shown. 1H NMR (400MHz, MeOD) δ8.34(s,1H),5.76(s,1H),5.30(dd,J=15.8,9.6Hz,1H),5.22(d,J=5.8Hz,1H),4.36(d,J=7.9Hz,1H),4.15–3.98(m,1H),3. 90(s,1H),3.58–3.50(m,1H),3.31–3.17(m,1H),2.94–2.83(m,1H),2.5 7–2.34(m,2H),2.31–2.17(m,1H),2.11–1.94(m,1H),1.32–1.20(m,3H). 13 C NMR(101MHz,MeOD)δ167.92,135.36,131.44,89.91,71.68,70.38,70.23,69.63,57.26,43.88,36.06,29.03,18.09.HRMS(ESI+,m / z):[M+H] + Calculated value C 12 H 21 NO4S, 276.1264; measured value 276.1264.

[0764]

[0765] (4S,5aS,8S,8aR)-4-isobutyl-N-((1R,7S,8R,9R,10R,11S,12R,E)-10,11,12-trihydroxy-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)octahydro-2H-oxepino[2,3-c]pyrrole-8-carboxamide formate (FSA1507068·HCOOH): To ((1R,7S,8R,9R,10R,11S,12R,E)-10,11,12-trihydroxy-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)octahydro-2H-oxepino[2,3-c]pyrrole-8-carboxamide formate) was added. Thiabicyclo[7.3.1]tridec-5-en-8-amine formate (1.5 mg, 0.0047 mmol, 1.00 equiv) was added (4S,5aS,8S,8aR)-7-(tert-butyloxycarbonyl)-4-isobutyloctahydro-2H-oxepin-[2,3-c]pyrrole-8-carboxylic acid (1.9 mg, 0.0056 mmol, 1.20 equiv), HATU (2.1 mg, 0.0056 mmol, 1.20 equiv) and (5.9 uL, 0.0336 mmol, 6.00 equiv). The reaction mixture was stirred at room temperature overnight (16 hours). After concentration under reduced pressure, 1 M HCl / MeOH (0.5 mL, 0.50 mmol, 106 equiv) was added, and the reaction mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure and then purified by preparative chromatography (5–50% MeCN / H₂O containing 0.1% HCOOH over 30 minutes) to afford the product, FSA1507068·HCOOH (0.737 mg, 0.00135 mmol, 29% yield over two steps), as a thin, clear film. 1 H NMR(400MHz,MeOD)δ8.38(s,1H),5.40–5.26(m,2H),5.21(d,J=5.7Hz,1H),4.41–4.23(m,3H),4.19(d,J=10 .8Hz,1H),4.07–3.93(m,2H),3.84–3.71(m,2H),3.59(dd,J=11.3,7.4Hz,1H),3.38(dd,J=10.3,3.3Hz,1H) ,3.21(dt,J=14.6,3.5Hz,1H),2.88(t,J=11.7Hz,1H),2.71–2.47(m,3H),2.34–2.25(m,1H),2.03–1.88(m, 2H),1.85–1.57(m,4H),1.31–1.11(m,2H),1.03(d,J=7.1Hz,3H),1.01–0.92(m,1H),0.89(d,J=6.5Hz,6H). 13C NMR(101MHz,MeOD)δ168.17,168.09,136.37,131.08,93.81,80.95,72.81,71.80,70.59,69.95,69.05,62.51,52.01 ,49.59,48.11,43.57,40.93,37.86,37.28,36.49,36.20,36.02,26.29,23.16,22.93,16.73.HRMS(ESI+,m / z):[M+H] + Calculated value C 25 H 42 N2O6S, 499.2836; measured value 499.2836.

[0766] FSA1507068·HCOOH was prepared and isolated as a single diastereomer. The C-7 methyl group was designated as the S-stereocenter. In addition, one of ordinary skill will recognize that compounds having either an R or S-stereocenter at the C-7 methyl group can be obtained by the synthetic routes described herein.

[0767] Synthesis of FSA1503054, FSA1503055, and FSA1503058

[0768]

[0769] (2R,3R,4S,5S,6R)-2-(Allylthio)-6-((benzoyloxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate: Allyl bromide (2.12 mL, 24.5 mmol, 1.5 equiv) was added to a solution of (2R,3S,4S,5R,6R)-2-((benzoyloxy)methyl)-6-mercaptotetrahydro-2H-pyran-3,4,5-triyl tribenzoate (10.0 g, 16.3 mmol, 1.0 equiv) in distilled THF (60 mL). The solution was cooled to 0°C and DBU (3.65 mL, 24.5 mmol, 1.5 equiv) was added, resulting in the immediate formation of a white precipitate. The reaction mixture was stirred for 10 minutes and concentrated under reduced pressure. Purification by flash column chromatography (10-20% ethyl acetate / hexanes) afforded the product (6.38 g, 9.78 mmol, 60% yield) as a white foam. 1H NMR (500MHz, CDCl3) δ8.13–8.06(m,2H),8.06–8.01(m,2H),8.00–7.95(m,2H),7.80–7.77(m,2H),7.66–7.59(m,1 H),7.59–7.51(m,1H),7.54–7.47(m,3H),7.46–7.35(m,5H),7.28–7.21(m,2H),6.06–6.03(m,1H),5.96(d,J=4.6 Hz,1H),5.96–5.84(m,2H),5.72(dddd,J=16.9,9.9,8.6,5.6Hz,1H),5.16–5.06(m,2H),5.04–5.00(m,1H),4.64( dd,J=11.5,7.3Hz,1H),4.46(dd,J=11.5,5.5Hz,1H),3.27(dd,J=13.6,8.6Hz,1H),3.16(dd,J=13.7,5.7Hz,1H). 13 CNMR (126MHz, CDCl3) δ166.14,165.71,165.68,165.55,133.75,133.61,133.40,133.36,132.73,130.11,130.06,129.86,129.85,129.63, 129.24,129.17,129.14,128.79,128.61,128.60,128.41,118.45,81.21,69.32,69.18,68.81,67.54,62.76,32.15.HRMS(ESI+,m / z):[M+H] + Calculated value C 37 H 32 O9S, 653.1840; measured value 653.1832.

[0770]

[0771] (2R,3R,4S,5S,6R)-2-(Allylthio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate: Dichlorotetrakis(1,1-dimethylethyl)di-μ-hydroxydistannic acid (0.30 g, 0.521 mmol, 0.17 equiv) was added to (2R,3R,4S,5S,6R)-2-(allylthio)-6-((benzoyloxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (2.00 g, 3.06 mmol, 1.0 equiv) dissolved in a mixture of anhydrous MeOH (20 mL) and anhydrous THF (6 mL). The reaction mixture was stirred at 65°C overnight (16 hours) and concentrated under reduced pressure. Purification by flash column chromatography (10-25% ethyl acetate / hexanes) afforded the product (1.37 g, 2.50 mmol, 82% yield) as a white foam. 1 H NMR (400MHz, CDCl3) δ8.16–8.09(m,2H),8.05–7.97(m,2H),7.87–7.79(m,2H),7.67–7.61(m,1H), 7.57–7.35(m,6H),7.30–7.21(m,2H),5.99–5.84(m,4H),5.77(dddd,J=16.9,9.9,8.4,5.8Hz,1H), 5.18(dd,J=17.0,1.4Hz,1H),5.13(dd,J=9.9,1.5Hz,1H),4.75(td,J=6.6,1.2Hz,1H),3.86–3.77 (m,1H),3.75–3.66(m,1H),3.29(ddt,J=13.8,8.5,1.0Hz,1H),3.19(ddt,J=13.8,5.9,1.3Hz,1H). 13 C NMR (126MHz, CDCl3) δ166.81,165.79,165.49,133.93,133.62,133.40,133.12,130.17,130.06,129.82,129.16,129. 15,129.02,128.82,128.62,128.44,118.27,81.53,69.91,69.79,69.39,69.03,60.93,32.46.HRMS(ESI+,m / z):[M+H] + Calculated value C 30 H 28 O8S, 549.1578; measured value 549.1570.

[0772]

[0773] (2R,3R,4S,5R,6S)-2-(allylthio)-6-formyltetrahydro-2H-pyran-3,4,5-triyl tribenzoate: To a solution of (2R,3R,4S,5S,6R)-2-(allylthio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (1.37 g, 2.50 mmol, 1.00 equiv) in dichloromethane (15 mL) was added Dess-Martin periodinane (1.59 g, 3.75 mmol, 1.50 equiv) and the resulting white suspension was stirred for 1 hour. The reaction mixture was diluted with diethyl ether (60 mL) and treated with saturated aqueous sodium bicarbonate (22.5 mL) followed by aqueous sodium thiosulfate (50 wt%, 22.5 mL). The resulting bilayer mixture was stirred vigorously at 23°C for 1 hour before the layers were separated. The aqueous layer was extracted with ether (3 x 10 mL), and the combined organic extracts were washed sequentially with saturated aqueous sodium bicarbonate solution (22.5 mL) and brine (22.5 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated to afford the product as a white foam (1.37 g, 2.49 mmol, 100% yield), which was used in the subsequent sulfenimine condensation without further purification.

[0774]

[0775]

[0149] (2R,3R,4S,5S,6R)-2-(Allylthio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate: To a mixture of (2R,3R,4S,5R,6S)-2-(allylthio)-6-formyltetrahydro-2H-pyran-3,4,5-triyl tribenzoate (1.37 g, 2.49 mmol, 1.00 equiv), (R)-(+)-2-methyl-2-propanesulfenamide (604 mg, 4.98 mmol, 2.00 equiv) and anhydrous copper(II) sulfate (596 mg, 3.74 mmol, 1.50 equiv) was added anhydrous toluene (8 mL). The resulting white suspension was heated to 40°C and stirred for 16 hours, during which time the suspension turned emerald green. The reaction mixture was allowed to cool to room temperature and filtered through celite, washing (3 x 15 mL CH2Cl2). The combined organic extracts were concentrated and purified by flash column chromatography (10-50% ethyl acetate / hexanes) to give the product (1.05 g, 1.62 mmol, 65% yield) as a white foam. 1H NMR(400MHz, CDCl3)δ8.05(d,J=2.1Hz,1H),8.02–7.94(m,4H),7.82–7.74(m,2H),7.63–7.56(m,1H),7.55–7.50(m ,1H),7.48–7.34(m,5H),7.30–7.21(m,2H),6.32(dd,J=3.1,1.5Hz,1H),6.05(d,J=5.5Hz,1H),5.89(dd,J=10.7,5. 5Hz,1H),5.82(dd,J=10.6,3.1Hz,1H),5.74(dddd,J=16.8,9.8,8.5,5.7Hz,1H),5.51(t,J=1.9Hz,1H),5.22(dd,J =17.0,1.3Hz,1H),5.17(d,J=10.1Hz,1H),3.28(dd,J=13.8,8.6Hz,1H),3.20(dd,J=13.8,5.8Hz,1H),0.99(s,9H). 13 C NMR (126MHz, CDCl3) δ165.58,165.51,165.37,133.66,133.61,133.32,132.45,129.99,129.95,129.80,129.19,129.03, 128.99,128.66,128.57,128.34,118.83,81.81,71.47,69.49,69.40,68.34,57.15,32.46,22.14.HRMS(ESI+,m / z):[M+H] + Calculated value C 34 H 35 NO8S2, 650.1877; measured value 650.1867.

[0776]

[0777] (2R,3R,4S,5S,6R)-2-(allylthio)-6-((R)-1-(((R)-tert-butylsulfinyl)amino)pent-4-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate: (2R,3R,4S,5S,6R)-2-(allylthio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (0.200 g, 0.309 mmol) was added to the mixture at –78°C. To a solution of 1.68 mL, 0.370 mmol, 1.20 equiv) in THF (3 mL) was added butenylmagnesium bromide (prepared according to: Wolleb, H.; Ogawa, S.; Schneider, M.; Shemet, A.; Muri, J.; Kopf, M.; Carreira, EM Org. Lett. 2018, 20, 10, 3014–3016) (0.22 M in THF, 1.68 mL, 0.370 mmol, 1.20 equiv) and stirred at –78 ° C for 1 hour. The mixture was diluted with ethyl acetate (10 mL) and quenched with saturated aqueous ammonium chloride (15 mL). The layers were separated and the aqueous layer was further extracted with ethyl acetate (3×15 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (10-40% ethyl acetate / hexanes) afforded the product (0.188 g, 0.266 mmol, 86% yield) as a white foam. 1H NMR (400MHz, CDCl3) δ8.12–8.04(m,2H),8.01–7.93(m,2H),7.79–7.72(m,2H),7.67–7.58(m,1H),7.56–7.45(m,3H),7.45–7.34(m,3H),7.22(t, J=7.9Hz,2H),6.09(d,J=3.0Hz,1H),5.95(d,J=5.7Hz,1H),5.85(dd,J=10.7,5.8Hz,1H),5.82–5.66(m,3H),5.20(dd,J=17.0,1.4Hz,1H),5.17( d,J=1.5Hz,1H),5.04(dq,J=17.1,1.7Hz,1H),4.97(dq,J=10.1,1.4Hz, 1H),4.70(d,J=7.7Hz,1H),3.78(d,J=5.1Hz,1H),3.58–3.47(m,1H),3.2 6(dd,J=13.7,8.4Hz,1H),3.20(dd,J=13.7,5.9Hz,1H),2.35(ddt,J=14.6,10.4,5.8Hz,1H),2.26–2.10(m,1H),2.06–1.83(m,2H),1.19(s,9H). 13 C NMR (101MHz, CDCl3) δ165.78,165.74,165.49,137.73,133.81,133.59,133.31,132.67,130.11,130.04,129.80,129.27,129.17,129.17,12 8.83,128.60,128.38,118.69,115.54,81.68,70.47,69.88,68.91,68 .72,56.33,54.75,32.58,30.51,29.76,22.74.HRMS(ESI+,m / z):[M+H] + Calculated value C 38 H 43 NO8S2,706.2503; measured value 706.2500.

[0778]

[0779]

[0266] (R)-1-((2R,3R,4S,5R,6R)-6-(Allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)pent-4-en-1-amine formate: NaOMe in MeOH (0.5 M, 4.0 mL, 2.0 mmol, 14.1 equiv) was added to (2R,3R,4S,5S,6R)-2-(allylthio)-6-((R)-1-(((R)-tert-butylsulfinyl)amino)pent-4-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (100 mg, 0.142 mmol, 1.00 equiv) and the resulting solution was stirred for 1 h. Then HCl / dioxane (4.0M, 1.00 mL, 4.0 mmol, 28.2 equiv) was added to the mixture and the resulting white suspension was stirred for 1 hour. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (5-50% MeCN / H2O, containing 0.1% HCOOH, 30 minutes) to give the product (35 mg, 0.104 mmol, 73% yield over two steps) as a light yellow film. 1 HNMR(400MHz,MeOD)δ8.46(br s,1H),5.93–5.78(m,2H),5.43(d,J=5.6Hz,1H),5.24–5.03(m,4H),4.30(dd,J=4.8,1.6Hz,1H),4.22–4.06(m,2H),3.63(dd,J=10.1,3.3Hz,1H ), 3.43(td,J=7.1,4.7Hz,1H), 3.23(dd,J=13.9,8.1Hz,1H), 3.17(dd,J=13.8,6.3Hz,1H), 2.35–2.16(m,J=6.8,6.4Hz,2H), 2.00–1.80(m,2H). 13 C NMR(101MHz,MeOD)δ169.28,137.74,135.32,117.73,116.76,86.74,71.55,70.47,68.91,68.70,54.16,33.36,30.63,29.50.HRMS(ESI+,m / z): [M+H] + Calculated value C 13 H 23 NO4S, 290.1421; measured value 290.1423.

[0780]

[0781] tert-Butyl (4S,5aS,8S,8aR)-8-(((R)-1-((2R,3R,4S,5R,6R)-6-(allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)pent-4-en-1-yl)carbamoyl)-4-isobutyloctahydro-7H-oxepino[2,3-c]pyrrole-7-carboxylate: To a solution of (R)-1-((2R,3R,4S,5R,6R)-6-(allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)pent-4-en-1-yl)carbamoyl)-4-isobutyloctahydro-7H-oxepino[2,3-c]pyrrole-7-carboxylate was added. To the mixture of (4S,5aS,8S,8aR)-7-(tert-butyloxycarbonyl)-4-isobutyloctahydro-2H-oxepino[2,3-c]pyrrole-8-carboxylic acid (42.1 mg, 0.125 mmol, 1.20 equiv), HATU (46.8 mg, 0.125 mmol, 1.20 equiv) and DIPEA (108 uL, 0.624 mmol, 6.00 equiv) was added 2H-pyran-2-yl)pent-4-en-1-amine formate (35 mg, 0.104 mmol, 1.00 equiv). The reaction mixture was stirred at room temperature overnight (16 hours), concentrated in vacuo, redissolved in ethyl acetate (25 mL), and washed with 1:1 brine:saturated aqueous NaHCO3 (25 mL). The organic extract was dried over sodium sulfate and concentrated to afford the product as a yellow oil (41 mg, 0.0669 mmol, 64% yield), which was used in the subsequent olefin metathesis without further purification.

[0782]

[0783] (4S,5aS,8S,8aR)-4-isobutyl-N-((1R,8R,9R,10R,11S,12R,E)-10,11,12-trihydroxy-13-oxa-2-thiabicyclo[7.3.1]tridec-4-en-8-yl)octahydro-2H-oxepin[2,3-c]pyrrole-8-carboxamide formate (FSA1503054·HCOOH) and (4S,5aS,8S,8aR)-4-isobutyl-N-((1R,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-13-oxa-2-thiabicyclo[7.3.1]tridec-4-en-8-yl)octahydro-2H-oxepin[2,3-c]pyrrole-8-carboxamide formate

[0266] Tert-butyl (4S,5aS,8S,8aR)-8-(((R)-1-((2R,3R,4S,5R,6R)-6-(allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)pent-4-en-1-yl)carbamoyl)-4-isobutyloctahydro-7H-oxepino[2,3-c]pyrrole-7-carboxylate (41 mg, 0.0669 mmol, 1.00 equiv) was dissolved in toluene (330 mL) and the solution was heated to reflux. Freshly sublimed benzoquinone (2.9 mg, 0.026 mmol, 0.40 equiv) and Grubbs II catalyst (11.3 mg, 0.013 mmol, 0.20 equiv) were dissolved in toluene (5 mL) and added to the reaction mixture. After stirring at reflux for 20 minutes, the reaction mixture was quenched with DMSO (0.236 mL, 3.35 mmol, 50 equiv) and then cooled to room temperature. The reaction mixture was concentrated in vacuo, redissolved in ethyl acetate (10 mL) and brine (10 mL), and the layers were separated. The aqueous layer was washed with ethyl acetate (3×10 mL), and the combined organic extracts were dried over sodium sulfate and concentrated.

[0784] After concentration under reduced pressure, 1M HCl / MeOH (1 mL, 1.00 mmol, 25.6 equiv) was added, and the reaction mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure and then purified by preparative HPLC (5–50% MeCN / H₂O containing 0.1% HCOOH over 30 minutes) to afford the byproduct FSA1503054·HCOOH (0.731 mg, 0.00138 mmol, 1.3% yield over three steps) and the main product FSA1503055·HCOOH (0.932 mg, 0.00176 mmol, 1.7% yield over three steps), both as thin, transparent films. A mixed fraction (0.666 mg, 0.00126 mmol, 1.2% yield over three steps) was also obtained for subsequent olefin reduction.

[0785] FSA1503054·HCOOH: 1 H NMR(400MHz,MeOD)δ8.44(br s,1H), δ5.78(d,J=5.3Hz,1H),5.54–5.32(m,2H),4.69–4.55(m,2H),4.32(d,J=5.3Hz,2H),4.20( d,J=10.3Hz,1H),4.05–3.90(m,2H),3.82–3.72(m,2H),3.56(dd,J=11.2,7.2Hz,1H),3.45–3.34( m,1H),3.16(d,J=13.9Hz,1H),2.85(t,J=11.7Hz,1H),2.33–2.15(m,2H),2.08–1.96(m,2H),1.89 –1.60(m,6H),1.26–1.10(m,2H),1.01–0.91(m,1H),0.89(d,J=6.5Hz,6H).HRMS(ESI+,m / z):[M+H] + Calculated value C 24 H 40 N2O6S, 485.2680; measured value 485.2682.

[0786] FSA1503055 HCOOH: 1 H NMR(400MHz,MeOD)δ8.41(br s,1H),5.56(br s,2H),5.46(q,J=9.8,9.3Hz,1H),4.41–4.15(m,4H),4.06–3.93(m,2H),3.88(br s,1H),3.86–3.75(m,1H),3.70(dd,J=9.0,3.0Hz,1H),3.56–3.50(m,1H),3.29–3.15(m,2H),2.84–2.76(m,1H),2.35–2.19(m,1H),2.16 –1.95(m,3H),1.81–1.57(m,5H),1.36–1.27(m,1H),1.26–1.10(m,2H),1.02–0.91(m,1H),0.90(d,J=6.5Hz,6H).HRMS(ESI+,m / z):[M+H] + Calculated value C 24 H 40 N2O6S, 485.2680; measured value 485.2684.

[0787]

[0788] (4S,5aS,8S,8aR)-4-isobutyl-N-((1R,8R,9R,10R,11S,12R)-10,11,12-trihydroxy-13-oxa-2-thiabicyclo[7.3.1]tridec-8-yl)octahydro-2H-oxepino[2,3-c]pyrrole-8-carboxamide formate (FSA1503058 HCOOH): A mixture of FSA1503054 HCOOH and FSA1503055 HCOOH (0.666 mg, 1.26 μmol, 1.00 equiv) was added to THF (1 mL) and purged with argon while stirring. While purging, 10 wt% Pd / C (1 mg, 0.94 μmol, 0.75 equiv) was added to the mixture. The vent needle was removed and replaced with a needle connected to a hydrogen balloon. Hydrogen gas was bubbled through the solution for 5 minutes, after which the needle was lifted above the solution and stirred for 5 hours. Pd / C was removed using a syringe filter, and the filtrate was concentrated in vacuo. Purification by preparative HPLC (5–50% MeCN / H₂O containing 0.1% HCOOH over 30 minutes) afforded the product, FSA1503058·HCOOH (0.577 mg, 1.08 μmol, 86% yield), as a thin, clear film. 1 H NMR(400MHz,MeOD)δ8.49(br s,1H),5.52(d,J=6.0Hz,1H),4.62–4.42(m,2H),4.28(t,J=9.2Hz,1H),4.20(d,J=8.9Hz,1H),4.02(dd,J=10.1,5.9Hz,1H),3.97(dt, J=12.7,3.6Hz,1H),3.80(d,J=3.2Hz,1H),3.79–3.73(m,1H),3.55(dd,J=10.1,3.3Hz,1H),3.52–3.47(m,1H),3.40–3.32(m,1H),3.19 –3.11(m,1H),2.76(t,J=11.5Hz,1H),2.46(td,J=13.7,4.5Hz,1H),2.24(dtd,J=11.7,9.8,8.5,2.9Hz,1H),2.17–2.05(m,2H),2.03–1 .90(m,2H),1.80–1.51(m,6H),1.48–1.33(m,2H),1.25–1.10(m,2H),0.98–0.91(m,1H),0.89(d,J=6.6Hz,6H).HRMS(ESI+,m / z):[M+H] + Calculated value C 24 H 42 N2O6S, 487.2836; measured value 487.2841.

[0789] Synthesis of FSA1504066A, FSA1504066B and FSA1504068

[0790]

[0791] (R)-1-((2R,3R,4S,5R,6R)-6-(allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)-2,2-dimethylpent-4-en-1-amine formate: (2R,3R,4S,5S,6R)-2-(allylthio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyltrityl formate at –78°C was added. To a solution of 2-methylpent-4-en-2-yl ester (0.100 g, 0.154 mmol, 1.00 equiv) in THF (1 mL) was added (2-methylpent-4-en-2-yl)lithium (prepared according to: Mudryk, B.; Cohen, T. Am. Chem. Soc. 1993, 115, 3855–3865) (0.15 M in THF, 3.08 mL, 0.462 mmol, 3.00 equiv) at –78°C. The reaction was warmed to 0°C and stirred for 2 hours. The solution was warmed to room temperature and 0.5 M NaOMe / MeOH (2 mL, 1.00 mmol, 6.49 equiv) was added. After stirring for 1 hour, 4 M HCl / 1,4-dioxane (0.5 mL, 2.0 mmol, 12.99 equiv) was added and the resulting white suspension was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (5-50% MeCN / H2O with 0.1% HCOOH over 30 min) to afford the product (16 mg, 0.044 mmol, 29% yield over three steps) as a yellow oil. 1 H NMR(400MHz,MeOD)δ8.52(br s,1H),5.97–5.77(m,2H),5.42(d,J=5.6Hz,1H),5.30–5.09(m,4H),4.47(dd,J=3.9,1.5Hz,1H),4.25(dd,J=3.3,1.6Hz,1H),4.13(dd,J =10.1,5.6Hz,1H),3.64(dd,J=10.1,3.3Hz,1H),3.24(d,J=3.8Hz,1H),3.23–3.11(m,2H),2.31–2.17(m,2H),1.15(s,3H),1.14(s,3H).

[0792] 13C NMR(101MHz,MeOD)δ169.95,135.35,134.28,119.90,117.78,87.04,72.17,71.52 ,68.74,67.87,62.77,45.39,36.51,33.63,24.85,23.44.HRMS(ESI+,m / z):[M+H] + Calculated value C 15 H 27 NO4S, 318.1734; measured value 318.1738.

[0793]

[0794] tert-Butyl (4S,5aS,8S,8aR)-8-(((R)-1-((2R,3R,4S,5R,6R)-6-(allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)-2,2-dimethylpent-4-en-1-yl)carbamoyl)-4-isobutyloctahydro-7H-oxepino[2,3-c]pyrrole-7-carboxylate: To a solution of (R)-1-((2R,3R,4S,5R,6R)-6-(allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)-2,2-dimethylpent-4-en-1-yl)carbamoyl)-4-isobutyloctahydro-7H-oxepino[2,3-c]pyrrole-7-carboxylate was added to a 1% ethanol solution of 1% ethanol. To the mixture of (4S,5aS,8S,8aR)-7-(tert-butyloxycarbonyl)-4-isobutyloctahydro-2H-oxepino[2,3-c]pyrrole-8-carboxylic acid (17.8 mg, 0.053 mmol, 1.20 equiv), HATU (19.8 mg, 0.053 mmol, 1.20 equiv) and DIPEA (45.7 uL, 0.264 mmol, 6.00 equiv) was added (4S,5aS,8S,8aR)-7-(tert-butyloxycarbonyl)-4-isobutyloctahydro-2H-oxepino[2,3-c]pyrrole-8-carboxylic acid (17.8 mg, 0.053 mmol, 1.20 equiv), HATU (19.8 mg, 0.053 mmol, 1.20 equiv) and DIPEA (45.7 uL, 0.264 mmol, 6.00 equiv). The reaction mixture was stirred at room temperature overnight (16 hours), concentrated in vacuo, redissolved in ethyl acetate (10 mL) and washed with 1:1 brine:saturated aqueous NaHCO3 solution (10 mL). The organic extract was dried over sodium sulfate and concentrated to give the product as a yellow oil (25 mg, 0.039 mmol, 89% yield), which was used in the subsequent olefin metathesis without further purification.

[0795]

[0796] (4S,5aS,8S,8aR)-4-isobutyl-N-((1R,8R,9R,10R,11S,12R,E)-10,11,12-trihydroxy-7,7-dimethyl-13-oxa-2-thiabicyclo[7.3.1]tridec-4-en-8-yl)octahydro-2H-oxepino[2,3-c]pyrrole-8-carboxamide formate (FSA1504066A·HCOOH) and (4S,5aS,8S,8aR)-4-isobutyl-N-((1R,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-7,7-dimethyl-13-oxa-2-thiabicyclo[7.3.1]tridec-4-en-8-yl)octahydro-2H-oxepino[2,3-c]pyrrole-8-carboxamide formate

[0266] tert-Butyl (4S,5aS,8S,8aR)-8-(((R)-1-((2R,3R,4S,5R,6R)-6-(allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)-2,2-dimethylpent-4-en-1-yl)carbamoyl)-4-isobutyloctahydro-7H-oxepino[2,3-c]pyrrole-7-carboxylate (25 mg, 0.039 mmol, 1.00 equiv) was dissolved in toluene (190 mL) and the solution was heated to reflux. Freshly sublimed benzoquinone (1.7 mg, 0.015 mmol, 0.40 equiv) and Grubbs II catalyst (6.6 mg, 0.0078 mmol, 0.20 equiv) were dissolved in toluene (5 mL) and added to the reaction mixture. After stirring at reflux for 20 minutes, the reaction mixture was quenched with DMSO (0.275 mL, 3.9 mmol, 100 equiv) and then cooled to room temperature. The reaction mixture was concentrated in vacuo, redissolved in ethyl acetate (5 mL) and brine (5 mL), and then separated. The aqueous layer was washed with ethyl acetate (3×5 mL), and the combined organic extracts were dried over sodium sulfate and concentrated. After concentration under reduced pressure, 1 M HCl (1 mL, 1.00 mmol, 25.6 equiv) in MeOH was added and the reaction mixture was stirred for 1 hour. After concentration under reduced pressure, purification by preparative HPLC (5–50% MeCN / H₂O containing 0.1% HCOOH over 30 minutes) afforded the major first-eluting product, FSA1504066A·HCOOH (1.911 mg, 0.00342 mmol, 8% yield over three steps), and the minor second-eluting product, FSA1504066B·HCOOH (1.492 mg, 0.00267 mmol, 6% yield over three steps), both as thin, clear films. In addition, a mixed fraction (1.262 mg, 0.00226 mmol, 5% yield over three steps) was obtained and used for subsequent olefin reduction.

[0797] FSA1504066A HCOOH: 1 H NMR(400MHz,MeOD)δ8.42(br s,1H),5.80(d,J=5.3Hz,1H),5.72(t,J=12.3Hz,1H),5.58(t,J=12.4Hz,1H),4.43–4.24(m,3H),4.22(d,J=9 .6Hz,1H),4.02–3.90(m,2H),3.78(td,J=11.2,10.7,3.5Hz,1H),3.73–3.63(m,2H),3.58(dd,J=11.3,7.6Hz, 1H),3.42(t,J=12.1Hz,1H),3.20–3.12(m,1H),2.88(t,J=11.7Hz,1H),2.35–2.20(m,2H),2.00(d,J=13.3Hz, 1H),1.79–1.58(m,5H),1.22(s,3H),1.23–1.11(m,2H),1.00–0.92(m,1H)0.97(s,3H),0.89(d,J=6.6Hz,6H). 13 C NMR(101MHz,MeOD)δ168.77,167.97,132.57,126.77,89.91,81.31,72.96,72.20,71.16,70.15,69.01,62.47,57.66 ,49.28,48.10,43.63,40.31,37.33,36.51,35.99,35.72,32.58,26.51,26.29,23.17,22.92.HRMS(ESI+,m / z):[M+H] + Calculated value C 26 H 44 N2O6S, 513.2993; measured value 513.2992.

[0798] FSA1504066B·HCOOH was found to exist as a mixture of two equilibrium atropisomers by NMR analysis, and its coalescence temperature was close to ambient temperature. 1 H and 13 Peaks in the C spectrum attributable to the amino sugar portion are significantly broadened and / or poorly visible and can be resolved by VT-NMR at –60° C. For comparison, peaks corresponding to the spectrum obtained at 23° C. are shown. 1HNMR(400MHz,MeOD)δ8.31(br s,1H),5.77(br s,1H),5.53(pent,J=9.3Hz,1H),4.46–4.26(m,3H),4.15(br s,1H),4.00(dt,J=12.2,4.1Hz,1H),3.96(br s,1H),3.87–3.79(m,1H),3.76(br s,1H),3.64(dd,J=8.6,2.8Hz,1H),3.59(dd,J=11.4,7.7Hz,1H),2.88(t,J=11.7Hz,1H),2.30–2.15(m,1H),2.00(d,J= 13.5Hz,1H),1.84–1.59(m,4H),1.29–1.16(m,2H),1.16(s,3H),1.06(s,3H),1.03–0.90(m,1H),0.89(d,J=6.6Hz,6H).

[0799] 13 C NMR(101MHz,MeOD)δ167.42,81.18,71.03,69.19,62.00,49.54,48.11,43.45,3 8.82,37.41,36.16,36.02,26.29,25.67,23.15,22.93.HRMS(ESI+,m / z):[M+H] + Calculated value C 26 H 44 N2O6S, 513.2993; measured value 513.2991.

[0800]

[0801] (4S,5aS,8S,8aR)-4-isobutyl-N-((1R,8R,9R,10R,11S,12R)-10,11,12-trihydroxy-7,7-dimethyl-13-oxa-2-thiabicyclo[7.3.1]tridec-8-yl)octahydro-2H-oxepino[2,3-c]pyrrole-8-carboxamide formate: THF (1 mL) was added to a mixture of FSA1504066A·HCOOH and FSA1504066B·HCOOH (1.262 mg, 2.26 μmol, 1.00 equiv) and stirred with argon. While purging, 10 wt% Pd / C (1 mg, 0.94 μmol, 0.42 equiv) was added to the mixture. The vent needle was removed and replaced with a needle connected to a hydrogen balloon. Hydrogen was bubbled through the solution for 5 minutes, after which the needle was lifted above the solution and stirred for 5 hours. The Pd / C was removed using a syringe filter, and the filtrate was concentrated in vacuo. Purification by preparative HPLC (5–50% MeCN / H₂O containing 0.1% HCOOH over 30 minutes) afforded the product, FSA1504068·HCOOH (0.894 mg, 1.59 μmol, 71% yield), as a thin, clear film. 1 H NMR(400MHz,MeOD)δ8.42(br s,1H),5.39(d,J=6.2Hz,1H),4.51(d,J=8.3Hz,1H),4.36–4.18(m,2H),4.06(dd,J=10.2,6.2Hz,1H),4.04– 4.00(m,1H),3.98(d,J=11.6Hz,1H),3.87–3.75(m,2H),3.56(dd,J=10.1,7.2Hz,1H),3.51(dd,J=10.3,3.0 Hz,1H),2.94–2.62(m,3H),2.25(s,1H),1.97(s,2H),1.84–1.61(m,6H),1.54(s,1H),1.49–1.30(m,2H),1. 24–1.11(m,2H),0.99(s,3H),0.98–0.86(m,1H),0.93(s,3H),0.89(d,J=6.6Hz,6H).HRMS(ESI+,m / z):[M+H] + Calculated value C 26 H 46 N2O6S, 515.3149; measured value 515.3156.

[0802] Synthesis of FSA1503085

[0803]

[0804] (R)-1-((2R,3R,4S,5R,6R)-6-(allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)-3,3-dimethylpent-4-en-1-amine formate: A solution of (2R,3R,4S,5S,6R)-2-(allylthio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (0.100 g, 0.154 mmol, 1.00 equiv) in THF (1 mL) at –78°C was added (2,2-dimethylbut-3-en-1-yl)lithium 7 (0.15M in THF, 3.08mL, 0.462mmol, 3.00equiv). The reaction was warmed to 0°C and stirred for 2 hours. The solution was warmed to room temperature and 0.5M NaOMe / MeOH (2mL, 1.00mmol, 6.49equiv) was added. After stirring for 1 hour, 4M HCl / 1,4-dioxane (0.5mL, 2.0mmol, 12.99equiv) was added and the resulting white suspension was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (5-50% MeCN / H2O with 0.1% HCOOH over 30 minutes) to give the product (12mg, 0.033mmol, 22% yield over three steps) as a yellow oil. 1 H NMR(400MHz,MeOD)δ8.39(s,1H),5.93–5.77(m,2H),5.42(d,J=5.5Hz,1H),5.17(dq,J=16.9,1.5Hz,1H) ,5.13–5.05(m,3H),4.27(dd,J=4.5,1.5Hz,1H),4.20(dd,J=3.4,1.5Hz,1H),4.12(dd,J=10.1,5.5Hz,1 H),3.58(dd,J=10.2,3.3Hz,1H),3.36(dt,J=7.1,4.7Hz,1H),3.22(dd,J=13.9,8.0Hz,1H),3.16(dd,J= 14.0, 6.5Hz, 1H), 1.92 (dd, J=14.8, 7.0Hz, 1H), 1.72 (dd, J=14.8, 4.9Hz, 1H), 1.14 (s, 3H), 1.11 (s, 3H). 13 C NMR (101MHz, MeOD) δ168.35,147.67,135.50,117.66,113.40,86.97,71.51,70.36,69.27,68.92,52.73,42.21,37.25,33.49,28.18,26.41.

[0805] HRMS (ESI+, m / z): [M+H] + Calculated value C 15 H 27 NO4S, 318.1734; measured value 318.1735.

[0806]

[0807] tert-Butyl (4S,5aS,8S,8aR)-8-(((R)-1-((2R,3R,4S,5R,6R)-6-(allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)-3,3-dimethylpent-4-en-1-yl)carbamoyl)-4-isobutyloctahydro-7H-oxepino[2,3-c]pyrrole-7-carboxylate: To a solution of (R)-1-((2R,3R,4S,5R,6R)-6-(allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)-3,3-dimethylpent-4-en-1-yl)carbamoyl)-4-isobutyloctahydro-7H-oxepino[2,3-c]pyrrole-7-carboxylate was added to a 1% ethanol solution of 1% ethanol. To the mixture of (4S,5aS,8S,8aR)-7-(tert-butyloxycarbonyl)-4-isobutyloctahydro-2H-oxepino[2,3-c]pyrrole-8-carboxylic acid (13.4 mg, 0.040 mmol, 1.20 equiv), HATU (14.9 mg, 0.040 mmol, 1.20 equiv) and DIPEA (34.3 uL, 0.198 mmol, 6.00 equiv) was added (4S,5aS,8S,8aR)-7-(tert-butyloxycarbonyl)-4-isobutyloctahydro-2H-oxepino[2,3-c]pyrrole-8-carboxylic acid (13.4 mg, 0.040 mmol, 1.20 equiv), HATU (14.9 mg, 0.040 mmol, 1.20 equiv) and DIPEA (34.3 uL, 0.198 mmol, 6.00 equiv). The reaction mixture was stirred at room temperature overnight (16 hours), concentrated in vacuo, redissolved in ethyl acetate (10 mL) and washed with 1:1 brine:saturated aqueous NaHCO3 solution (10 mL). The organic extract was dried over sodium sulfate and concentrated to give the product (12 mg, 0.019 mmol, 57% yield) as a light yellow film, which was used for subsequent olefin metathesis without further purification. HRMS (ESI+, m / z): [M+H] + Calculated value C 33 H 56 N2O8S, 641.3830; measured value 641.3829.

[0808]

[0809] (4S,5aS,8S,8aR)-4-isobutyl-N-((1R,8R,9R,10R,11S,12R,E)-10,11,12-trihydroxy-6,6-dimethyl-13-oxa-2-thiabicyclo[7.3.1]tridec-4-en-8-yl)octahydro-2H-oxepin[2,3-c]pyrrole-8-carboxamide formate (FSA1503085·HCOOH): (4S,5aS,8S,8aR)- Tert-butyl 8-(((R)-1-((2R,3R,4S,5R,6R)-6-(allylthio)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)-2,2-dimethylpent-4-en-1-yl)carbamoyl)-4-isobutyloctahydro-7H-oxepino[2,3-c]pyrrole-7-carboxylate (12 mg, 0.019 mmol, 1.00 equiv) was dissolved in toluene (90 mL) and the solution was heated to reflux. Freshly sublimed benzoquinone (0.83 mg, 0.0076 mmol, 0.40 equiv) and Grubbs II catalyst (3.2 mg, 0.0038 mmol, 0.20 equiv) were dissolved in toluene (5 mL) and added to the reaction mixture. After stirring at reflux for 20 minutes, the reaction mixture was quenched with DMSO (0.134 mL, 1.9 mmol, 100 equivalents) and then cooled to room temperature. The reaction mixture was concentrated in vacuo, redissolved in ethyl acetate (2.5 mL) and brine (2.5 mL), and the layers were separated. The aqueous layer was washed with ethyl acetate (3 × 2.5 mL), and the combined organic extracts were dried over sodium sulfate and concentrated.

[0810] After concentration under reduced pressure, 1M HCl / MeOH (1 mL, 1.00 mmol, 52.6 equiv) was added, and the reaction mixture was stirred for 1 hour. After concentration under reduced pressure, purification by preparative HPLC (5–50% MeCN / H₂O containing 0.1% HCOOH over 30 minutes) afforded the product, FSA1503085·HCOOH (0.633 mg, 0.00119 mmol, 6% yield over three steps), as a thin, clear film. 1HNMR(400MHz,MeOD)δ8.50(br s,1H),5.65(br s,1H),5.58–5.33(m,2H),4.43(br s,1H),4.27(t,J=9.2Hz,1H),4.12(d,J=9.0Hz,1H),4.02–3.76(m,5H),3.70(s,1 H),3.54–3.42(m,1H),3.40–3.35(m,1H),3.22(dd,J=13.3,3.9Hz,1H),2.75(t,J =11.4Hz,1H),2.27(dt,J=19.2,10.8Hz,1H),1.99(d,J=13.4Hz,1H),1.84–1.60( m,6H),1.31–1.11(m,5H),0.97(s,3H),0.95–0.86(m,7H).HRMS(ESI+,m / z):[M+H] + Calculated value C 26 H 44 N2O6S, 513.2993; Found 513.2995. Prepare the following compound:

[0811] It can be prepared by the following scheme:

[0812]

[0813] Prepare the following compound:

[0814]

[0815] It can be prepared by the following scheme:

[0816]

[0817] Additional exemplary compounds were prepared as described below.

[0818]

[0819] (2R,3S,4S,5R,6R)-2-((Benzoyloxy)methyl)-6-((1-((tert-butyldimethylsilyl)oxy)-4-oxobutan-2-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (1:1 mixture of diastereomers) (A1): A 1000 mL three-necked round-bottom flask was charged with a solution of Et3N (0.626 mL, 4.49 mmol) in CH2Cl2 (200 mL) and equipped with two addition funnels. A solution of (2R,3S,4S,5R,6R)-2-((benzoyloxy)methyl)-6-mercaptotetrahydro-2H-pyran-3,4,5-triyl tribenzoate (Doyle, LM et. al.; Org. Lett. 2017, 19, 5802–5805) (2.5 g, 4.08 mmol) in CHCl (200 mL) and (Z)-4-((tert-butyldimethylsilyl)oxy)but-2-enal (Ding, P. et al.; Org. Lett. 2004, 6, 11, 1805–1808) (0.818 g, 4.08 mmol) in CHCl (200 mL) were simultaneously added dropwise to the reaction mixture over 45 minutes at 23° C. After the addition was complete, the reaction mixture was stirred at 23° C. for an additional 60 minutes. The reaction mixture was concentrated in vacuo and purified by flash chromatography (5-40% EtOAc / hexanes) to afford the product A1 as a white solid (2.35 g, 4.08 mmol, 71% yield). 1H NMR(400MHz, CDCl3)δ9.62(s,1H),8.15–8.06(m,2H),8.06–8.00(m,2H),8.00–7.92(m,2H) ,7.83–7.75(m,2H),7.63(t,J=7.4Hz,1H),7.59–7.47(m,4H),7.47–7.33(m,5H),7.29–7.21 (m,2H),6.19(d,J=5.4Hz,0.5H),6.14(d,J=4.6Hz,0.5H),6.05(dt,J=3.2,1.6Hz,1H),5.9 1–5.76(m,2H),5.04(t,J=6.2Hz,0.5H),4.98(t,J=6.4Hz,0.5H),4.67(dd,J=11.5,7.0Hz,0 .5H), 4.60 (dd, J=11.4, 6.7Hz, 1H), 4.46 (td, J=10.7, 5.9Hz, 1H), 3.82 (dd, J=10.2, 4.4Hz, 0.5H),3.75(dd,J=10.1,4.4Hz,0.5H),3.66–3.53(m,1H),3.53–3.38(m,1H),2.92–2.75(m, 1H), 2.69 (ddd, J = 17.6, 6.5, 1.6 Hz, 0.5H), 2.62 (ddd, J = 17.5, 7.3, 1.8 Hz, 0.5H), 0.85 (s, 4.5H), 0.80 (s, 4.5H), 0.01 (d, J = 7.1 Hz, 3H), -0.05 (d, J = 3.4 Hz, 3H). HRMS (ESI+, m / z): calculated value [C 44 H 48 O 11 SSi+NH4] + :830.3025; measured value:830.3019.

[0820]

[0821] (2R,3S,4S,5R,6R)-2-((Benzoyloxy)methyl)-6-((1-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (A2, 1:1 mixture of diastereomers): To a suspension of methyltriphenylphosphonium bromide (0.395 g, 1.107 mmol) in THF (18.45 mL) at 0°C was added BuLi (0.410 ml, 2.7 M in hexanes, 1.107 mmol) dropwise. The resulting suspension was stirred for 30 minutes until the reaction turned into a light yellow solution, indicating the formation of methylenetriphenylphosphine. This solution was added dropwise via cannula to a solution of (2R,3S,4S,5R,6R)-2-((benzoyloxy)methyl)-6-((1-((tert-butyldimethylsilyl)oxy)-4-oxobutan-2-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (0.75 g, 0.923 mmol) in THF (10 mL) and cooled to -78 °C. The reaction was maintained at this temperature for an additional five minutes before being diluted with diethyl ether (40 mL) and stirred at -78 °C for an additional five minutes. The reaction mixture was filtered through a pad of celite, concentrated in vacuo, and purified by flash chromatography (5-40% EtOAc / hexanes) to afford the product A2 (0.59 g, 0.74 mmol, 80% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ8.13–8.06(m,2H),8.05–8.00(m,2H),7.98(ddd,J=8.5,3.5,1.3Hz,2H),7.79(ddd,J=8.4,2.5,1.3Hz,2H),7.66–7.60(m ,1H),7.59–7.46(m,4H),7.46–7.35(m,5H),7.25(td,J=7.9,1.8Hz,2H ),6.11(t,J=2.6Hz,0.5H),6.08(t,J=2.6Hz,0.5H),6.06–6.02(m,1H), 5.90–5.87(m,1H),5.87–5.83(m,1H),5.83–5.72(m,0.5H),5.72–5.61 (m,0.5H),5.12–4.98(m,2H),4.99–4.87(m,1H),4.61(dd,J=7.0,1.7Hz ,0.5H),4.58(dd,J=7.0,1.7Hz,0.5H),4.43(td,J=11.4,5.8Hz,1H),3.74(dd,J=10.2,4.9Hz,0.5H),3.66(dd,J=10.3,5.2Hz,0.5H),3.59(app ddd, J = 12.9, 10.3, 6.8 Hz, 1H), 3.00 (ddd, J = 10.9, 6.4, 4.4 Hz, 0.5H), 2.97–2.91 (m, 0.5H), 2.58–2.43 (m, 1H), 2.37–2.20 (m, 1H), 0.87 (s, 4.5H), 0.81 (s, 4.5H), 0.03 (d, J = 2.2 Hz, 3H), -0.04 (d, J = 1.8 Hz, 3H). HRMS (ESI+, m / z): calculated value [C 45 H 50 O 10 SSi+NH4] + : 829.3232; measured value: 828.3222.

[0822]

[0823] (2R,3S,4S,5R,6R)-2-((benzoyloxy)methyl)-6-((2-(((tert-butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate A3 (1:1 mixture of diastereomers): To a solution of tert-butyl((2-(iodomethyl)but-3-en-1-yl)oxy)dimethylsilane (1.57 g, 1.75 Eq, 4.80 mmol) in THF (3.4 mL) at 23 °C was added (2R,3S,4S,5R,6R)-2-((benzoyloxy)methyl)-6-mercaptotetrahydro-2H-pyran-3,4,5-triyl tribenzoate (2.80 g, 60% methyl)thio)-4-((2-((tert-butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (2.80 g, 60% methyl)thio)-4-((2-(iodomethyl)but-3-en-1-yl)oxy)dimethylsilane (1.57 g, 1.75 Eq, 4.80 mmol) To the mixture was added 40% ethyl acetate (10% ethyl acetate, 10% ethanol, 0.2% ethanol, 0.5% ethanol, 0.6% ethanol, 0.7% ethanol, 0.9% ethanol, 1.0% ethanol, 0.8% ethanol, 1.2% ethanol, 0.9% ethanol, 1.3% ethanol, 0.9% ethanol, 1.4% ethanol, 0.8% ethanol, 1.2% ethanol, 0.9% ethanol, 1.3% ethanol, 0.8% ethanol, 1.4% ethanol, 0.9% ethanol, 1.2% ethanol, 0.8% ethanol, 1.3% ethanol, 0.9% ethanol, 1.4% ethanol, 0.8% ethanol, 1.2% ethanol, 0.8% ethanol, 1.3% ethanol, 0.8% ethanol, 1.4% ethanol, 0.9% ethanol, 1.2% ethanol, 0.8% ethanol, 1.3% ethanol, 0.8% ethanol, 1.4% ethanol, 1.4% ethanol, 0.8% ethanol, 1.2% ethanol, 0.8% ethanol, 1.3% ethanol, 0.8% ethanol, 1.4 ... 1 H NMR (400MHz, CDCl3) δ8.12–8.05(m,2H),8.02(dt,J=8.4,1.3Hz,2H),7.98(dt,J=8.3,1.2Hz,2H),7.82–7.76(m,2H),7.66–7.58(m,1H),7.58–7. 45(m,5H),7.45–7.35(m,6H),7.28–7.21(m,4H),6.06–5.98(m,2H),5.91 –5.82(m,2H),5.73–5.56(m,1H),5.09–4.93(m,3H),4.60(ddd,J=11.5,7 .2,2.3 Hz,1H),4.44(dd,J=11.4,5.6 Hz,1H),3.57(ddd,J=13.3,9.9,5.0 Hz,1H),3.45(ddd,J=13.2,9.9,5.9 Hz,1H),2.86(dd,J=12.7,6.2 Hz,0.5H),2.73(qd,J=13.0,6.8 Hz,1H),2.57(dd,J=12.6,7.8 Hz,0.5H),2.47–2.34(m,1H),0.84(d,J=4.8 Hz,9H),-0.05(s,6H).HRMS(ESI+,m / z):calcd.[C 45 H 50 O 10 SSi+NH4] + : 828.3238; measured value: 828.3238.

[0824]

[0825] (2R,3R,4S,5S,6R)-2-((1-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (3:2 mixture of diastereomers) (A4): (2R,3S,4S,5R,6R)-2-((benzoyloxy)methyl)-6-((1-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (940 mg, 1.159 mmol) was dissolved in MeOH (8.6 mL) and THF (2.9 mL). Tetrakis(1,1-dimethylethyl)di-μ-hydroxytin dichloride (112 mg, 0.197 mmol) was added, and the reaction was stirred at 66° C. for 2 days. The reaction was cooled to 23° C., concentrated in vacuo, and the crude residue was purified by flash chromatography (10–60% EtOAc / hexanes) to afford product A4 (0.55 g, 0.78 mmol, 67% yield) with recovered starting material (120 mg, 12%). 1 H NMR (400MHz, CDCl3) δ8.16–8.06(m,2H),8.02–7.94(m,2H),7.81(ddd,J=8.5,2.1,1.3H z,2H),7.68–7.59(m,1H),7.57–7.48(m,3H),7.46–7.35(m,3H),7.28–7.20(m,2H),6.0 6(d,J=5.5Hz,0.4H),6.02(d,J=5.6Hz,0.6H),5.93–5.67(m,4H),5.17–5.05(m,1H),5. 02–4.89(m,1H),4.76(q,J=6.9Hz,1H),3.83–3.71(m,2H),3.71–3.56(m,2H),2.92(app dddd, J = 12.7, 10.3, 7.5, 5.3 Hz, 1H), 2.61–2.50 (m, 1H), 2.27 (app dtd, J = 14.8, 7.4, 4.5 Hz, 1H), 0.89 (s, 6H), 0.82 (s, 3H), 0.06 (d, J = 4.0 Hz, 4H), -0.03 (d, J = 4.8 Hz, 2H). HRMS (ESI+, m / z): calculated value [C 38 H 46 O9SSi+Na] + : 729.2524; measured value: 729.2512.

[0826]

[0827] (2R,3R,4S,5S,6R)-2-((2-(((tert-butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (A5) (1:1 mixture of diastereomers): Product A5 was prepared in a manner analogous to product A4 from (2R,3S,4S,5R,6R)-2-((benzoyloxy)methyl)-6-((2-(((tert-butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate. 1 H NMR (400MHz, CDCl3) δ8.14–8.08(m,2H),8.03–7.95(m,2H),7.84–7.77(m, 2H),7.67–7.60(m,1H),7.55–7.47(m,3H),7.46–7.36(m,3H),7.25(t,J=7 .8Hz,2H),5.96(t,J=5.2Hz,1H),5.92–5.81(m,3H),5.69(dddd,J=17.1,1 5.1,10.5,8.1Hz,1H),5.15–4.98(m,2H),4.72(t,J=6.7Hz,1H),3.85–3.7 1 (m, 1H), 3.64 (ddd, J = 11.2, 10.0, 5.0 Hz, 2H), 3.56 (dd, J = 10.0, 6.2 Hz, 0.5H), 3.49 (dd, J = 9.9, 6.6 Hz, 0.5H), 2.85 (ddd, J = 15.0, 12.9, 5.9 Hz, 1H), 2.66 (dd, J = 13.0, 7.4 Hz, 0.5H), 2.58 (dd, J = 12.8, 7.8 Hz, 0.5H), 2.53–2.40 (m, 2H), 0.87 (d, J = 4.6 Hz, 9H), 0.07–0.06 (m, 6H). HRMS (ESI+, m / z): calculated value [C 38 H 46 O9SSi+H] + : 707.2705; measured value: 707.2699.

[0828]

[0829] (2R,3R,4S,5R,6S)-2-((1-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)-6-formyltetrahydro-2H-pyran-3,4,5-triyl tribenzoate (A6, 3:2 mixture of diastereomers): To a solution of (2R,3R,4S,5S,6R)-2-((1-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (550 mg, 1 Eq, 778 μmol) in CHCl (7.78 mL) was added Dess-Martin periodinane (363 mg, 1.1 Eq, 856 μmol). The reaction was stirred for 1 hour. The reaction mixture was diluted with CH2Cl2 (10 mL) and quenched by adding saturated aqueous NaHCO3 (10 mL) and saturated aqueous Na2S2O3 (10 mL). The resulting biphasic mixture was stirred vigorously for 30 minutes and then separated. The aqueous layer was extracted with CH2Cl2 (2×10 mL), the combined organics were dried over sodium sulfate and concentrated in vacuo to give the product. A6 (0.55 g, 0.78 mmol, 99% yield). 1H NMR(400MHz, CDCl3)δ9.65(s,1H),8.03–7.94(m,4H),7.83–7.75(m,2H),7.63–7.55(m ,1H),7.56–7.49(m,1H),7.49–7.42(m,3H),7.42–7.36(m,2H),7.30–7.22(m,2H),6.2 8(ddd,J=4.6,3.0,1.7Hz,1H),6.21(d,J=5.3Hz,0.4H),6.19(d,J=5.0Hz,0.6H),5.89 –5.66(m,3H),5.21(d,J=1.7Hz,0.4H),5.18(d,J=1.7Hz,0.6H),5.11(dd,J=17.1,1.7 Hz,0.4H),5.06(dd,J=10.1,1.8Hz,0.4H),5.00(dd,J=17.1,1.7Hz,0.6H),4.97–4.93 (m,0.6H),3.76(dd,J=10.3,5.3Hz,0.6H),3.70(dd,J=10.3,5.6Hz,0.4H),3.66–3.60 (m, 1H), 2.97 (tt, J = 7.1, 5.4 Hz, 1H), 2.62–2.47 (m, 1H), 2.35–2.20 (m, 1H), 0.89 (s, 6H), 0.83 (s, 3H), 0.05 (d, J = 1.5 Hz, 4H), -0.02 (d, J = 4.9 Hz, 2H). HRMS (ESI+, m / z): calculated value [C 38 H 44 O9SSi+Na] + : 705.2548; measured value: 705.2539.

[0830]

[0831] (2R,3R,4S,5R,6S)-2-((2-(((tert-Butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)-6-formyltetrahydro-2H-pyran-3,4,5-triyl tribenzoate (1:1 mixture of A7 diastereomers): Product A7 was prepared in a manner analogous to product A6 from (2R,3R,4S,5S,6R)-2-((2-(((tert-Butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate. 1H NMR (400MHz, CDCl3) δ9.64(s,1H),7.98(ddt,J=8.5,6.9,1.7Hz,3H),7.78(dd,J=8.3,1.4Hz,2H),7.62–7.56(m,1H),7.55–7.49(m,1H),7.48–7.41(m ,3H),7.38(t,J=7.8Hz,3H),7.30–7.20(m,2H),6.26(dd,J=2.9,1.5Hz,1H) ,6.09(t,J=4.3Hz,1H),5.83–5.76(m,2H),5.77–5.56(m,1H),5.13(t,J=1. 5Hz,1H),5.12–4.97(m,3H),3.62(ddd,J=9.9,6.2,4.8Hz,1H),3.56–3.45(m,1H),2.92(dd,J=12.8,5.5Hz,0.5H),2.86(dd,J=13.0,6.1Hz,0.5H),2.70(dd,J=13.0,7.6Hz,0.5H),2.61(dd,J=12.8,8.1Hz,0.5H),2.44(d,J=6.6Hz,1H),0.85(d,J=7.1Hz,9H),0.02–0.05(m,6H).HRMS(ESI+,m / z):calcd. 38 H 44 O9SSi+H] + : 705.2548; measured value: 705.2558.

[0832]

[0833] (2R,3R,4S,5S,6R)-2-((1-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (A8, characterized as a 9:1 mixture of diastereomers): To a solution of (R)-2-methylpropane-2-sulfinamide (186 mg, 2 Eq, 1.53 mmol) and CuSO (183 mg, 1.5 Eq, 1.15 mmol) in PhCH (0.6 mL) was added (R)-2-methylpropane-2-sulfenamide (186 mg, 2 Eq, 1.53 mmol) and CuSO (183 mg, 1.5 Eq, 1.15 mmol). The reaction was stirred at 40 ° C for 2 days. The reaction was cooled to 23 ° C and filtered through a celite pad. The celite pad was washed with CH Cl (2×25 mL) and the combined organics were concentrated in vacuo. The crude residue was purified by flash chromatography (10-60% EtOAc / hexanes) to give the product A8 (511 mg, 0.63 mmol, 82.5%). 1H NMR (400MHz, CDCl3) δ8.03 (d, J = 2.2Hz, 1H), 7.98 (app ddd,J=8.4,2.8,1.3Hz,4H),7.81–7.73(m,2H),7.62–7.56(m,1H),7.56–7.48(m,1H),7.48–7.41(m,3H),7.41–7.35(m,2H),7 .30–7.19(m,2H),6.29(dd,J=3.0,1.5Hz,1H),6.21(d,J=5.2Hz,0.1H),6.18(d,J=5.1Hz,0.9H),5.89–5.67(m,3H),5.58(t,J =1.9Hz,0.1H),5.57(t,J=1.9Hz,0.9H),5.11(dd,J=17.1,1.7Hz,0.1H),5.08–5.04(m,0.1H),5.00(dd,J=17.1,1.8Hz,0.9H) ,4.98–4.92(m,0.9H),3.76(dd,J=10.3,5.2Hz,0.9H),3.70(dd,J=10.3,5.5Hz,0.1H),3.64(dd,J=10.2,6.9Hz,1H),2.96(app tt, J = 7.1, 5.5 Hz, 1H), 2.62–2.48 (m, 1H), 2.39–2.25 (m, 1H), 0.99 (s, 0.9H) 0.98 (s, 8.1H), 0.89 (s, 8.1H), 0.83 (s, 0.9H), 0.05 (s, 5.4H), -0.02 (d, J = 5.0 Hz, 0.6H). HRMS (ESI+, m / z): calculated value [C 32 H 53 NO9S2Si+H] + :808.3004; measured value:808.2986.

[0834]

[0835] (2R,3R,4S,5S,6R)-2-((2-(((tert-Butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (1:1 mixture of A9 diastereomers): Product A9 was prepared in a manner analogous to product A8 from (2R,3R,4S,5R,6S)-2-((2-(((tert-Butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)-6-formyltetrahydro-2H-pyran-3,4,5-triyl tribenzoate.1 H NMR (400MHz, CDCl3) δ8.04 (dd, J=2.2, 1.2Hz, 1H), 8.00–7.94 (m, 4H), 7.82–7 .74(m,2H),7.62–7.56(m,1H),7.56–7.50(m,1H),7.49–7.42(m,3H),7.39(t, J=7.8Hz,2H),7.28–7.21(m,2H),6.30(dt,J=3.6,1.9Hz,1H),6.14–6.05(m,1 H),5.89–5.78(m,2H),5.77–5.59(m,1H),5.52(q,J=1.9Hz,1H),5.13–4.98(m ,2H),3.64(td,J=9.7,4.9Hz,1H),3.53(ddd,J=14.7,10.0,6.2Hz,1H),2.91(dd,J=12.8,5.7Hz,0.5H),2.84(dd,J=13.1,6.3Hz,0.5H),2.70(dd,J=13.1,7.3Hz,0.5H),2.61(dd,J=12.8,8.0Hz,0.5H),2.45(dh,J=13.0,6.2Hz,1H),0.98(s,9H),0.87(d,J=7.6Hz,9H),0.10–0.35(m,6H).HRMS(ESI+,m / z):calcd. 42 H 53 NO9S2Si+H] + :808.3004; measured value:808.3069.

[0836]

[0837] (2R,3R,4S,5S,6R)-2-((1-((tert-Butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)-6-((R)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (A10, 3:2 mixture of diastereomers): Add (2R,3R,4S,5S,6R)-2-((1-((tert-Butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)-6-((R)-1-(((R)-tert-Butylsulfinyl)amino)but-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate at -78°C. To a solution of 1-((1-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (511 mg, 1 Eq, 632 μmol) in THF (6.3 mL) was added allylzinc lithium chloride (256 mg, 6.62 mL, 0.21 M in THF, 2.2 Eq, 1.39 mmol) dropwise over 15 minutes. After the addition of allylzinc was complete, the reaction was quenched with saturated aqueous NH4Cl (10 mL). The reaction was heated to 23°C and diluted with EtOAc (30 mL) and H2O (10 mL). The layers of the resulting biphasic mixture were separated and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography (0-70% EtOAc / hexanes) to afford the product A10 (472 mg, 555 μmol, 87.8%) 1H NMR (400MHz, CDCl3) δ8.08 (dd, J=8.2, 1.4Hz, 2H), 8.01–7.92 (m, 2H), 7.80–7.68 (m,2H),7.68–7.58(m,1H),7.58–7.46(m,3H),7.46–7.33(m,3H),7.24–7.18(m, 2H),6.13–6.08(m,1.4H),6.07(d,J=5.7Hz,0.6H),5.95–5.62(m,4H),5.27–5.0 7(m,2.8H),4.97(dd,J=17.0,1.8Hz,0.6H),4.92–4.86(m,0.6H),4.75(d,J=7.3H z, 0.4H), 4.69 (d, J = 7.6Hz, 0.6H), 3.83 (dd, J = 10.1, 4.4Hz, 0.6H), 3.78 (t, J = 4. 8Hz,1H),3.67(dd,J=10.3,5.2Hz,0.4H),3.62–3.54(m,2H),3.00–2.88(m,1H),2 .67–2.48(m,3H),2.35–2.21(m,1H),1.11(s,6H),1.09(s,3H),0.89(s,6H),0.8 2(s,3H),0.07(d,J=4.1Hz,4H),-0.03(d,J=10.2Hz,2H).HRMS(ESI+,m / z): Calculated value [C 45 H 59 NO9S2Si+H] + : 850.3473; measured value: 850.3465.

[0838]

[0839] (2R,3R,4S,5S,6R)-2-((1-((tert-Butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)-6-((1R)-1-(((R)-tert-butylsulfinyl)amino)-2-methylbut-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (6:3:4:2 mixture of A11 diastereomers): (2R,3R,4S,5S,6R)-2-((1 To a solution of -((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (650 mg, 1 Eq, 804 μmol) in THF (8.04 mL) was added crotylzinc lithium chloride (191 mg, 3.22 mL, 0.30 mole, 1.2 Eq, 965 μmol) dropwise over 15 minutes. After the addition of allylzinc was complete, the reaction was quenched with saturated aqueous NH4Cl solution (10 mL). The reaction was warmed to 23 ° C and diluted with EtOAc (30 mL) and H2O (10 mL). The layers of the resulting biphasic mixture were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude residue containing the product A11 (650 mg, 0.75 mmol, 94%) was used directly in the next step without additional purification. 1H NMR (400MHz, CDCl3) δ8.15–8.05(m,2H),8.01–7.91(m,2H),7.79–7.71(m,2 H),7.65–7.58(m,1H),7.54–7.46(m,3H),7.46–7.33(m,3H),7.25–7.18(m, 2H),6.28–6.18(m,1H),6.14–5.93(m,1.6H),5.89–5.59(m,3.4H),5.25–5. 04(m,2.6H),5.02–4.81(m,1.4H),4.75(d,J=6.4Hz,0.2H),4.69–4.61(m,0. 4H),4.58(d,J=7.3Hz,0.4H),3.83(dd,J=10.0,4.4Hz,0.6H),3.73–3.43(m ,3.4H),3.04–2.84(m,1.6H),2.70–2.47(m,1.4H),2.36–2.22(m,1H),1.13 –1.11(m,6H),1.08(s,1.8H),1.07(s,1.2H),0.90(s,2H),0.89(s,4H),0.8 1 (s, 3H), 0.10–0.03 (m, 4H), -0.04 (d, J = 2.0Hz, 1H), -0.07 (d, J = 1.9Hz, 1H).

[0840]

[0841] (2R,3R,4S,5S,6R)-2-((2-(((tert-Butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)-6-((R)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (1:1 mixture of A12 diastereomers): product A12 was prepared in a manner analogous to product A11 from (2R,3R,4S,5S,6R)-2-((2-(((tert-butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate and allylzinc lithium chloride. 1H NMR(400MHz, CDCl3)δ8.11–8.06(m,2H),7.97(dt,J=8.4,1.2Hz,2H),7.77–7.72 (m,2H),7.65–7.60(m,1H),7.55–7.46(m,3H),7.40(dt,J=13.7,7.6Hz,3H),7.2 5–7.17(m,2H),6.09(d,J=3.2Hz,1H),6.00(t,J=5.2Hz,1H),5.94–5.78(m,2H), 5.77–5.58(m,2H),5.26–5.12(m,2H),5.12–4.98(m,2H),4.72(dd,J=7.6,5.1Hz ,1H),3.80(d,J=4.3Hz,1H),3.67–3.56(m,2H),3.52(ddd,J=9.9,7.6,6.1Hz,1H),2.86(dd,J=12.8,5.7Hz,1H),2.81(dd,J=13.1,6.5Hz,1H),2.68(dd,J=13.1,6.8Hz,1H),2.64–2.57(m,3H),2.43(dh,J=12.8,6.1Hz,1H),1.14(d,J=2.9Hz,9H),0.87(s,5H),0.85(s,4H),0.01(s,3H),-0.03(s,3H).HRMS(ESI+,m / z):calcd. 45 H 59 NO9S2Si+H] + :850.3473 Measured value:850.3496.

[0842]

[0843] (1R,8R,9R,10S,11S,12R,Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-8-(((R)-tert-butylsulfinyl)amino)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (7:3 mixture of A13 diastereomers): (2R,3R,4S,5S A degassed solution of 2-((1-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)-6-((R)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (450 mg, 1 Eq, 529 μmol) in PhCH3 (529 mL) was heated to reflux. A solution of Grubbs II (89.9 mg, 0.2 Eq, 106 μmol) and benzoquinone (22.9 mg, 0.4 Eq, 212 μmol) in PhCH3 (1 mL) was added and the reaction mixture was refluxed for 15 minutes. The reaction was quenched by the addition of DMSO (0.75 mL, 20 Eq, 10.6 mmol) and cooled to 0°C. The reaction was concentrated in vacuo and dissolved in EtOAc (100 mL). The EtOAc was washed with saturated aqueous NaCl solution (1 x 50 mL). The combined aqueous layer was extracted with EtOAc (50 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography (0–70% EtOAc / hexane) to give product A13 (370 mg, 0.45 mmol, 85.0%) as an off-white solid. 1H NMR(400MHz, CDCl3)δ8.15–8.06(m,2H),8.01–7.93(m,2H),7.80–7.73(m,2H) ,7.67–7.58(m,1H),7.54–7.46(m,3H),7.43–7.34(m,3H),7.21(t,J=7.5Hz,2 H),6.47(d,J=4.7Hz,0.7H),6.07(d,J=5.8Hz,0.3H),5.86–5.60(m,5H),4.66 (d,J=9.8Hz,0.7H),4.63(d,J=10.0Hz,0.3H),4.22(t,J=4.1Hz,1H),3.87(app d, J = 10.2, 5.5 Hz, 1.4 H), 3.79–3.65 (m, 0.6 H), 3.61–3.51 (m, 0.7 H), 3.45 (q, J = 6.7 Hz, 0.3 H), 3.05–2.74 (m, 3 H), 2.62 (app d, J = 14.4 Hz, 1 H), 2.39 (t, J = 13.7 Hz, 1 H), 1.31 (br. s, 9 H), 0.84 (s, 6.3 H), 0.83 (s, 2.7 H), 0.03 (s, 1 H), 0.02 (s, 2 H), 0.02 (s, 1 H), -0.01 (s, 2 H). HRMS (ESI+, m / z): calculated value [C 43 H 55 NO9S2Si+H] + :823.3160; measured value:822.3146

[0844]

[0845] (1R,3S,7R,8R,9R,10S,11S,12R,Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-8-(((R)-tert-butylsulfinyl)amino)-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (A14, inseparable from other diastereomers, minor components not reported): (2R,3R A degassed solution of 2-((1-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)thio)-6-((1R)-1-(((R)-tert-butylsulfinyl)amino)-2-methylbut-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (650 mg, 1 Eq, 752 μmol) in PhCH3 (375 mL) was heated to reflux. A solution of Grubbs II (128 mg, 0.2 Eq, 150 μmol) and benzoquinone (32.5 mg, 0.4 Eq, 301 μmol) in PhCH3 (1 mL) was added and the reaction mixture was refluxed for 15 minutes. The reaction was quenched by the addition of DMSO (1.0 mL, 20 Eq, 15 mmol) and cooled to 0°C. The reaction was concentrated in vacuo and dissolved in EtOAc (100 mL). The EtOAc was washed with saturated aqueous NaCl (1 x 50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography (0-70% EtOAc / hexanes) to give the product A14 (370 mg, 0.45 mmol, 85.0%) as an off-white solid. 1H NMR (400MHz, CDCl3) δ8.15–8.01(m,2H),8.00–7.88(m,2H),7.83–7.72(m,2H),7.66–7.55(m,1H),7.55–7.45(m,3H),7.45– 7.31(m,3H),7.25–7.16(m,2H),6.46(t,J=2.8Hz,1H),6.20(d,J=2.0Hz,1H),6.13–5.51(m,4H),4.75(d,J=10.6Hz,1H),3.9 3–3.66 (m, 2H), 3.48 (ddd, J = 10.5, 7.2, 3.2 Hz, 1H), 3.31 (d, J = 7.3 Hz, 1H), 3.14 (ddd, J = 10.4, 6.9, 3.3 Hz, 1H), 2.96–2.67 (m, 2H), 2.50–2.33 (m, 1H), 1.27 (s, 9H), 1.11 (d, J = 6.9 Hz, 3H), 0.85 (s, 9H), 0.02 (s, 3H), -0.01 (s, 3H). HRMS (ESI+, m / z): calculated value [C 44 H 58 NO9S2Si+H] + :836.3317 Measured value:836.3365.

[0846]

[0847] (1R,4S,8R,9R,10S,11S,12R,Z)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-8-(((R)-tert-Butylsulfinyl)amino)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate and (1R,8R,9R,10S,11S,12R,E)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-8-(((R)-tert-Butylsulfinyl)amino)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate Thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (A15 is an inseparable mixture of isomers): Product A15 is prepared in a manner similar to product A12 from the following: (2R,3R,4S,5S,6R)-2-((2-(((tert-butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)-6-((R)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate. 1H NMR(400MHz,CDCl3)1H NMR (400MHz, CDCl3) δ8.16–8.02(m,2H),8.02–7.89(m,2H),7.85–7.70(m,2H),7.6 8–7.58(m,1H),7.55–7.45(m,3H),7.45–7.34(m,3H),7.24–7.13(m,2H),6.11–5.93 (m,1H),5.89–5.06(m,5H),4.83–4.43(m,1H),4.28–3.10(m,5H),2.95–2.09(m,4H),1.36–1.26(m,9H),1.00–0.79(m,9H),0.17–-0.06(m,6H).HRMS(ESI+,m / z):calcd.[C 43 H 56 NO9S2Si+H] + :822.3160 ​​Measured value:822.3169.

[0848]

[0849] (1R,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-3-(hydroxymethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (A16, 7:3 mixture of diastereomers): (1R,8R,9R,10S,11S,12R,Z)-3-(((tert-butyldimethylamino)amino)-3-(hydroxymethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate was added at 23°C. To a solution of 8-(((R)-tert-butylsulfinyl)amino)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (106 mg, 1 Eq, 129 μmol) in MeOH (0.64 mL) and CHCl (0.65 mL) was added camphorsulfonic acid (15.0 mg, 0.5 Eq, 64.5 μmol). The reaction was stirred at 23° C. for 30 minutes. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with CHCl (2×10 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography (0-70% EtOAc / hexanes) to give the product A16 (72 mg, 0.10 mmol, 79%) as a white solid. 1H NMR (400MHz, CD3OD) δ8.18–8.06(m,2H),8.00–7.89(m,2H),7.83–7.73(m,2H),7.69–7.59(m,1H),7.56–7.46(m,3H),7.46–7.34(m,3H), 7.26–7.16(m,2H),6.44(d,J=6.0Hz,0.7H),6.09(d,J=5.8Hz,0.3H),5.87–5.56(m,5H),4.63(t,J=9.5Hz,0.3H),4.61(t,J=9.7Hz,0.7H) ,4.25(t,J=4.9Hz,0.3H),4.23(d,J=4.4Hz,0.7H),3.84–3.74(m,2H),3.60–3.52(m,1H),3.50(q,J=5.8Hz,0.3H),3.19–2.98(m,1H),2.93–2.71(m,1.7H),2.71–2.52(m,1H),2.34(d,J=14.3Hz,0.3H),2.18(d,J=13.9Hz,0.7H),1.31(d,J=1.6Hz,9H).HRMS(ESI+,m / z):calcd.[C 37 H 42 NO9S2+H] + :708.2295 Measured value:708.318.

[0850]

[0851] (1R,3S,7R,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-3-(hydroxymethyl)-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate A17: (1R,7R,8R,9R,10S,11S,12R,Z)-3-(((tert-butyldimethylsilane)amino)-3-(hydroxymethyl)-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate A17 was added to (1R,7R,8R,9R,10S,11S,12R,Z)-3-(((tert-butyldimethylsilane)amino)-3-(hydroxymethyl)-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate A17 at 23°C. To a solution of (4-(((R)-tert-butyl)oxy)methyl)-8-(((R)-tert-butylsulfinyl)amino)-7-methyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl)benzoate (350 mg, 1 Eq, 0.41 mmol) in MeOH (2.0 mL) and CHCl (2.0 mL) was added camphorsulfonic acid (48.6.0 mg, 0.5 Eq, 0.2 mmol). The reaction was stirred at 23 °C for 30 minutes. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with CHCl (2 x 10 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography (0–70% EtOAc / hexanes) to give the product A17 (117 mg, 0.16 mmol, 39%) as a white solid. 1 H NMR (400MHz, CDCl3) δ8.15–8.01(m,2H),8.00–7.88(m,2H),7.84–7.76(m,2H),7.67–7.57(m,1H),7.56–7.47(m,3H),7.47–7.41( m,1H),7.41–7.34(m,2H),7.29–7.22(m,2H),6.47(d,J=6.2Hz,1H),6.23(d,J=3.1Hz,1H),5.77–5.62(m,2H),5.62–5.45(m,2H), 4.71 (d, J = 10.2 Hz, 1H), 3.76 (d, J = 7.3 Hz, 2H), 3.48 (ddd, J = 10.6, 7.3, 3.3 Hz, 1H), 3.32 (d, J = 7.3 Hz, 1H), 3.09 (ddt, J = 11.7, 8.1, 4.1 Hz, 1H), 3.06–2.95 (m, 1H), 2.94–2.77 (m, 1H), 2.24–2.16 (m, 1H), 1.28 (s, 9H), 1.10 (d, J = 6.9 Hz, 3H). HRMS (ESI+, m / z): calculated value [C 38 H 43 NO9S2+H] + :722.2452 Measured value:722.2465.

[0852]

[0853] (1R,8R,9R,10S,11S,12R,E)-8-(((R)-tert-butylsulfinyl)amino)-4-(hydroxymethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (A18 single diastereomer, unassigned): Product A18 was prepared in a manner analogous to product A17 from (1R,8R,9R,10S,11S,12R,E)-4-(((tert-butyldimethylsilyl)oxy)methyl)-8-(((R)-tert-butylsulfinyl)amino)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate. 1 H NMR (400MHz, CDCl3) δ8.13–8.06(m,2H),7.98–7.93(m,2H),7.78–7.72(m,2H),7.65–7.59(m,1H),7.54–7.46(m,3H),7.45–7.35(m,3H),7. 22(t,J=7.8Hz,2H),6.00(d,J=3.4Hz,1H),5.90(td,J=14.9,3.3Hz,2H),5.83(d,J=5.6Hz,1H),5.74(dd,J=10.8,5.6Hz,1H),5.65(dd,J=10 .8,3.4 Hz,1H),5.18(dd,J=14.9,10.4 Hz,1H),4.78(d,J=10.4 Hz,1H),4.17(d,J=5.1 Hz,1H),3.62(dt,J=11.5,6.1 Hz,1H),3.59–3.51(m,2H),3.22(dd,J=14.6,3.0 Hz,1H),2.93–2.81(m,1H),2.61–2.42(m,2H),2.32(dd,J=14.6,11.7 Hz,1H),1.31(s,9H).HRMS(ESI+,m / z):calcd. 37 H 42 NO9S2+H] + :708.2995 Measured value:708.2302.

[0854]

[0855] (1R,8R,9R,10S,11S,12R,E)-8-(((R)-tert-butylsulfinyl)amino)-4-(hydroxymethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (A19 single diastereomer, unassigned, 4:1 mixture of rotamers): Product A19 was prepared in a manner analogous to product A17 from (1R,8R,9R,10S,11S,12R,E)-4-(((tert-butyldimethylsilyl)oxy)methyl)-8-(((R)-tert-butylsulfinyl)amino)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate. 1 H NMR (400MHz, CDCl3) δ8.12–8.06(m,2H),7.99–7.91(m,2H),7.80–7.69(m,2H),7.65–7. 59(m,1H),7.54–7.45(m,3H),7.44–7.35(m,3H),7.25–7.13(m,2H),6.02–5.40(m,5H),4 .73–4.49 (m, 1H), 4.31–4.12 (m, 1H), 4.05–3.88 (m, 0.8H), 3.84 (dd, J=10.4, 8.3 Hz, 0.8H), 3.64–3.08 (m, 2.6H), 3.02–2.43 (m, 3.8H), 1.33–1.28 (m, 9H). HRMS (ESI+, m / z): calculated [C 37 H 42 NO9S2+H] + :708.2995 Measured value:708.2302

[0856]

[0857] (1R,4S,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-4-(hydroxymethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (A20): Product A20 was prepared in a manner analogous to product A17 from (1R,4S,8R,9R,10S,11S,12R,Z)-4-(((tert-butyldimethylsilyl)oxy)methyl)-8-(((R)-tert-butylsulfinyl)amino)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate. 1H NMR (400MHz, CDCl3) δ8.15–8.09(m,2H),7.99–7.95(m,2H),7.79–7.74(m,2 H),7.66–7.60(m,1H),7.56–7.47(m,3H),7.44–7.36(m,3H),7.24–7.17(m, 2H),6.05(d,J=5.7Hz,1H),5.90(td,J=11.4,4.9Hz,1H),5.83(d,J=3.2Hz, 1H),5.80(dd,J=10.8,5.6Hz,1H),5.72(dd,J=10.8,3.5Hz,2H),5.45(t,J=1 1.0Hz,1H),4.64(d,J=9.9Hz,1H),4.28(d,J=4.0Hz,1H),3.62–3.55(m,1H) ,3.53(dd,J=10.5,5.3Hz,1H),3.41(dd,J=10.6,7.1Hz,1H),3.33(dt,J=11 .4,5.4Hz,1H),3.12(dd,J=14.1,4.0Hz,1H),2.88–2.75(m,1H),2.73–2.62 (m,1H),2.44(dd,J=14.2,12.3Hz,1H),1.31(s,9H).HRMS(ESI+,m / z): Calculated value [C 37 H 42 NO9S2+H] + :708.2995 Measured value:708.2308.

[0858]

[0859]

[0266] (1R,8R,9R,10R,11S,12R,Z)-8-Amino-3-(hydroxymethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triol formate (A21, 7:3 mixture of diastereomers): NaOMe (0.5 M, 0.65 mL, 0.35 mmol, 10 equiv) in MeOH was added to (1R,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-3-(hydroxymethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (29 mg, 0.035 mmol, 1.00 equiv) and the resulting solution was stirred for 1 h. Then HCl / dioxane (4.0 M, 0.25 mL, 1.0 mmol, 28.8 equiv) was added to the mixture and the resulting white suspension was stirred for 1 hour. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (1-30% MeCN / H2O, containing 0.1% HCOOH over 30 minutes) to give the product A21 (9.5 mg, 0.033 mmol, 93% over 2 steps) as a white solid. 1 H NMR(400MHz,CD3OD)δ8.09(s,1H),5.92–5.73(m,1H),5.79(d,J=6.1Hz,1H),5.64–5.49(m,1H), 5.53(d,J=5.8Hz,1H),4.47(dd,J=10.5,1.2Hz,0.7H),4.43(dd,J=10.5,1.1Hz,0.3H),4.05(app dt,J=10.1,6.1Hz,2H),3.90(dd,J=11.6,6.7Hz,0.7H),3.85(dd,J=3.4,1.3Hz,1H ),3.78(dd,J=11.5,6.3Hz,0.7H),3.76–3.69(m,0.6H),3.69–3.62(m,1H),3.52(dd , J=10.2,3.4 Hz,0.7H),3.47(dd,J=10.2,3.4 Hz,0.3H),3.08–2.77(m,3H),2.39(d,J=14.1 Hz,0.3H),2.31–2.24(m,0.7H),2.23–2.08(m,1H).HRMS(ESI+,m / z):calcd.[C 12 H 21 NO5S+H] + : 292.1213 Measured value: 292.1210.

[0860]

[0861] (2R,3S,4S,5R,6R)-2-((Benzoyloxy)methyl)-6-((2-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (A22; 1:1 mixture of diastereomers): Product A22 was prepared in a manner analogous to product A3 from (2R,3S,4S,5R,6R)-2-((Benzoyloxy)methyl)-6-mercaptotetrahydro-2H-pyran-3,4,5-triyl tribenzoate and ((1-bromobut-3-en-2-yl)oxy)(tert-butyl)dimethylsilane. 1 H NMR (400MHz, CDCl3) δ8.12–8.05(m,2H),8.05–7.95(m,4H),7.83–7.75(m,2H),7.68–7.59(m,1H),7.58–7.46(m ,4H),7.46–7.33(m,5H),7.28–7.22(m,2H),6.06–5.99(m,1H),5.95–5.85(m,2H),5.79–5.63(m,1H),5.13(app tt,J=17.4,1.4Hz,1H),5.08–4.95(m,2H),4.60(app ddd,J=11.5,7.4,5.3Hz,1H),4.45(app ddd, J = 11.5, 10.2, 5.4 Hz, 1H), 4.29–4.16 (m, 1H), 2.78 (app ddd, J = 13.4, 10.7, 6.1 Hz, 1H), 2.64 (dt, J = 12.9, 6.6 Hz, 1H), 0.83 (d, J = 2.8 Hz, 9H), 0.00 (app d, J = 4.6 Hz, 3H), -0.03 (s, 3H). HRMS (ESI+, m / z): calculated value [C 44 H 48 O 10 SSi+NH4] + :814.3070; measured value:814.3094

[0862]

[0863] (2R,3R,4S,5S,6R)-2-((2-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (A23, 1:1 mixture of diastereomers): Product A23 was prepared in a manner analogous to product A4 from (2R,3S,4S,5R,6R)-2-((benzoyloxy)methyl)-6-((2-(((tert-butyldimethylsilyl)oxy)methyl)but-3-en-1-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate. 1 H NMR(400MHz, CDCl3)8.14–8.09(m,2H),8.05–7.96(m,3H),7.84–7.75(m,2H),7.65–7.57(m,1H),7.26 –7.21(m,2H)7.44–7.35(m,3H),7.24(d,J=7.8Hz,2H),6.06–5.64(m,5H),5.26–4.99(m,2H),4.72(app td,J=6.8,3.9Hz,1H),4.25(app dq,J=7.9,6.1Hz,1H),3.77(app ddd, J = 11.2, 6.6, 4.3 Hz, 1H), 3.71–3.55 (m, 1H), 2.84–2.58 (m, 2H), 0.85 (app d, J = 5.4 Hz, 9H), 0.06 (app d, J = 4.9 Hz, 3H), -0.00 (s, 3H). HRMS (ESI+, m / z): calculated value [C 37 H 44 O9SSi+H] + : 710.2803; measured value: 710.2811.

[0864]

[0865] (2R,3R,4S,5R,6S)-2-((2-((tert-Butyldimethylsilyl)oxy)but-3-en-1-yl)thio)-6-formyltetrahydro-2H-pyran-3,4,5-triyl tribenzoate (A25, 1:1 mixture of diastereomers): Product A25 was prepared in a manner analogous to product A6 from (2R,3R,4S,5S,6R)-2-((2-((tert-Butyldimethylsilyl)oxy)but-3-en-1-yl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate. 1HNMR(400MHz, CDCl3)δ9.66(d,J=2.9Hz,1H),8.02–7.94(m,4H),7.81–7.75( m,2H),7.66–7.57(m,2H),7.55–7.35(m,5H),7.30–7.22(m,2H),6.28(dd,J= 3.2,1.7Hz,1H),6.11(dd,J=10.0,5.2Hz,1H),5.92–5.72(m,3H),5.24–4.97 (m,3H),4.30–4.19(m,1H),2.83(appddd,J=14.4,13.2,6.2Hz,1H),2.69(app ddd, J = 16.3, 13.1, 6.1 Hz, 1H), 0.85 (d, J = 3.6 Hz, 9H), 0.03 (app d, J = 6.5 Hz, 3H), -0.00 (app d, J = 1.8 Hz, 3H). HRMS (ESI+, m / z): calculated value [C 37 H 42 O9SSi+H] + : 691.2391; measured value: 691.2402

[0866]

[0867] (2R,3R,4S,5S,6R)-2-((2-((tert-Butyldimethylsilyl)oxy)but-3-en-1-yl)thio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (1:1 mixture of A26 diastereomers): Product A26 was prepared in a manner analogous to product A8 from (2R,3R,4S,5S,6R)-2-((2-((tert-Butyldimethylsilyl)oxy)but-3-en-1-yl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate. 1H NMR(400MHz, CDCl3)δ8.04(dd,J=3.4,2.3Hz,1H),8.01–7.90(m,4H),7.82–7.70(m,2H),7.64–7.55(m,1H),7.55–7.47(m,1H),7.45(t,J=7.7Hz, 3H),7.38(t,J=7.7Hz,2H),7.25(t,J=7.8Hz,2H),6.30(td,J=3.7,1.5H z,1H),6.11(dd,J=11.4,5.3Hz,1H),5.92–5.75(m,3H),5.51(dt,J=5.3, 1H), 5.18 (ddt, J = 17.1, 10.1, 1.4 Hz, 1H), 5.08 (ddt, J = 17.0, 10.4, 1.3 Hz, 1H), 4.25 (p, J = 6.4 Hz, 1H), 2.81 (ddd, J = 14.9, 13.1, 6.3 Hz, 1H), 2.67 (ddd, J = 14.2, 13.1, 6.1 Hz, 1H), 0.98 (d, J = 0.9 Hz, 9H), 0.85 (d, J = 6.3 Hz, 9H), 0.06 (d, J = 3.3 Hz, 3H), -0.01 (s, 3H). HRMS (ESI+, m / z): calculated value [C 41 H 51 NO9S2Si+H] + : 794.2842; measured value: 794.2852.

[0868]

[0869] (2R,3R,4S,5S,6R)-2-((2-((tert-Butyldimethylsilyl)oxy)but-3-en-1-yl)thio)-6-((R)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate (1:1 mixture of A27 diastereomers): Product A27 was prepared in a manner analogous to product A10 from (2R,3R,4S,5S,6R)-2-((2-((tert-Butyldimethylsilyl)oxy)but-3-en-1-yl)thio)-6-((E)-(((R)-tert-butylsulfinyl)imino)methyl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate and allylzinc lithium chloride. 1H NMR (400MHz, CDCl3) δ8.12–8.04(m,2H),8.03–7.90(m,2H),7.79–7.70(m,2H),7.66–7.58(m,1H ),7.57–7.47(m,3H),7.46–7.33(m,3H),7.22(t,J=7.7Hz,2H),6.10(d,J=3.2Hz,1H),6.02(app dd,J=15.7,5.7Hz,1H),5.94–5.69(m,4H),5.26–5.14(m,2H),5.14–5.00(m,2H),4.73(d,J=7.4Hz,1H),4.24(dq,J=12.1,6.2Hz,1H),3 .82(d,J=4.1Hz,1H),3.66–3.54(m,1H),2.84–2.64(m,2H),2.64–2.54(m,2H),1.13(d,J=7.0Hz,9H),0.84(d,J=4.8Hz,10H),0.03(app d, J = 10.1 Hz, 3H), -0.02 (d, J = 1.4 Hz, 3H). HRMS (ESI+, m / z): calculated value [C 44 H 57 NO9S2Si+H] + :836.3317 Measured value:836.3362.

[0870]

[0871] (1R,8R,9R,10S,11S,12R,E)-4-((tert-Butyldimethylsilyl)oxy)-8-(((R)-tert-butylsulfinyl)amino)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (A28, reported single isomer): Product A28 was prepared in a manner analogous to product A12 from (2R,3R,4S,5S,6R)-2-((2-((tert-Butyldimethylsilyl)oxy)but-3-en-1-yl)thio)-6-((R)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate. 1H NMR (400MHz, CDCl3) δ8.13–8.07(m,2H),8.00–7.96(m,2H),7.81–7.74(m,2H),7.64–7.57(m,1H),7.52–7.45(m,3H), 7.45–7.33(m,3H),7.23–7.15(m,2H),6.01–5.85(m,2H),5.83–5.64(m,3H),5.42–5.27(m,1H),4.66(d,J=9.9Hz,1H), 4.58(dd,J=4.4,2.6Hz,1H),4.11(d,J=4.8Hz,1H),3.56(dt,J=10.9,5.7Hz,1H),3.13(dd,J=14.8,3.9Hz,1H),2.96(d ,J=14.3Hz,1H),2.64(dd,J=14.8,1.6Hz,1H),2.58–2.43(m,1H),1.30(s,9H),0.94(s,9H),0.07(s,3H),0.04(s,3H).

[0872]

[0873] N-((1R,8R,9R,10R,11S,12R,E)-4-((tert-butyldimethylsilyl)oxy)-10,11,12-trihydroxy-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)-2-methylpropane-2-sulfenamide (A29, 3:2 mixture of diastereomers): The crude residue of (Z)-4-((tert-butyldimethylsilyl)oxy)-8-(((R)-tert-butylsulfinyl)amino)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (110 mg, 1 Eq, 136 μmol) was dissolved in sodium methoxide (1.36 mL, 0.5 mole, 5 Eq, 681 μmol) in MeOH. The reaction was maintained at 23° C. for 1 hour and neutralized by the addition of formic acid (77 μL, 15 equiv, 2.0 mmol). The reaction mixture was filtered (0.2 μM syringe filter) and purified by preparative HPLC (5–50% MeCN / HO with 0.1% HCOOH over 30 minutes) to provide the product A29 (45 mg, 67%). 1H NMR(400MHz,CDCl3)δ5.83(dddd,J15.0,11.5,3.6,1.9Hz,0.6H),5.57(dd,J16). .3.4.9Hz,0.4H),5.37(dd,J14.9,2.3Hz,0.6H),5.33–5.27(m,0.4H),5.17(app dd,J8.2,5.9Hz,1H),4.78–4.74(m,0.4H),4.65(hept,J1.8Hz,0.6H),4.32(dd ,JH10.7,1.0Hz,0.6H),4.13(d,JS3.5Hz,1H),4.12–4.09(m,0.4H),4.06(dd,JS10 .2,6.0Hz,0.4H),4.00(dd,J10.3,5.7Hz,0.6H),3.75(ddd,J10.7,5.8,1.5Hz,0 .6H),3.50(dd,J10.3,3.3Hz,0.4H),3.43(dd,J10.3,3.4Hz,0.6H),3.30–3.28( m,0.4H),3.28–3.22(m,0.4H),3.15(dd,J14.9,3.7Hz,0.6H),2.75(dd,JS14.8, 1.8Hz,0.6H),2.69(dd,J11.8,5.7Hz,0.4H),2.55(dd,J13.8,3.5Hz,0.4H),2 7(ddd,JS13.3,11.5,5.8Hz,0.6H),2.42–2.34(m,0.6H),1.98(q,J11.0Hz,0.4H) ,1.26(s,9H),0.91(d,J615.2Hz,9H),0.12–-0.01(m,6H).HRMS(ESI+,m / z):Definition [C 21 H 41 NO6S2Si+H] + ::496.2217According to::496.2222.

[0874]

[0875] (4S,5aS,8S,8aR)-4-Isobutyl-N-((1R,4S,8R,9R,10R,11S,12R,E)-4,10,11,12-tetrahydroxy-13-oxa-2-thiabicyclo[7.3.1]trideca-5-en-8-yl)octahydro-2H-oxepino[2,3-c]pyrrole-8-carboxamide formate (4:1 mixture of FSA1608009 rotamers). The product FSA1608009 was prepared in a similar manner to FSA1609033 from (R)-N-((1R,8R,9R,10R,11S,12R,E)-4-((tert-butyldimethylsilyl)oxy)-10,11,12-trihydroxy-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)-2-methylpropane-2-sulfenamide. 1 HNMR (400MHz, CD3OD) δ8.47 (s, 2H), 5.73 (dddd, J=12.7, 10.5, 4.6, 1.9Hz, 0.8H), 5.59 (dd, J=1 6.2,5.1Hz,0.2H),5.42(dd,J=15.3,2.2Hz,0.8H),5.0–5.32(m,0.2H),5.21(d,J=5.7Hz,1H),4 .69(br.s,0.2H),4.58(dt,J=4.0,2.0Hz,0.8H),4.40–4.29(m,2.8H),4.26(d,J=11.2Hz,1H), 4.21(d,J=8.5Hz,0.2H),4.10–3.90(m,2H),3.87–3.76(m,2H),3.56(dd,J=11.3,7.4Hz,1H),3. 44(dd,J=10.3,3.4Hz,1H),3.38(d,J=13.9Hz,0.2H),3.23(dd,J=15.0,3.8Hz,0.8H),2.87(t, J=11.8Hz,1H),2.79(dd,J=14.9,1.8Hz,0.8H),2.58(dd,J=14.3,3.9Hz,0.4H),2.48–2.32(m,1 .6H), 2.37–2.22 (m, 1H), 2.10–2.04 (m, 0.2H), 1.99 (d, J = 3.1 Hz, 1H), 1.81–1.60 (m, H), 1.18 (td, J = 6.8, 4.2 Hz, 2H), 1.03–0.91 (m, 1H), 0.89 (appt. d, J = 6.6 Hz, 6H). HRMS (ESI–TOF) m / z: calculated [C 24 H 40 N2O7S+H] +:501.2629 Measured value:501.2717.

[0876]

[0877] (4S,5aS,8S,8aR)-4-isobutyl-N-((1R,4R,8R,9R,10R,11S,12R,E)-4,10,11,12-tetrahydroxy-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)octahydro-2H-oxepin[2,3-c]pyrrole-8-carboxamide formate (FSA1608016): Compound FSA1608016 was prepared in a similar manner to FSA1609033 from (R)-N-((1R,8R,9R,10R,11S,12R,E)-4-((tert-butyldimethylsilyl)oxy)-10,11,12-trihydroxy-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)-2-methylpropane-2-sulfenamide. 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),5.71(td,J=14.7,4.0Hz,1H),5.33(dd,J=14.8,9.7Hz,1H),5.28(d,J=5.6Hz,1H),4.39–4.25(m,2H),4.25 –4.20(m,1H),4.17(d,J=10.8Hz,1H),4.04–3.91(m,3H),3.82(d,J=3.4Hz,1H),3.81–3.72(m,1H),3.55–3.42(m,1H),3.53–3.44(m,1H),3.3 7(dd,J=10.3,3.3Hz,1H),3.16(dd,J=14.3,3.9Hz,1H),2.83–2.69(m,1H),2.51(dd,J=14.3,10.8Hz,1H),2.45–2.32(m,2H),2.26(s,1H),1. 99(d,J=12.9Hz,1H),1.82–1.58(m,4H),1.18(h,J=6.9Hz,2H),0.95(d,J=11.8Hz,1H),0.89(appt.d,J=6.6Hz,6H).HRMS(ESI–TOF)m / z: Calculated value [C 24 H 40 N2O7S+H] + :501.2629 Measured value:501.2635

[0878]

[0879] (R)-2-Methyl-N-((1R,3S,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-3-(pyrrolidin-1-ylmethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)propane-2-sulfenamide formate (B1): At 23°C, add (1R,8R,9R,10S,11S,12R, To a solution of Z-8-(((R)-tert-butylsulfinyl)amino)-3-(hydroxymethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (6 mg, 1 Eq, 8 μmol) in CHCl (0.1 mL) was added Dess-Martin periodinane (4 mg, 1.1 Eq, 9 μmol). The reaction was stirred for 1 hour. The reaction mixture was quenched by addition of saturated aqueous NaHCO (0.5 mL), saturated aqueous NaS0 (0.5 mL), and CHCl (0.5 mL). The biphasic reaction mixture was stirred vigorously for 30 minutes, then the layers were separated. The aqueous layer was extracted with DCM (2 x 0.5 mL) and the combined organics were dried over sodium sulfate and concentrated in vacuo to give crude (1R,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-3-formyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (6 mg, 1 Eq, 9 μmol).

[0880] To a solution of (1R,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-3-formyl-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate (6 mg, 1 Eq, 9 μmol) in MeOH (0.2 mL) was added pyrrolidine (0.6 mg, 0.7 μL, 1 Eq, 9 μmol) and sodium cyanoborohydride (0.5 mg, 1 Eq, 9 μmol) at 23° C. The resulting reaction mixture was maintained at 23° C. for 16 hours. The reaction mixture was concentrated in vacuo, and the crude residue containing (1R,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-3-(pyrrolidin-1-ylmethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-ene-10,11,12-triyl tribenzoate was dissolved in sodium methoxide (95 μL, 0.5 mol, 6 Eq, 47 μmol) in MeOH. The reaction was maintained at 23°C for 1 hour and then neutralized by the addition of formic acid (1.1 mg, 0.89 μL, 3 Eq, 24 μmol). The reaction mixture was filtered (0.2 μM syringe filter) and purified by preparative HPLC (5–50% MeCN / H2O containing 0.1% HCOOH over 30 minutes) to give the product B1 (2.0 mg, 4.5 μmol, 57% over 3 steps). 1 HNMR(400MHz,CD3OD)δ8.36(s,1H),5.79(d,J=6.0Hz,1H),5.65(app tdd,J=14.1,11.3,6.5Hz,2H),5.38(d,J=8.7Hz,1H),4.26(d,J=10.5Hz,1H),4.14(d,J=2.5Hz,1H),4.12( dd,J=9.9,5.8Hz,1H),3.82(dd,J=14.2,12.9Hz,1H),3.79–3.68(m,1H),3.68–3.32(m,5H),3.47(dd,J=10 .1,3.3 Hz,1H),3.34(t,J=3.6 Hz,1H),2.94(dt,J=13.5,11.2 Hz,1H),2.72(ddd,J=14.6,11.1,3.7 Hz,1H),2.14(br.s,4H),2.09(d,J=13.7 Hz,1H),1.98(dd,J=13.3,3.0 Hz,1H),1.26(s,9H).LRMS(ESI+,m / z):calcd. 20 H 36 N2O6S2+H] + :449.2 Actual measured value:449.2.

[0881]

[0882] (R)-2-Methyl-N-((1R,3S,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-3-(morpholinomethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)propane-2-sulfenamide formate (B2): Product B2 was prepared in a manner similar to product B1 from: (1R,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-3-(hydroxymethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-10,11,12-triyl tribenzoate and morpholine. 1 H NMR (400MHz, CD3OD) δ8.27(s,1H),5.74(d,J=6.0Hz,1H),5.66–5.57(m,2H),5.35(s,1H),4.28(d,J=10.5Hz,1H ),4.13(d,J=3.4Hz,1H),4.09(dd,J=10.2,6.0Hz,1H),3.84(t,J=4.8Hz,4H),3.78–3.65(m,1H),3.46(dd,J=10. 2,3.3 Hz,1H),3.30–3.20 (m,2H),3.14–3.06 (m,1H),3.00 (dt, J=10.0,4.9 Hz,4H),2.88 (dt, J=13.7,11.1 Hz,1H),2.79–2.65 (m,1H),2.21 (d, J=14.8 Hz,1H),1.96 (dt, J=14.3,3.3 Hz,1H),1.26 (s,9H).LRMS(ESI+,m / z):calcd. 20 H 36 N2O6S2+H] + :464.2 Measured value:464.2

[0883]

[0884] (S)-2-Methyl-N-((1R,3S,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-3-(morpholinomethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)propane-2-sulfenamide formate (B3): Product B3 was prepared in a similar manner to A1 from: (1R,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-3-(hydroxymethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-10,11,12-triyl tribenzoate and morpholine. 1 H NMR(400MHz,CD3OD)1H NMR(400MHz,MeOD)δ8.27(s,1H),5.74–5.59(m,2H),5.47(d,J=5.9Hz,1H),5.32(d,J=8.6Hz,1H),4.27 (d,J=10.6Hz,1H),4.12(d,J=3.3Hz,1H),4.04(dd,J=10.2,5.9Hz,1H),3.83–3.75(m,1H),3.72(t,J=4 .7Hz,4H),3.54(d,J=6.3Hz,1H),3.42(dd,J=10.2,3.3Hz,1H),3.12–3.01(m,1H),2.85–2.73(m,1H),2.69–2.50(m,6H),2.28(d,J=13.8Hz,1H),1.95(d,J=13.3Hz,1H),1.25(s,9H).LRMS(ESI+,m / z):calcd. 20 H 36 N2O6S2+H] + :464.2 Actual measured value:464.2.

[0885]

[0886] (R)-2-Methyl-N-((1R,4S,8R,9R,10R,11S,12R,Z)-10,11,12-trihydroxy-4-(morpholinomethyl)-13-oxa-2-thiabicyclo[7.3.1]tridec-5-en-8-yl)propane-2-sulfenamide formate (B4): Product B4 was prepared in a manner similar to product B1 from: (1R,4S,8R,9R,10S,11S,12R,Z)-8-(((R)-tert-butylsulfinyl)amino)-4-(...

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of P is independently hydrogen or a protecting group; A is a substituted or unsubstituted heteroaliphatic group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaralkyl group; R 7 is hydrogen or unsubstituted alkyl; R is a heterocyclic group; Each occurrence of R 2 independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, -OR A 、-N(R A )2. -SR A 、-CN、-SCN、-C(=NR A )R A 、-C(=NR A )OR A 、-C(=NR A )N(R A )2, -C(=O)R A 、-C(=O)OR A 、-C(=O)N(R A )2, -NO2, -NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)N(R A )2.-NR A C(=NR A )N(R A )2, -OC(=O)R A 、-OC(=O)OR A 、-OC(=O)N(R A )2.-NR A S(O)2R A 、-OS(O)2R A , or -S(O)2R A ; or two R 2 The groups are connected to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; t is 0-12; and Each occurrence of R A R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: A is a substituted or unsubstituted heteroaliphatic group.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: A is a substituted or unsubstituted heterocyclic group.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: A is a substituted or unsubstituted 4- to 8-membered monocyclic heterocyclic group, or a substituted or unsubstituted condensed bicyclic heterocyclic group.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: A is a substituted or unsubstituted 4- to 8-membered monocyclic heterocyclic group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: A is the formula: in: n is 1, 2 or 3; R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaliphatic group, -C(=NR A )R A , –C(=NR A )OR A , –C(=NR A )N(R A )2. –C(=O)R A 、–C(=O)OR A , –C(=O)N(R A )2, –S(O)2R A or a nitrogen protecting group; Each occurrence of R 9 independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, -OR A 、-N(R A )2. -SR A 、-CN、-SCN、-C(=NR A )R A 、-C(=NR A )OR A 、-C(=NR A )N(R A )2, -C(=O)R A 、-C(=O)OR A 、-C(=O)N(R A )2, -NO2, -NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)N(R A )2.-NR A C(=NR A )N(R A )2, -OC(=O)R A 、-OC(=O)OR A 、-OC(=O)N(R A )2.-NR A S(O)2R A 、-OS(O)2R A , or -S(O)2R A ;and p is 0-4.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein: A is the formula:

8. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: A is a substituted or unsubstituted fused bicyclic heterocyclic group.

9. The compound of any one of claims 1-4 or 8, or a pharmaceutically acceptable salt thereof, wherein: A is the formula: in: B is a carbocyclic group or a heterocyclic group; R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaliphatic group, -C(=NR A )R A , –C(=NR A )OR A , –C(=NR A )N(R A )2. –C(=O)R A 、–C(=O)OR A , –C(=O)N(R A )2, –S(O)2R A or a nitrogen protecting group; Each occurrence of R 9 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic, -OR A , –N(R A 2. –SR A , –CN, –SCN, –C(=NR A )R A , –C(=NR A )OR A , –C(=NR A )N(R A )2. –C(=O)R A 、–C(=O)OR A , –C(=O)N(R A )2, –NO2, –NR A C(=O)R A ,–NR A C(=O)OR A ,–NR A C(=O)N(R A )2. –NR A C(=NR A )N(R A )2. –OC(=O)R A 、–OC(=O)OR A 、–OC(=O)N(R A )2. –NR A S(O)2R A 、-OS(O)2R A , or -S(O)2R A ; or two R 9 The groups are connected to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring; and p is 0-4.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein: A is the formula: in: X is O, S, NR 9 or C(R 9 )2; Y is O, S, N, NR 9 , C(R 9 2.CR 9 , CH2 or CH; n is 0 or 1; p is 0-4; and Represents a single bond or a double bond.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein: A is the formula:

12. The compound according to claim 10 or 11, or a pharmaceutically acceptable salt thereof, wherein: A is the formula:

13. The compound of any one of claims 10-12, or a pharmaceutically acceptable salt thereof, wherein: A is the formula:

14. The compound of any one of claims 9 to 13, or a pharmaceutically acceptable salt thereof, wherein: A is the formula:

15. The compound of any one of claims 9 to 14, or a pharmaceutically acceptable salt thereof, wherein: A is the formula:

16. The compound of any one of claims 9 to 15, or a pharmaceutically acceptable salt thereof, wherein: A is the formula:

17. The compound of any one of claims 9 to 16, or a pharmaceutically acceptable salt thereof, wherein: A is the formula:

18. The compound of any one of claims 9 to 17, or a pharmaceutically acceptable salt thereof, wherein: A is the formula:

19. The compound of any one of claims 1-4 or 8-18, or a pharmaceutically acceptable salt thereof, wherein: A is the formula:

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein: R 7 For hydrogen.

21. The compound of any one of claims 6 to 20, or a pharmaceutically acceptable salt thereof, wherein: R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group or -C(=O)R A .

22. The compound of any one of claims 6 to 21, or a pharmaceutically acceptable salt thereof, wherein: R 8 is hydrogen or substituted or unsubstituted alkyl.

23. The compound of any one of claims 6 to 22, or a pharmaceutically acceptable salt thereof, wherein: R 8 It is hydrogen or methyl.

24. The compound of any one of claims 6 to 23, or a pharmaceutically acceptable salt thereof, wherein: R 8 For hydrogen.

25. The compound of any one of claims 6-23, or a pharmaceutically acceptable salt thereof, wherein: R 8 It is methyl.

26. The compound of any one of claims 6-25, or a pharmaceutically acceptable salt thereof, wherein: R 9 is a substituted or unsubstituted alkyl group.

27. The compound of any one of claims 6 to 26, or a pharmaceutically acceptable salt thereof, wherein: R 9 is substituted or unsubstituted C 1-6 alkyl.

28. The compound of any one of claims 6-26, or a pharmaceutically acceptable salt thereof, wherein: R 9 is –CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, or -CH(CH3)3.

29. The compound of any one of claims 6-28, or a pharmaceutically acceptable salt thereof, wherein: R 9 It is -CH2CH(CH3)2.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein: Each P is hydrogen.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein: R is a 6- to 14-membered heterocyclic group.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein: R is an 8-12 membered heterocyclic group.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein: R is a 9-12 membered heterocyclic group.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein: R is a 9- to 11-membered heterocyclic group.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein: R is an 11-membered heterocyclic group.

36. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein: R is a 10-membered heterocyclic group.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein: R contains at least one unsaturated bond in its ring.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein: R contains at least one unsaturated carbon-carbon bond in its ring.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein: R contains at least one heteroatom in its ring in addition to oxygen.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein: R contains at least one sulfur atom in its ring.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein: R contains a sulfur atom in its ring.

42. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula: in: R 1 For-NR 2 -, -O-, or -S-.

43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula:

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula: in: Each R 1 Independently bonded, -CR 2 R 2 -、CR 2 , C, N, -NR 2 -, -O-, or S; and q is 3-6.

45. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula: in: Each R 1 Independently for a bond or -CR 2 R 2 -;and Represents a single bond or a double bond.

46. ​​The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula: in: Each R 1 Independently for a bond or -CR 2 R 2 -.

47. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula: in: Each R 1 Independently for a bond or -CR 2 R 2 -.

48. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula: in: Each R 1 Independently for a bond or -CR 2 R 2 -.

49. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula: in: Each R 1 Independently for a bond or -CR 2 R 2 -.

50. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula:

51. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula:

52. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula:

53. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula:

54. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula:

55. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula:

56. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R is a heterocyclic group of the formula:

57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of R 2 are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A 、-N(R A )2. -SR A , or -CN; or two R 2 The groups are linked to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of R 2 are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, a nitrogen protecting group when attached to a nitrogen atom, -OR A 、-N(R A )2. -SR A , or -CN; or two R 2 The groups are linked to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of R 2 are independently hydrogen, halogen, substituted or unsubstituted alkyl, -OR A 、-N(R A )2, or -SR A ; or two R 2 The groups are linked to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heterocyclyl ring.

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of R 2 are independently halogen, substituted or unsubstituted alkyl, or -OR A ; or two R 2 The groups are linked to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heterocyclyl ring.

61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of R 2 are independently halogen, substituted or unsubstituted alkyl, or -OR A .

62. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of R 2 and R and R are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

63. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of R 2 and R and R are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

64. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of R 2 are independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl.

65. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of R 2 are independently halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl.

66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of R 2 and are independently substituted or unsubstituted alkyl.

67. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt thereof, wherein: Each occurrence of R 2 is independently unsubstituted alkyl.

68. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt thereof, wherein: t is 0-4.

69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt thereof, wherein: t is 0-2.

70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt thereof, wherein: t is 0 or 1.

71. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt thereof, wherein: t is 0.

72. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt thereof, wherein: t is 1 or 2.

73. The compound of claim 1, wherein the compound is of formula (Ia): or a pharmaceutically acceptable salt thereof.

74. The compound of claim 1, wherein the compound is of formula (Ib): or a pharmaceutically acceptable salt thereof, wherein: R 1 For-NR 2 -, -O-, or -S-.

75. The compound of claim 1, wherein the compound is of formula (Ic): or a pharmaceutically acceptable salt thereof.

76. The compound of claim 1, wherein the compound is of formula (Id): or a pharmaceutically acceptable salt thereof, wherein: Each R 1 Independently bonded, -CR 2 R 2 -、CR 2 , C, N, -NR 2 -, -O-, or S; and q is 3-6.

77. The compound of claim 1, wherein the compound is of formula (Ie): or a pharmaceutically acceptable salt thereof, wherein: Each R 1 Independently for a bond or -CR 2 R 2 -;and Represents a single bond or a double bond.

78. The compound of claim 1, wherein the compound is of formula (Ie-1): or a pharmaceutically acceptable salt thereof, wherein: Each R 1 Independently for a bond or -CR 2 R 2 -.

79. The compound of claim 1, wherein the compound is of formula (If): or a pharmaceutically acceptable salt thereof, wherein: Each R 1 Independently for a bond or -CR 2 R 2 -;and Represents a single bond or a double bond.

80. The compound of claim 1, wherein the compound is of formula (If-1): or a pharmaceutically acceptable salt thereof, wherein: Each R 1 Independently for a bond or -CR 2 R 2 -.

81. The compound of claim 1, wherein the compound is of formula (If-2): or a pharmaceutically acceptable salt thereof, wherein: Each R 1 Independently for a bond or -CR 2 R 2 -.

82. The compound of claim 1, wherein the compound is of formula (Ig): or a pharmaceutically acceptable salt thereof, wherein: Each R 1 Independently for a bond or -CR 2 R 2 -;and Represents a single bond or a double bond.

83. The compound of claim 1, wherein the compound is of formula (Ig-1): or a pharmaceutically acceptable salt thereof, wherein: Each R 1 Independently for a bond or -CR 2 R 2 -.

84. The compound of claim 1, wherein the compound is of formula (Ig-2): or a pharmaceutically acceptable salt thereof, wherein: Each R 1 Independently for a bond or -CR 2 R 2 -.

85. The compound of claim 1, wherein the compound is of formula (Ih): or a pharmaceutically acceptable salt thereof.

86. The compound of claim 1, wherein the compound is of formula (Ih-1): or a pharmaceutically acceptable salt thereof.

87. The compound of claim 1, wherein the compound is of formula (Ih-2): or a pharmaceutically acceptable salt thereof.

88. The compound of claim 1, wherein the compound is of formula (Ii): or a pharmaceutically acceptable salt thereof.

89. The compound of claim 1, wherein the compound is of formula (Ii-1): or a pharmaceutically acceptable salt thereof.

90. The compound of claim 1, wherein the compound is of formula (Ii-2): or a pharmaceutically acceptable salt thereof.

91. The compound of claim 1, wherein the compound is of formula (Ii-8): or a pharmaceutically acceptable salt thereof.

92. The compound of claim 1, wherein the compound is of formula (Ij): or a pharmaceutically acceptable salt thereof.

93. The compound of claim 1, wherein the compound is of formula (Ij-1): or a pharmaceutically acceptable salt thereof.

94. The compound of claim 1, wherein the compound is of formula (Ik): or a pharmaceutically acceptable salt thereof.

95. The compound of claim 1, wherein the compound is of formula (Ik-1): or a pharmaceutically acceptable salt thereof.

96. The compound of claim 1, wherein the compound is of formula (II): or a pharmaceutically acceptable salt thereof.

97. The compound of claim 1, wherein the compound is of formula (I1-4): or a pharmaceutically acceptable salt thereof.

98. The compound of claim 1, wherein the compound is of formula (Im-1): or a pharmaceutically acceptable salt thereof.

99. The compound of claim 1, wherein the compound is of formula (Im-5): or a pharmaceutically acceptable salt thereof.

100. The compound of claim 1, wherein the compound is of formula (In-1): or a pharmaceutically acceptable salt thereof.

101. The compound of claim 9, wherein the compound is of formula (In-2): or a pharmaceutically acceptable salt thereof.

102. The compound of claim 10, wherein the compound is of formula (In-4): or a pharmaceutically acceptable salt thereof.

103. The compound of claim 9, wherein the compound is of formula (In-8): or a pharmaceutically acceptable salt thereof.

104. The compound of claim 1, wherein the compound is of formula (In-11): or a pharmaceutically acceptable salt thereof.

105. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is: or a pharmaceutically acceptable salt thereof.

106. A pharmaceutical composition comprising a compound according to any one of claims 1 to 105 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

107. The pharmaceutical composition of claim 106, comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

108. A kit comprising a compound of any one of claims 1-105 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 106 or 107, and instructions for administering the compound or pharmaceutical composition to a subject in need thereof.

109. A method for treating an infectious disease, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 105 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 106 or 107.

110. The method of claim 109, wherein the infectious disease is a bacterial infection.

111. The method of claim 110, wherein the bacterial infection is an infection caused by a gram-positive bacterium.

112. The method of claim 110, wherein the bacterial infection is an infection caused by a gram-negative bacterium.

113. The method of claim 110, wherein the bacterial infection is a Staphylococcus infection, a Streptococcus infection, an Enterococcus infection, an Acinetobacter infection, a Clostridium infection, a Bacteroides infection, an Escherichia coli infection, a Pseudomonas infection, a Neisseria infection, a Klebsiella infection, or a Haemophilus infection.

114. The method of claim 110, wherein the bacterial infection is a Clostridium difficile infection or a Bacteroides fragilis infection.

115. The method of claim 109, wherein the infectious disease is a parasitic infection.

116. A method of killing a microorganism, comprising contacting the microorganism with an effective amount of a compound according to any one of claims 1 to 105 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 106 or 107, to a subject in need thereof.

117. A method for inhibiting the growth of a microorganism, comprising contacting the microorganism with an effective amount of a compound according to any one of claims 1 to 105 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 106 or 107, to a subject in need thereof.

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