Lincosamides and their uses

Abstract

Provided are compounds useful for the treatment and prevention of infectious diseases. The structures of the compounds are lincosamide analogs modified in the aminooctose (Northern) and amino acid (Southern) regions. Also provided are methods for preparing the lincosamide compounds, pharmaceutical compositions containing the lincosamide compounds, and methods for treating infectious diseases using the disclosed lincosamide compounds.

Description

[Technical Field]

[0001] Related Applications This patent application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Patent Application USSN 63 / 332,993, filed April 20, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] background The emergence of resistance to existing antibiotics is rapidly becoming a global crisis, particularly for infectious diseases caused by drug-resistant Gram-negative bacteria. Pathogenic bacteria can transmit genes encoding antibiotic resistance both vertically (to offspring) and horizontally (to neighboring bacteria of different lineages), resulting in the rapid evolution of antibiotic resistance, especially in nosocomial (hospital) settings. See, e.g., Wright, Chem. Commun. (2011) 47:4055-4061. In the United States, more than 99,000 people die each year from healthcare-associated infections, exceeding all deaths from automobile accidents, HIV, and breast cancer, resulting in an estimated burden of up to $45 billion in U.S. healthcare costs. See, e.g., Klevens et al., Public Health Rep (2007) 122:160-166. The current crisis is exacerbated by a decline in new antibiotic development 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 not adequately keeping up with increasing resistance, and with increased international travel and increasing population densities, the need for innovation in this field is greater than ever.

[0003] Lincosamides are a class of antibiotics that prevent bacterial growth by interfering with protein synthesis. They bind to the 23S portion of the 50S subunit of the bacterial ribosome, causing premature dissociation of peptidyl-tRNA from the ribosome. Because human ribosomes are structurally different from bacterial ones, lincosamides do not interfere with protein synthesis in human cells (or in other eukaryotic cells).

[0004] The first lincosamide discovered was lincomycin, but its use as an antibiotic has been largely superseded by clindamycin, which exhibits improved antibacterial activity. Clindamycin also exhibits some efficacy against parasitic protozoa and has been used to treat toxoplasmosis and malaria. Lincosamides are typically used to treat Staphylococcus and Streptococcus infections, but have also proven useful in treating infections caused by Bacteroides fragilis and other anaerobic bacteria. They are used in the treatment of toxic shock syndrome, where they are believed to directly block the production of M protein, which leads to a severe inflammatory response. [ka]

[0005] The target bacteria may alter the binding site of the drug, resulting in resistance (similar to the resistance found with macrolides and streptogramins). The mechanism of resistance is methylation of the 23s binding site. If this occurs, the bacteria then become resistant to both macrolides and lincosamides. In rare instances, enzymatic inactivation of clindamycin has also been reported.

[0006] Lincosamide antibiotics are also associated with pseudomembranous colitis, an inflammation of the colon associated with the overgrowth of C. difficile. This C. difficile overgrowth is most often associated with the use of lincosamide antibiotics in the recent past. For example, clindamycin, the only lincosamide currently in clinical use, carries a black box warning about its tendency to promote C. difficile-associated diarrhea (CDAD).

[0007] Therefore, the discovery and development of new antibiotics, particularly new lincosamides, that are effective against drug-resistant bacteria represents a currently unmet medical need. Summary of the Invention

[0008] overview The primary degradation pathway of clindamycin in vivo is the "first-pass" oxidation of its methylthioglycoside by hepatic cytochrome P450 enzymes, which forms the relatively inactive clindamycin sulfoxide diastereomer. Generally, reducing the metabolic degradation of an antibiotic can improve its therapeutic index by achieving the same inhibitory effect at a lower dose. This disclosure stems from the recognition that targeted glycoside modification offers significant unrealized potential for significantly improving the therapeutic efficacy of lincosamides against MDR ESKAPE pathogens in vivo, a claim supported by preliminary data. In particular, crystal structure analysis of the lincosamide analog ivoxamycin bound to bacterial ribosomes suggested that the formation of a macrocyclic moiety that constrains the aminooctose (northern) region promotes pre-positioning of the analog into its preferred binding conformation, thereby reducing entropy loss upon binding and increasing target association.

[0009] Thus, disclosed are compounds that are analogs of lincosamides. The compounds have modified northern and amino acid (southern) regions. The compounds contain novel heterocyclic moieties that constrain the northern region. The disclosed synthetic lincosamides exhibit potent activity against both gram-positive and gram-negative pathogens.

[0010] In one aspect, the present disclosure provides a compound of formula (I): [ka] and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof, During the ceremony: each occurrence of P is independently hydrogen or a protecting group; A is a substituted or unsubstituted heteroaliphatic, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; R 7 is hydrogen or unsubstituted alkyl; R is heterocyclyl; R 2 each occurrence is independently selected from 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 hetaralkyl, and, when attached to a nitrogen atom, a nitrogen protecting group, -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)R 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; t is 0 to 12; and R A each occurrence of 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 het-aralkyl, a nitrogen protecting group if attached to a nitrogen atom, an oxygen protecting group if attached to an oxygen atom, or a sulfur protecting group if 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.

[0011] The disclosed compounds have antimicrobial activity and may be used to treat and / or prevent infectious diseases. Pharmaceutical compositions of the compounds, kits containing the compounds and / or compositions, and methods of treatment using the compounds or compositions are provided herein. Infectious diseases that can be treated with the compounds of the present invention include, but are not limited to, bacterial infections caused by Staphylococcus, Streptococcus, Enterococcus, Acinetobacter, Clostridium, Bacteroides, Klebsiella, Escherichia, Pseudomonas, and Haemophilus species.

[0012] Methods for preparing the disclosed compounds are also provided herein. In some embodiments, the disclosed compounds are prepared by ring-closing metathesis reactions (see, e.g., Scheme 1). DETAILED DESCRIPTION OF THE INVENTION

[0013] Details of certain embodiments of the invention are presented in the Detailed Description of Certain Embodiments, as set forth below. Other features, objects, and advantages of the invention will be apparent from the definition, examples, and claims.

[0014] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS The compounds disclosed herein include lincosamide analogs. The disclosed compounds have increased structural diversity compared to known lincosamides, such as lincomycin and clindamycin. The compounds have modified northern and southern amino acid (southern) regions, which include novel heterocyclic moieties that constrain the northern region. The disclosed compounds provide unexpected and potent activity against a variety of microorganisms, including Gram-negative bacteria. Also disclosed are methods for preparing the disclosed compounds, pharmaceutical compositions containing the compounds, uses of the compounds, and methods of using the compounds (e.g., treating infectious diseases, preventing infectious diseases).

[0015] In one aspect, provided is a compound of formula (I): [ka] and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof, During the ceremony: each occurrence of P is independently hydrogen or a protecting group; A is a substituted or unsubstituted heteroaliphatic, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl; R is heterocyclyl; R 7 is hydrogen or unsubstituted alkyl; R 2 each occurrence independently represents 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 het-aralkyl, if attached to a nitrogen atom, a nitrogen protecting group, -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, -NRA 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)R 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; t is 0 to 12; and R A each occurrence of 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 het-aralkyl, a nitrogen protecting group if attached to a nitrogen atom, an oxygen protecting group if attached to an oxygen atom, or a sulfur protecting group if 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.

[0016] Unless otherwise stated, any formula described herein is also intended to encompass its salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives. In some embodiments, a provided compound is a salt of any of the formulas described herein. In some embodiments, a provided compound is a pharmaceutically acceptable salt of any of the formulas described herein. In some embodiments, a provided compound is a solvate of any of the formulas described herein. In some embodiments, a provided compound is a hydrate of any of the formulas described herein. In some embodiments, a provided compound is a polymorph of any of the formulas described herein. In some embodiments, a provided compound is a co-crystal of any of the formulas described herein. In some embodiments, a provided compound is a tautomer of any of the formulas described herein. In some embodiments, a provided compound is a stereoisomer of any of the formulas described herein. In some embodiments, a provided compound is an isotopically labeled form of any of the formulas described herein. For example, replacement of hydrogen with deuterium or tritium, 19 F 18 Replaced by F, or 12 C 13 C or 14 Compounds having the structures of the present invention, except for the replacement by C, are within the scope of this disclosure. In certain embodiments, provided compounds are deuterated forms of any of the formulas or compounds described herein.

[0017] In certain embodiments of a compound of Formula (I), each occurrence of P is hydrogen.

[0018] base R 7 As generally defined herein, R 7 is hydrogen or unsubstituted alkyl.

[0019] In some embodiments, R7 is hydrogen or unsubstituted alkyl. In some embodiments, R 7 is unsubstituted alkyl. In some embodiments, R 7 is the unsubstituted C 1-6 In some embodiments, R 7 is the unsubstituted C 1-4 In some embodiments, R 7 is the unsubstituted C 1-3 In some embodiments, R 7 is the unsubstituted C 1-2 In some embodiments, R 7 is ethyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is hydrogen.

[0020] Base A As generally defined herein, A is a substituted or unsubstituted heteroaliphatic, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl.

[0021] In some embodiments, A is substituted or unsubstituted heteroaliphatic.

[0022] In some embodiments, A is substituted or unsubstituted heterocyclyl.

[0023] In certain embodiments, A is a substituted or unsubstituted 4- to 8-membered monocyclic heterocyclyl or a substituted or unsubstituted fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 4- to 8-membered monocyclic heterocyclyl or a substituted or unsubstituted 8- to 12-membered fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 5- to 8-membered monocyclic heterocyclyl or a substituted or unsubstituted 8- to 12-membered fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 5- to 8-membered monocyclic heterocyclyl or a substituted or unsubstituted 9- to 11-membered fused bicyclic heterocyclyl. In certain embodiments, A is a substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl or a substituted or unsubstituted 9- to 11-membered fused bicyclic heterocyclyl. In some embodiments, A is a substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl or a substituted or unsubstituted 9- to 10-membered fused bicyclic heterocyclyl. In some embodiments, A is a substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl or a substituted or unsubstituted 10-membered fused bicyclic heterocyclyl.

[0024] In some embodiments, A is a substituted or unsubstituted 4- to 8-membered monocyclic heterocyclyl. In some embodiments, A is a substituted or unsubstituted 5- to 8-membered monocyclic heterocyclyl. In some embodiments, A is a substituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl. In some embodiments, A is a substituted or unsubstituted 5-membered monocyclic heterocyclyl. In some embodiments, A is a substituted or unsubstituted 6-membered monocyclic heterocyclyl. In some embodiments, A is a substituted or unsubstituted 7-membered monocyclic heterocyclyl.

[0025] In some embodiments, A has the formula: [ka] wherein: n is 1, 2, or 3; R 8is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, -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; R 9 each occurrence is independently selected from 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, -NRA S(O)2R A , -OS(O)2R A , or -S(O)R A and p is 0 to 4.

[0026] In some embodiments, A has the formula: [ka] or [ka] In some embodiments, A is of the formula: [ka] In some embodiments, A is of the formula: [ka] In some embodiments, A is of the formula: [ka] It is of the type.

[0027] In some embodiments, A has the formula: [ka] or [ka] In some embodiments, A is of the formula: [ka] In some embodiments, A is of the formula: [ka] In some embodiments, A is of the formula: [ka] It is of the type.

[0028] In some embodiments, A is a substituted or unsubstituted fused bicyclic heterocyclyl. In some embodiments, A is a substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl. In some embodiments, A is a substituted or unsubstituted 9-11 membered fused bicyclic heterocyclyl. In some embodiments, A is a substituted or unsubstituted 9-10 membered fused bicyclic heterocyclyl. In some embodiments, A is a substituted or unsubstituted 10 membered fused bicyclic heterocyclyl.

[0029] In some embodiments, A has the formula: [ka] wherein: B is carbocyclyl or heterocyclyl; R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, -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; R 9each occurrence is independently selected from 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)R 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 p is 0 to 4.

[0030] In some embodiments, B is cycloalkyl, cycloalkenyl, or heterocyclyl. In some embodiments, B is heterocyclyl. In some embodiments, B is a 5- to 8-membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In some embodiments, B is a 5- to 8-membered heterocyclyl ring. In some embodiments, B is a 5- to 7-membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In some embodiments, B is a 5- to 7-membered heterocyclyl ring. In some embodiments, B is a 6- to 7-membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In some embodiments, B is a 6- to 7-membered heterocyclyl ring. In some embodiments, B is a 6-membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In some embodiments, B is a 6-membered heterocyclyl ring. In some embodiments, B is a 7-membered cycloalkyl, cycloalkenyl, or heterocyclyl ring. In some embodiments, B is a 7-membered heterocyclyl ring.

[0031] In some embodiments, A has the formula: [ka] wherein: X is O, S, or 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 to 4; and [ka] represents a single or double bond.

[0032] In some embodiments, X is O, S, NR 9 or C(R 9 In some embodiments, X is O, S, or NR 9In some embodiments, X is O or S. In some embodiments, X is O.

[0033] In some embodiments, Y is O, S, NR 9 , C(R 9 )2, CR 9 , CHR 9 , CH, or CH. In some embodiments, Y is O, NR 9 , C(R 9 )2, CR 9 , CHR 9 , CH, or CH. In some embodiments, Y is NR 9 , C(R 9 )2, CR 9 , CHR 9 , CH, or CH. In some embodiments, Y is C(R 9 )2, CR 9 , CHR 9 , CH, or CH. In some embodiments, Y is C(R 9 )2, CR 9 , CHR 9 , CH, or CH. In some embodiments, Y is C(R 9 )2, CHR 9 or CH2. In some embodiments, Y is C(R 9 In some embodiments, Y is CHR 9 In some embodiments, Y is CH. In some embodiments, Y is CR. 9 or CH. In some embodiments, Y is CR 9 In some embodiments, Y is CH.

[0034] In some embodiments, n is 0. In some embodiments, n is 1.

[0035] In some embodiments, p is 0 to 3. In some embodiments, p is 0 to 2. In some embodiments, p is 0 to 1. In some embodiments, p is 1 to 2. In some embodiments, p is 0 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0036] In some embodiments, X is O; and Y is NR 9 , C(R 9 )2, CR 9 , CHR 9 , CH, or CH; n is 1; and p is 0 to 2. In some embodiments, X is O; Y is C(R 9 )2, CR 9 , CHR 9 , CH2, or CH; n is 1; and p is 0 to 2. In some embodiments, X is O; Y is CR 9 or CH; n is 1; and p is 1. In some embodiments, X is O and Y is C(R 9 )2, CHR 9 or CH2, n is 1, and p is 0 to 2.

[0037] In some embodiments, A has the formula: [ka] It is of the type.

[0038] In some embodiments, A has the formula: [ka] It is of the type.

[0039] In some embodiments, A has the formula: [ka] It is of the type.

[0040] In some embodiments, A has the formula: [ka] It is of the type.

[0041] In some embodiments, A has the formula: [ka] It is of the type.

[0042] In some embodiments, A has the formula: [ka] It is of the type.

[0043] In some embodiments, A has the formula: [ka] It is of the type.

[0044] In some embodiments, A has the formula: [ka] It is of the type.

[0045] In some embodiments, A has the formula: [ka] It is of the type.

[0046] In some embodiments, A has the formula: [ka] It is of the type.

[0047] In some embodiments, A has the formula: [ka] It is of the type.

[0048] In some embodiments, A has the formula: [ka] It is of the type.

[0049] In some embodiments, A has the formula: [ka] It is of the type.

[0050] In some embodiments, A has the formula: [ka] It is of the type.

[0051] In some embodiments, A has the formula: [ka] It is of the type.

[0052] In some embodiments, A has the formula: [ka] It is of the type.

[0053] In some embodiments, A has the formula: [ka] It is of the type.

[0054] In some embodiments, A has the formula: [ka] It is of the type.

[0055] In some embodiments, A has the formula: [ka] It is of the type.

[0056] In some embodiments, A has the formula: [ka] It is of the type.

[0057] In some embodiments, A has the formula: [ka] It is of the type.

[0058] base R 8 As generally defined herein, R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, -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.

[0059] In some embodiments, R 8 is hydrogen, substituted or unsubstituted alkyl, or —C(═O)R A In some embodiments, R 8 is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 8 is hydrogen or unsubstituted alkyl. In some embodiments, R 8 is hydrogen or unsubstituted C 1-6 In some embodiments, R 8 is hydrogen or unsubstituted C 1-4 In some embodiments, R 8is hydrogen or unsubstituted C 1-3 In some embodiments, R 8 is hydrogen or unsubstituted C 1-2 In some embodiments, R 8 is hydrogen or ethyl. In some embodiments, R 8 is hydrogen or methyl. In some embodiments, R 8 is hydrogen.

[0060] In some embodiments, R 8 is the unsubstituted C 1-6 In some embodiments, R 8 is the unsubstituted C 1-4 In some embodiments, R 8 is the unsubstituted C 1-3 In some embodiments, R 8 is the unsubstituted C 1-2 In some embodiments, R 8 is ethyl. In some embodiments, R 8 is methyl.

[0061] base R 9 As generally defined herein, R 9 each occurrence is independently selected from 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(RA )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)R A or two R 9 The groups are linked to form a substituted or unsubstituted heterocyclyl ring or a substituted or unsubstituted carbocyclyl ring. 9 The substituent is an (S) stereogenic center (i.e., the carbon to which it is attached is of the (S) configuration). 9 The substituent is an (R) stereogenic center (ie, the carbon to which it is attached is of the (R) configuration).

[0062] In some 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.

[0063] In some embodiments, R 9is 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.

[0064] In some 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.

[0065] In some embodiments, R 9 is halogen, unsubstituted ethenyl, substituted or unsubstituted phenethynyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted phenethyl; or two R 9 The groups are joined to form an unsubstituted cycloalkyl ring.

[0066] In some embodiments, R 9 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. 9 is substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. 9 is substituted or unsubstituted phenyl, or substituted or unsubstituted phenethyl.

[0067] In some embodiments, R 9is 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 substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted carbocyclyl.

[0068] In some embodiments, R 9 is substituted or unsubstituted alkenyl. In some embodiments, R 9 is unsubstituted alkenyl. In some embodiments, R 9 is -CH=CH2.

[0069] In some embodiments, R 9 is substituted or unsubstituted carbocyclyl. In some embodiments, R 9 is unsubstituted carbocyclyl. In some embodiments, R 9 is the unsubstituted C 3-6 In some embodiments, R 9 is the unsubstituted C 5-6 In some embodiments, R 9 is unsubstituted cyclopentyl. In some embodiments, R 9 is unsubstituted cyclohexyl.

[0070] In some embodiments, R 9 is substituted or unsubstituted alkyl. In some embodiments, R 9 is a substituted or unsubstituted C 1-6 In some embodiments, R 9 is a substitution C 1-6 In some embodiments, R 9 is halogen, alkenyl, C 3-6 Cycloalkyl, or -OR A C replaced with 1-6 In some embodiments, R9 is halogen, alkenyl, C 3-6 Cycloalkyl, heterocyclyl, -N(R A )2, -SO2R A , or -OR A C replaced with 1-6 In some embodiments, R 9 is -CHCH=CH. In some embodiments, R 9 is -CH2CH2F. In some embodiments, R 9 is —CH2CHF2. In some embodiments, R 9 is -CH2CH2CH2F. In some embodiments, R 9 is —CH2CH2CF2H. In some embodiments, R 9 is —CH2CH2CH2Cl. In some embodiments, R 9 teeth, [ka] In some embodiments, R 9 is -CH2CH2CH2OCH3. In some embodiments, R 9 is -CH2CH2CH2OH. In some embodiments, R 9 is -CH2CH2CH2SO2CH3. In some embodiments, R 9 teeth, [ka] In some embodiments, R 9 is -CH2CH2CH2NH2. In some embodiments, R 9 is —CHCHCHN(CH) In some embodiments, R 9 is —CHC(CH)OH. In some embodiments, R 9 is -CHCFCH. In some embodiments, R 9 are -CH2CH=CH2, -CH2CH2F, -CH2CHF2, [ka] or -CH2CH2CH2OCH3. In some embodiments, R 9 are -CH2CH=CH2, -CH2CH2F, -CH2CHF2, -CH2CF2CH3, -CH2CH2CH2F, -CH2CH2CF2H, -CH2CH2CH2Cl, [ka] , -CH2CH2CH2OCH3, -CH2CH2CH2OH, -CH2C(CH3)2OH, -CH2CH2CH2SO2CH3, CH2CH2CH2NH2, -CH2CH2CH2N(CH3)2, or [ka] is.

[0071] In some embodiments, R 9 is the unsubstituted C 1-6 In some embodiments, R 9 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, or -C(CH3)3. In some embodiments, R 9 is -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2C(CH3)3, or -C(CH3)3. 9 is -CH3. In some embodiments, R 9 is -CH2CH3. In some embodiments, R 9 is -CH2CH2CH3. In some embodiments, R 9 is —CH(CH). In some embodiments, R 9 is —C(CH). In some embodiments, R 9 is -CH2CH(CH3)2.

[0072] Ring R As described herein, R is heterocyclyl. In some embodiments, R is 6-14 membered heterocyclyl. In some embodiments, R is 8-12 membered heterocyclyl. In some embodiments, R is 9-12 membered heterocyclyl. In some embodiments, R is 9-11 membered heterocyclyl. In some embodiments, R is 11 membered heterocyclyl. R is 10 membered heterocyclyl.

[0073] In some embodiments, R contains at least one unsaturated bond in its ring. In some embodiments, R contains at least one double bond (e.g., carbon-carbon or carbon-nitrogen). In some embodiments, R contains at least one unsaturated carbon-carbon bond in its ring. In some embodiments, the unsaturated carbon-carbon bond is a double bond (i.e., an alkenyl bond). In some embodiments, the unsaturated carbon-carbon bond is a triple bond (i.e., an alkynyl bond). In some embodiments, R contains at least one heteroatom in addition to oxygen in its ring. In some embodiments, R contains at least one heteroatom in addition to oxygen in its ring, where the heteroatom is nitrogen, oxygen, or sulfur. In some embodiments, R contains at least one heteroatom in addition to oxygen in its ring, where the heteroatom is nitrogen. In some embodiments, R contains at least one heteroatom in addition to oxygen in its ring, where the heteroatom is oxygen. In some embodiments, R contains at least one heteroatom in addition to oxygen in its ring, where the heteroatom is sulfur. In some embodiments, R contains at least one sulfur atom in its ring. In some embodiments, R contains one sulfur atom in its ring.

[0074] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, R 1 is -NR 2 In some embodiments, R 1is -NR 2 In some embodiments, R 1 is —O—. In some embodiments, R 1 is -S-.

[0075] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0076] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, R 1a is -NR 2 -, -O-, or -S-; each R 1 are independently bonded, -CR 2 R 2 -, CR 2 , C, N, -NR 2 -, -O-, or -S-; and q is 3 to 6. In some embodiments, R 1 is -NR 2 In some embodiments, R 1 is —O—. In some embodiments, R 1 is -S-. In some embodiments, R 1a is -NR 2 In some embodiments, R 1a is —O—. In some embodiments, R 1a is -S-.

[0077] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, each R 1 are independently bonded, -CR 2 R 2 -, CR 2 , C, N, -NR 2-, -O-, or -S-; and q is 3 to 6. In some embodiments, each R 1 are independently -CR 2 R 2 -, CR 2 , C, N, -NR 2 -, or -O-. In some embodiments, each R 1 are independently -CR 2 R 2 -, CR 2 , N, -NR 2 -, or -O-. In some embodiments, each R 1 are independently -CR 2 R 2 -, CR 2 , C, N, or -NR 2 In some embodiments, each R 1 are independently -CR 2 R 2 -, CR 2 , N, or -NR 2 In some embodiments, each R 1 are independently -CR 2 R 2 -, CR 2 , C, or —O—. In certain embodiments, each R 1 are independently -CR 2 R 2 -, CR 2 or -O-. In certain embodiments, each R 1 are independently -CR 2 R 2 -, CR 2 or C. In certain embodiments, each R 1 are independently -CR 2 R 2 - or CR 2 In some embodiments, each R 1 are independently -CR 2 R 2 - or CR 2 In some embodiments, each R 1 are independently -CR 2 R 2 - or CR 2and q is 3. In some embodiments, each R 1 are independently -CR 2 R 2 - or CR 2 and q is 4. In some embodiments, each R 1 are independently -CR 2 R 2 - or CR 2 and q is 5. In some embodiments, each R 1 are independently -CR 2 R 2 - or CR 2 and q is 6.

[0078] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, each R 1 are independently a bond or -CR 2 R 2 - and; [ka] represents a single or double bond.

[0079] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, each R 1 are independently a bond or -CR 2 R 2 -It is.

[0080] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, each R 1 are independently a bond or -CR 2R 2 - and; [ka] represents a single or double bond.

[0081] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, each R 1 are independently a bond or -CR 2 R 2 -It is.

[0082] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, each R 1 are independently a bond or -CR 2 R 2 - and; [ka] represents a single or double bond.

[0083] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, each R 1 are independently a bond or -CR 2 R 2 -It is.

[0084] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0085] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0086] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0087] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0088] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0089] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0090] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0091] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0092] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0093] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0094] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0095] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0096] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0097] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0098] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0099] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0100] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0101] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0102] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0103] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0104] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0105] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0106] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0107] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0108] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0109] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0110] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0111] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0112] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0113] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0114] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, R 2is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl. 2 is substituted alkyl or substituted heteroaryl. In some embodiments, R 2 is haloalkyl or substituted triazolyl. 2 is fluoromethyl or triazolyl substituted with 2,4-difluorophenyl.

[0115] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0116] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, R 2 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl. 2 is substituted alkyl or substituted heteroaryl. In some embodiments, R 2 is haloalkyl or substituted triazolyl. 2 is fluoromethyl or triazolyl substituted with 2,4-difluorophenyl.

[0117] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0118] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0119] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0120] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0121] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0122] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0123] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0124] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl. In some embodiments, two 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.

[0125] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, X is —O—, —NR 2 - or -CR 2 R 2 -It is.

[0126] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, R represents 1 to 4 independent R 2 The group is optionally substituted.

[0127] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, R represents 1 to 4 independent R 2 The group is optionally substituted.

[0128] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, R represents 1 to 4 independent R 2 The group is optionally substituted.

[0129] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0130] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0131] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0132] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0133] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, R 2 is halogen. In some embodiments, R 2 is fluoro.

[0134] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0135] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, R 2 is halogen. In some embodiments, R 2 is fluoro.

[0136] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl of In the formula, R represents 1 to 4 independent R 2 The group is optionally substituted.

[0137] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0138] In some embodiments, R is a group of the formula: [ka] is a heterocyclyl.

[0139] base R 2 and t As described herein, R 2 each occurrence independently represents 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 het-aralkyl, 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(RA )2, -NR A S(O)2R A , -OS(O)2R A , or -S(O)R 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.

[0140] In some embodiments, R 2 each occurrence independently represents hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, a nitrogen protecting group if 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.

[0141] In some embodiments, R 2 each occurrence is independently selected from 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.

[0142] In some embodiments, R 2 Each occurrence of is independently selected from 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.

[0143] In some embodiments, R 2 Each occurrence of is 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.

[0144] In some embodiments, R 2 Each occurrence of R is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 2 Each occurrence of R is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted heteroaryl. 2 Each occurrence of R is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 2 Each occurrence of R is independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl. 2 Each occurrence of is independently halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl.

[0145] In some embodiments, R 2 Each occurrence of is independently [ka] or [ka] 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.

[0146] In some embodiments, R 2 Each occurrence of is independently [ka] or [ka] where R 20 is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -OR A , -N(R A )2, or -SR A and X is N or CH; and R 10 is hydrogen, [ka] or [ka] is.

[0147] In some embodiments, R 2 each occurrence independently represents hydrogen, fluoro, fluoromethyl, difluoromethyl, methyl, —OH, —CH2NH2, —CH2OH, —CHOAc, —C≡CH, [ka] or [ka] where R 20 is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -OR A , -N(R A )2, or -SR A and X is N or CH; and R 10 is hydrogen, [ka] or [ka] is.

[0148] In some embodiments, R 2 Each occurrence of is independently hydrogen, -OH, -CH2NH2, -CH2OH, -C≡CH, [ka] It is fluoro, fluoromethyl, difluoromethyl, or methyl.

[0149] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is —OH. In some embodiments, R 2 is —CH 2 NH 2 . In some embodiments, R 2 is —CHOH. In some embodiments, R 2 is —CH2OAc. In some embodiments, R 2 is -C≡CH. In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 is fluoro. In some embodiments, R 2 is fluoromethyl. In some embodiments, R 2 is difluoromethyl. In some embodiments, R 2 is methyl.

[0150] In some embodiments, R 2 Each occurrence of is independently fluoro, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl. 2Each occurrence of is independently fluoro, substituted or unsubstituted alkyl, or substituted or unsubstituted 5-membered heteroaryl. 2 Each occurrence of is independently fluoro, haloalkyl, unsubstituted alkyl, or substituted or unsubstituted 5-membered heteroaryl. 2 Each occurrence of may independently represent fluoro, C 1-6 Haloalkyl, unsubstituted C 1-6 alkyl, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 2 Each occurrence of may independently represent fluoro, C 1-4 Haloalkyl, unsubstituted C 1-4 alkyl, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 2 Each occurrence of may independently represent fluoro, C 1-3 Haloalkyl, unsubstituted C 1-3 alkyl, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 2 Each occurrence of may independently represent fluoro, C 1-2 Haloalkyl, unsubstituted C 1-2 alkyl, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 2 Each occurrence of R is independently fluoro, fluoromethyl, methyl, or substituted or unsubstituted triazolyl. 2 Each occurrence of R is independently fluoro, fluoromethyl, methyl, or substituted triazolyl. 2 each occurrence is independently fluoro, fluoromethyl, methyl, or [ka] is.

[0151] In some embodiments, R 2 Each occurrence of R is fluoro or methyl. 2 Each occurrence of R is fluoromethyl or methyl. 2Each occurrence of R is a substituted or unsubstituted triazolyl or methyl. 2 Each occurrence of R is a substituted triazolyl or methyl. 2 Each occurrence of [ka] is.

[0152] In some embodiments, R 2 Each occurrence of is independently halogen, substituted or unsubstituted alkyl, or -OR A In some embodiments, R 2 Each occurrence of is independently fluoro, substituted or unsubstituted alkyl, or -OR A In some embodiments, R 2 Each occurrence of is independently fluoro, substituted or unsubstituted alkyl, or —OH. 2 Each occurrence of is independently fluoro, unsubstituted alkyl, or —OH. 2 Each occurrence of is independently fluoro, unsubstituted C 1-6 alkyl, or —OH. In some embodiments, R 2 Each occurrence of is independently fluoro, unsubstituted C 1-4 alkyl, or —OH. In some embodiments, R 2 Each occurrence of is independently fluoro, unsubstituted C 1-3 alkyl, or —OH. In some embodiments, R 2 Each occurrence of is independently fluoro, unsubstituted C 1-3 alkyl, or —OH. In some embodiments, R 2 Each occurrence of is independently fluoro, methyl, or —OH.

[0153] In some embodiments, R 2 Each occurrence of R is independently hydrogen or substituted or unsubstituted alkyl. 2 Each occurrence of R is independently hydrogen or unsubstituted alkyl. 2Each occurrence of is independently hydrogen or unsubstituted C 1-6 In some embodiments, R 2 Each occurrence of is independently hydrogen or unsubstituted C 1-4 In some embodiments, R 2 Each occurrence of is independently hydrogen or unsubstituted C 1-3 In some embodiments, R 2 Each occurrence of is independently hydrogen or unsubstituted C 1-2 In some embodiments, R 2 Each occurrence of is independently hydrogen or methyl.

[0154] In some embodiments, R 2 Each occurrence of is independently substituted or unsubstituted alkyl. In some embodiments, R 2 Each occurrence of is independently unsubstituted alkyl. In some embodiments, R 2 Each occurrence of is independently an unsubstituted C 1-6 In some embodiments, R 2 Each occurrence of is independently an unsubstituted C 1-4 In some embodiments, R 2 Each occurrence of is independently an unsubstituted C 1-3 In some embodiments, R 2 Each occurrence of is independently an unsubstituted C 1-2 In some embodiments, R 2 Each occurrence of is independently methyl.

[0155] As described herein, t is an integer from 0 to 12. In some embodiments, t is 0 to 6. In some embodiments, t is 1 to 6. In some embodiments, t is 0 to 4. In some embodiments, t is 1 to 4. In some embodiments, t is 0 to 2. In some embodiments, t is 1 or 2. In some embodiments, t is 0 or 1. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 5. In some embodiments, t is 6. In some embodiments, t is 7. In some embodiments, t is 8. In some embodiments, t is 9. In some embodiments, t is 10. In some embodiments, t is 11. In some embodiments, t is 12.

[0156] Embodiments of formula (I) In some embodiments, the compound of formula (I) has the formula (Ia): [ka] (Ia) or a pharmaceutically acceptable salt thereof, wherein A, P, R, R 2 , R 7 , and t is as defined herein.

[0157] In some embodiments, the compound of formula (I) has the formula (Ib): [ka] (Ib) or a pharmaceutically acceptable salt thereof, wherein R 1 is -NR2-, -O-, or -S-; and A, P, R, R 2 , R 7 , and t is as defined herein.

[0158] In some embodiments, the compound of formula (I) has the formula (Ic): [ka] (I C) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , R 7 , and t is as defined herein.

[0159] In some embodiments, the compound of formula (I) has the formula (Id): [ka] (Id) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently bonded, -CR 2 R 2 -, CR 2 , C, N, -NR 2 -, -O-, or S; q is 3 to 6; and A, P, R 2 , and R 7 is as defined herein.

[0160] In some embodiments, the compound of formula (I) has the formula (Ie): [ka] (Ie) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 - and; [ka] represents a single or double bond; and A, P, R 2 , and R 7 is as defined herein.

[0161] In some embodiments, the compound of formula (I) has the formula (Ie-1): [ka] (Ie-1) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 and A, P, R 2 and R 7 is as defined herein.

[0162] In some embodiments, the compound of formula (I) has the formula (If): [ka] (If) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 - and; and A, P, R 2 and R 7 is as defined herein.

[0163] In some embodiments, the compound of formula (I) has the formula (If-1): [ka] (If-1) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 and A, P, R 2 and R 7 is as defined herein.

[0164] In some embodiments, the compound of formula (I) has the formula (If-2): [ka] (If-2) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 and A, P, R 2 and R 7 is as defined herein.

[0165] In some embodiments, the compound of formula (I) has the formula (If-3): [ka] (If-3) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 and A, P, R 2 and R 7 is as defined herein.

[0166] In some embodiments, the compound of formula (I) has the formula (If-4): [ka] (If-4) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 and A, P, R 2 and R 7 is as defined herein.

[0167] In some embodiments, the compound of formula (I) has the formula (If-5): [ka] (If-5) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R2 and A, P, R 2 and R 7 is as defined herein.

[0168] In some embodiments, the compound of formula (I) has the formula (Ig): [ka] (Ig) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 and A, P, R 2 and R 7 is as defined herein.

[0169] In some embodiments, the compound of formula (I) has the formula (Ig-1): [ka] (Ig-1) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 and A, P, R 2 and R 7 is as defined herein.

[0170] In some embodiments, the compound of formula (I) has the formula (Ig-2): [ka] (Ig-2) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 and A, P, R 2 and R 7 is as defined herein.

[0171] In some embodiments, the compound of formula (I) has the formula (Ig-3): [ka] (Ig-3) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 and A, P, R 2 and R 7 is as defined herein.

[0172] In some embodiments, the compound of formula (I) has the formula (Ig-4): [ka] (Ig-4) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 and A, P, R 2 and R 7 is as defined herein.

[0173] In some embodiments, the compound of formula (I) has the formula (Ig-5): [ka] (Ig-5) or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently a bond or -CR 2 R 2 and A, P, R 2 and R 7 is as defined herein.

[0174] In some embodiments, the compound of formula (I) has the formula (Ih): [ka] (Ih) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0175] In some embodiments, the compound of formula (I) has the formula (Ih-1): [ka] (Ih-1) or a pharmaceutically acceptable salt thereof, wherein A, P, and R 7 is as defined herein.

[0176] In some embodiments, the compound of formula (I) has the formula (Ih-2): [ka] (Ih-2) or a pharmaceutically acceptable salt thereof, wherein A, P, and R 7 is as defined herein.

[0177] In some embodiments, the compound of formula (I) has the formula (Ii): [ka] (II) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0178] In some embodiments, the compound of formula (I) has the formula (Ii-1): [ka] (Ii-1) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0179] In some embodiments, the compound of formula (I) has the formula (Ii-2): [ka] (Ii-2) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0180] In some embodiments, the compound of formula (I) has the formula (Ii-3): [ka] (Ii-3) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0181] In some embodiments, the compound of formula (I) has the formula (Ii-4): [ka] (Ii-4) or a pharmaceutically acceptable salt thereof, wherein A, P, and R 7 is as defined herein.

[0182] In some embodiments, the compound of formula (I) has the formula (Ii-5): [ka] (Ii-5) or a pharmaceutically acceptable salt thereof, wherein A, P, and R 7is as defined herein.

[0183] In some embodiments, the compound of formula (I) has the formula (Ii-6): [ka] (Ii-6) or a pharmaceutically acceptable salt thereof, wherein A, P, and R 7 is as defined herein.

[0184] In some embodiments, the compound of formula (I) has the formula (Ii-7): [ka] (Ii-7) or a pharmaceutically acceptable salt thereof, wherein A, P, and R 7 is as defined herein.

[0185] In some embodiments, the compound of Formula (I) has the formula (Ii-8): [ka] (Ii-8) or a pharmaceutically acceptable salt thereof, wherein A is as defined herein.

[0186] In some embodiments, the compound of formula (I) has the formula (Ij): [ka] (Ij) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0187] In some embodiments, the compound of formula (I) has the formula (Ij-1): [ka] (Ij-1) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0188] In some embodiments, the compound of formula (I) has the formula (Ij-2): [ka] (Ij-2) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0189] In some embodiments, the compound of formula (I) has the formula (Ij-3): [ka] (Ij-3) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0190] In some embodiments, the compound of formula (I) has the formula (Ij-4): [ka] (Ij-4) or a pharmaceutically acceptable salt thereof, wherein A, P, and R 7 is as defined herein.

[0191] In some embodiments, the compound of formula (I) has the formula (Ij-5): [ka] (Ij-5) or a pharmaceutically acceptable salt thereof, wherein A, P, and R 7 is as defined herein.

[0192] In some embodiments, the compound of formula (I) has the formula (Ij-6): [ka] (Ij-6) or a pharmaceutically acceptable salt thereof, wherein A, P, and R 7 is as defined herein.

[0193] In some embodiments, the compound of formula (I) has the formula (Ik): [ka] (Ik) or a pharmaceutically acceptable salt thereof, wherein A, P, and R 7 is as defined herein.

[0194] In some embodiments, the compound of formula (I) has the formula (Ik-1): [ka] (Ik-1) or a pharmaceutically acceptable salt thereof, wherein A, P, and R 7 is as defined herein.

[0195] In some embodiments, the compound of formula (I) has the formula (Il): [ka] (Il) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7is as defined herein.

[0196] In some embodiments, the compound of formula (I) has the formula (Il-1): [ka] (Il-1) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0197] In some embodiments, the compound of formula (I) has the formula (Il-2): [ka] (Il-2) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein. In certain embodiments of compounds of formula (Il-2), R 2 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl. In certain embodiments of compounds of formula (Il-2), R 2 is substituted alkyl or substituted heteroaryl. In certain embodiments of compounds of formula (Il-2), R 2 is haloalkyl or substituted triazolyl. In certain embodiments of compounds of formula (Il-2), R 2 is fluoromethyl or triazolyl substituted with 2,4-difluorophenyl.

[0198] In some embodiments, the compound of formula (I) has the formula (Il-3): [ka] (Il-3) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7is as defined herein. In certain embodiments of compounds of formula (Il-3), R 2 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl. In certain embodiments of compounds of formula (Il-3), R 2 is substituted alkyl or substituted heteroaryl. In certain embodiments of compounds of formula (Il-3), R 2 is haloalkyl or substituted triazolyl. In certain embodiments of compounds of formula (Il-3), R 2 is fluoromethyl or triazolyl substituted with 2,4-difluorophenyl.

[0199] In some embodiments, the compound of formula (I) has the formula (Il-4): [ka] (Il-4) or a pharmaceutically acceptable salt thereof, wherein A and R 2 is as defined herein. In certain embodiments of compounds of formula (II-4), R 2 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl. In certain embodiments of compounds of formula (Il-4), R 2 is substituted alkyl or substituted heteroaryl. In certain embodiments of compounds of formula (Il-4), R 2 is haloalkyl or substituted triazolyl. In certain embodiments of compounds of formula (Il-4), R 2 is fluoromethyl or triazolyl substituted with 2,4-difluorophenyl.

[0200] In some embodiments, the compound of formula (I) has the formula (Im): [ka] (Im) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7is as defined herein.

[0201] In some embodiments, the compound of formula (I) has the formula (Im-1): [ka] (Im-1) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0202] In some embodiments, the compound of formula (I) has the formula (Im-2): [ka] (Im-2) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein.

[0203] In some embodiments, the compound of formula (I) has the formula (Im-3): [ka] (Im-3) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein. In certain embodiments of compounds of formula (Im-3), R 2 is halogen. In certain embodiments of compounds of formula (Im-3), R 2 is fluoro.

[0204] In some embodiments, the compound of formula (I) has the formula (Im-4): [ka] (Im-4) or a pharmaceutically acceptable salt thereof, wherein A, P, R 2 , and R 7 is as defined herein. In certain embodiments of compounds of formula (Im-4), R 2 is halogen. In certain embodiments of compounds of formula (Im-4), R 2 is fluoro.

[0205] In some embodiments, the compound of formula (I) has the formula (Im-5): [ka] (Im-5) or a pharmaceutically acceptable salt thereof, wherein A and R 2 is as defined herein. In certain embodiments of compounds of formula (Im-5), R 2 is halogen. In certain embodiments of compounds of formula (Im-5), R 2 is fluoro.

[0206] In some embodiments, the compound of formula (I) has the formula (In): [ka] (In) or a pharmaceutically acceptable salt thereof, wherein A, R 2 , and R 7 is as defined herein.

[0207] In some embodiments, the compound of formula (I) has the formula (In-1): [ka] (In-1) or a pharmaceutically acceptable salt thereof, wherein A and R 2 is as defined herein.

[0208] In some embodiments, the compound of formula (I) has the formula (In-2): [ka] (In-2) or a pharmaceutically acceptable salt thereof, wherein B, R 2 , R 8 , R 9 , and p is as defined herein.

[0209] In some embodiments, the compound of formula (I) has the formula (In-3): [ka] (In-3) or a pharmaceutically acceptable salt thereof, wherein R 2 , R 8 , R 9 , X, Y, n, and p are as defined herein.

[0210] In some embodiments, the compound of formula (I) has the formula (In-4): [ka] (In-4) or a pharmaceutically acceptable salt thereof, wherein R 2 , R 8 , R 9 , Y, and P are as defined herein.

[0211] In some embodiments, the compound of formula (I) has the formula (In-5): [ka] (In-5) or a pharmaceutically acceptable salt thereof, wherein R 2 , R 8 , R 9 , Y, and P are as defined herein.

[0212] In some embodiments, the compound of formula (I) has the formula (In-6): [ka] (In-6) or a pharmaceutically acceptable salt thereof, wherein R 2 , R 8 , R 9 , Y, and P are as defined herein.

[0213] In some embodiments, the compound of formula (I) has the formula (In-7): [ka] (In-7) or a pharmaceutically acceptable salt thereof, wherein R 2 , R 8 , R 9 is as defined herein.

[0214] In some embodiments, the compound of formula (I) has the formula (In-8): [ka] (In-8) or a pharmaceutically acceptable salt thereof, wherein R 2 , R 8 , and R 9 is as defined herein.

[0215] In some embodiments, the compound of formula (I) has the formula (In-9): [ka] (In-9) or a pharmaceutically acceptable salt thereof, wherein R 2 , R 8 , and R 9 is as defined herein.

[0216] In some embodiments, the compound of formula (I) has the formula (In-10): [ka] (In-10) or a pharmaceutically acceptable salt thereof, wherein R 2 , R 8 , and R 9 is as defined herein.

[0217] In some embodiments, the compound of formula (I) has the formula (In-11): [ka] (In-11) or a pharmaceutically acceptable salt thereof, wherein R 2 and R 9 is as defined herein.

[0218] In some embodiments, the compound of formula (I) has the formula (In-12): [ka] (In-12) or a pharmaceutically acceptable salt thereof, wherein R 2 and R 9 is as defined herein.

[0219] In some embodiments, the compound of formula (I) has the formula (In-13): [ka] (In-13) or a pharmaceutically acceptable salt thereof, wherein R 2 and R 9 is as defined herein.

[0220] In some embodiments, the compound of formula (I) has the formula (In-14): [ka] (In-14) or a pharmaceutically acceptable salt thereof, wherein R 2 is as defined herein.

[0221] In some embodiments, the compound of formula (I) has the following formula: [ka] [ka] and pharmaceutically acceptable salts thereof.

[0222] In some embodiments, the compound of formula (I) has the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, the compound of formula (I) has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein each R 11 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or a nitrogen protecting group; or two R 11 The groups are linked to form a substituted or unsubstituted heterocyclyl ring. In some embodiments, -N(R 11 )2 is, [ka] ,or [ka] is.

[0224] In some embodiments, the compound of formula (I) has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the compound of formula (I) has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein each R 11 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, a nitrogen protecting group; or two R 11 The groups are linked to form a substituted or unsubstituted heterocyclyl ring. In some embodiments, -N(R 11 )2 is, [ka] or [ka] is.

[0226] In some embodiments, the compound of formula (I) has the formula: [ka] 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 is hydrogen, [ka] [ka] or [ka] is.

[0227] In some embodiments, the compound of formula (I) has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein X is N or CH; and R 10 is hydrogen, [ka] or [ka] is.

[0228] Exemplary Compounds Exemplary compounds of formula (I) include, but are not limited to, those listed in Table 1. [Table 1-1] [Table 1-2] [Table 1-3]

[0229] Exemplary compounds of Formula (I) include, but are not limited to, the compounds listed in Table 2. [Table 2-1] [Table 2-2] [Table 2-3]

[0230] Exemplary compounds of Formula (I) include, but are not limited to, the compounds listed in Table 3. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8]

[0231] Preparation of Compounds of Formula (I) Exemplary methods that may be used in preparing the compounds of the present disclosure are described below and should not be construed as limiting. The compounds herein may also be prepared by other methods of synthesis known in the art, and the procedures described herein may be modified or combined with other known methods.

[0232] In another aspect, 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. Scheme 1.

number

[0233] For all intermediates, A, P, R 1 , R 2 , and R 7 is as defined herein for compounds of formula (I) unless otherwise stated.

[0234] In some embodiments, ring-closing metathesis is achieved through the use of a transition metal catalyst. In some embodiments, the transition metal catalyst is a tungsten (W), molybdenum (Mo), or ruthenium (Ru) catalyst. In some embodiments, the catalyst is a ruthenium catalyst.

[0235] For examples of olefin metathesis reagents, catalysts, and reaction conditions useful in the present method, see, for example, Schrodi, Y.; Pederson, R.L. Aldrichimica Acta 2007, 40, 45; Adv. Synth. Catal. 2007, 349, 1-268; Grubbs, R.H. Tetrahedron 2004, 60, 7117; Handbook of Metathesis; Grubbs, R.H., Ed.; Wiley-VCH: Weinheim, 2003; Vols. 1-3; Trnka, T.M.; Grubbs, R.H. Acc. Chem. Res. 2001, 34, 18; Fürstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012; Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2036;Ritter, T. et al. Organometallics 2006, 25, 5740;Chatterjee, AK et al. J. Am. Chem. Soc. 2000, 122, 3783;Chatterjee, AK; Grubbs, RH Org. Lett. 1999, 1, 1751;Murelli, RP; Snapper, ML Org. Lett. 2007, 9, 1749;Stewart, IC et al. Org. Lett. 2007, 9, 1589;Ung, T. et al. Organometallics 2004, 23, 5399;Benitez, D.; Goddard, WA, III. J. Am. Chem. Soc. 2005, 127, 12218;Love, JA et 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 the references cited therein; each of which is incorporated herein by reference.

[0236] In some embodiments, the metathesis catalyst is a Grubbs catalyst. In some embodiments, the Grubbs catalyst has the formula: [ka] Things, Benzylidenebis-(tricyclohexylphosphine)dichlororuthenium (X=Cl); benzylidenebis-(tricyclohexylphosphine)dibromoruthenium (X=Br); benzylidenebis-(tricyclohexylphosphine)diiodoruthenium (X=I); [ka] 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tricyclohexyl-phosphine)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-( 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(triphenylphosphine)ruthenium (X=I; R=cyclohexyl); 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(triphenylphosphine)ruthenium (X=Cl; R=phenyl); 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tribenzylphosphine)ruthenium (X=Cl; R=benzyl); [ka] [ka] or [ka] is.

[0237] In some embodiments, the metathesis catalyst has the formula: [ka] This is the second generation Grubbs catalyst (Grubbs II).

[0238] In some embodiments, the metathesis catalyst is a Grubbs-Hoveyda catalyst. [ka] or [ka] It is of the type.

[0239] 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 depicted in Scheme 2 below. Scheme 2.

number

[0240] In some embodiments, the formation of the amide bond is facilitated by an amide coupling reagent (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), or the like, or a combination thereof). In some embodiments, the amide coupling reagent (e.g., HATU, EDC, HOBt) is reacted with a compound of Formula (C). In some embodiments, the amide coupling reagent (e.g., HATU, EDC, HOBt) is reacted with a compound of Formula (C) prior to amide coupling with a compound of Formula (B) or (B1). In some embodiments, the amide coupling reagent is HATU.

[0241] In some embodiments, the method includes 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 reagent. In some embodiments, the method includes carrying out the coupling reaction at room temperature, ambient temperature, or an elevated temperature. In some embodiments, the method includes 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.

[0242] In some embodiments, an additional reagent may be added to the amide bond forming reaction. In some embodiments, the additional reagent may facilitate amide coupling by protecting the free hydroxyl of the compound of Formula (B) or (B1). In some embodiments, the additional reagent is a silylating reagent. In some embodiments, the silylating reagent reacts with the free hydroxyl group of the compound of Formula (B) or (B1) to form a silyl protecting group in situ during the reaction. In some embodiments, the additional reagent is added to the compound of Formula (B) or (B1) prior to amide coupling. In some 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 silylating reagent.

[0243] In another aspect, compounds of the present disclosure are prepared by a process comprising 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 depicted in Scheme 3.

[0244] In certain embodiments, ring-closing metathesis is achieved through the use of any of the catalysts and conditions described herein. Scheme 3.

number

number

[0245] For all intermediates, A, P, R 1 , R 2 , and R 7 is as defined herein for compounds of formula (I) unless otherwise stated. In certain embodiments, R 7is substituted or unsubstituted acetyl. In some embodiments, R 7 is trifluoroacetyl.

[0246] 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 depicted in Scheme 4 below. Scheme 4.

number

[0247] In some embodiments, the formation of the amide bond is promoted by an amide coupling reagent (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), or the like, or a combination thereof). In some embodiments, the amide coupling reagent (e.g., HATU, EDC, HOBt) is reacted with a compound of Formula (C). In some embodiments, the amide coupling reagent (e.g., HATU, EDC, HOBt) is reacted with a compound of Formula (C) prior to amide coupling with a compound of Formula (E) or (E1). In some embodiments, the amide coupling reagent is HATU.

[0248] In some embodiments, the method includes 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 reagent. In some embodiments, the method includes carrying out the coupling reaction at room temperature, ambient temperature, or an elevated temperature. In some embodiments, the method includes 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.

[0249] In some embodiments, an additional reagent may be added to the amide bond forming reaction. In some embodiments, the additional reagent may facilitate amide coupling by protecting the free hydroxyl of the compound of Formula (E) or (E1). In some embodiments, the additional reagent is a silylating reagent. In some embodiments, the silylating reagent reacts with the free hydroxyl group of the compound of Formula (E) or (E1) to form a silyl protecting group in situ during the reaction. In some embodiments, the additional reagent is added to the compound of Formula (E) or (E1) prior to amide coupling. In some 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 silylating reagent.

[0250] Pharmaceutical Compositions and Administration The present disclosure provides a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0251] The present disclosure provides a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., as appropriate for the particular dosage form desired. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, 16th Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0252] The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacology.

[0253] Generally, such preparation methods include the step of bringing the compound of the present invention into association with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into the desired single-dose or multi-dose unit. 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 that would be administered to a subject, and / or a convenient fraction of such a dose, for example, one-half or one-third of such a dose.

[0254] The relative amounts of compound, pharmaceutically acceptable excipient, and / or additional components in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, and also depending on the route by which the composition is to be administered. By way of example, the composition may contain from 0.1% to 100% (w / w) of compound.

[0255] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweeteners, flavoring agents, and perfumes may also be present in the compositions.

[0256] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, emulsifiers, and mixtures thereof.In addition to inert diluents, oral compositions may contain adjuvants such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavoring agents, and perfumes.In some embodiments for parenteral administration, the conjugate of the present invention is mixed with solubilizers and mixtures thereof.

[0257] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents.Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol.Among acceptable vehicles and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solution can be used.In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0258] 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, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) humectants, such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clay; 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 also comprise buffering agents.

[0259] Dosage forms for topical and / or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the compound is admixed under sterile conditions with a pharmaceutically acceptable carrier and / or any needed preservatives and / or buffers, as may be required.

[0260] Although the description of pharmaceutical compositions provided herein is directed primarily to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to animals of all kinds. The modification of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to various animals is well understood, and a veterinary pharmacologist of ordinary skill can design and / or perform such modifications by routine experimentation.

[0261] The compound provided herein is usually formulated in the form of dosage unit for ease of administration and dosage uniformity.However, it will be understood that the total daily amount of compound will be determined by attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject will depend on a variety of factors, including the disease, disorder or condition being treated and the severity of disease; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of subject; the time of administration, route of administration and the excretion rate of the specific compound used; the duration of treatment; the drug used in combination with the specific compound used or at the same time; and similar factors well known in the field of medicine.

[0262] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intracerebroventricular, transdermal, intradermal, rectal, vaginal, intraperitoneal, topical (by powder, ointment, cream, and / or liquid drop), 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 administration route will depend on various factors, including the nature of the agent, the treatment regimen, and / or the condition of the subject.Oral administration is the preferred mode of administration.However, in some embodiments, the subject may not be able to tolerate oral administration, and therefore intravenous, intramuscular, and / or rectal administration are also preferred alternative modes of administration.

[0263] An effective amount may be contained 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 applied to tissues or cells, any two doses of the multiple doses contain different or substantially the same amount of the compound described herein. In some embodiments, when multiple doses are administered to a subject or applied to tissues or cells, the frequency of administering multiple doses to a subject or applying multiple doses to tissues or cells is 3 doses per day, 2 doses per day, 1 dose per day, 1 dose every other day, 1 dose every 3 days, 1 dose every week, 1 dose every 2 weeks, 1 dose every 3 weeks, or 1 dose every 4 weeks. In certain embodiments, the doses described herein (e.g., either a single dose or 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 described herein.

[0264] It will also be understood that the compounds or compositions described herein can be administered in combination with one or more additional therapeutically active agents. The compounds or compositions can be administered simultaneously with, prior to, or subsequent to one or more additional therapeutically active agents. Generally, each agent will be administered at a dose and / or time schedule determined for that agent. It will also be understood that the additional therapeutically active agents utilized in this combination can be administered together in a single composition or separately in different compositions. The specific combination used in the regimen will take into account the compatibility of the compound of the present invention with the additional therapeutically active agent and / or the desired therapeutic effect to be achieved. Generally, it is expected that the additional therapeutically active agents utilized in the combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in the combination will be lower than those utilized individually.

[0265] Exemplary additional therapeutically active agents include, but are not limited to, antibiotics, antivirals, anesthetics, anticoagulants, enzyme inhibitors, steroidal agents, steroidal or nonsteroidal anti-inflammatory agents, antihistamines, immunosuppressants, antigens, vaccines, antibodies, decongestants, sedatives, opioids, pain relievers, analgesics, antipyretics, hormones, and prostaglandins. Therapeutically active agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the U.S. Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic peptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0266] In some embodiments, the additional therapeutically active agent is an antibiotic. Examples of antibiotics include 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., cotrimoxazole, trimethoprim), tetracyclines (e.g., tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxorubicin, thiazolinone ... These include, but are not limited to, xycline, aureomycin, terramycin, minocycline, 6-deoxytetracycline, lymecycline, meclocycline, methacycline, rolitetracycline, and glycylcycline antibiotics (e.g., tigecycline), aminoglycosides (e.g., gentamicin, tobramycin, paromomycin), aminocyclitols (e.g., spectinomycin), chloramphenicol, sparsomycin, and quinupristin / dalfopristin (Syndercid™).

[0267] Also encompassed by the present invention are kits (e.g., pharmaceutical packs). The provided kits may include a pharmaceutical composition or compound of the present invention and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser package, or other suitable container). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound of the present invention. In some embodiments, the pharmaceutical composition or compound of the present invention provided in the container and the second container are combined to form a single unit dosage form.

[0268] Treatment Methods and Uses The present disclosure contemplates the use of the compounds of the present invention for the treatment of infectious diseases, such as fungal, bacterial, viral, and / or parasitic infections. Lincosamides are generally known to exhibit antibacterial activity.

[0269] Thus, as generally described herein, provided are methods of treating infectious diseases, the methods comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Such methods can be carried out in vivo (i.e., by administration to the subject). "Treating," as used herein, encompasses therapeutic and prophylactic treatments.

[0270] In some 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 some embodiments, the method improves the condition of a subject suffering from an infectious disease. In some embodiments, the subject is suspected of having or confirmed to have an infectious disease.

[0271] In some embodiments, the effective amount is a prophylactically effective amount.For example, in some embodiments, the method prevents or reduces the possibility of infectious disease, for example, in some embodiments, the method comprises administering to a subject in need thereof a compound of the present disclosure in an amount sufficient to prevent or reduce the possibility of infectious disease.In some embodiments, the subject is at risk of infectious disease (for example, has been exposed to another subject suspected of having or confirmed to have infectious disease, or has been exposed to a pathogen, or is thought to have been exposed to a pathogen).

[0272] In one aspect, provided is a method of killing a microorganism (e.g., a fungus, bacteria, virus, parasite), the method comprising contacting the microorganism with an effective amount of a compound of the present disclosure. The compound may be contacted with the microorganism in vivo (e.g., in a subject in need thereof) or in vitro.

[0273] In another aspect, provided is a method of inhibiting the growth of a microorganism (e.g., a fungus, bacteria, virus, parasite), the method comprising contacting the microorganism with an effective amount of a compound of the present disclosure. The compound may be contacted with the microorganism in vivo (e.g., in a subject in need thereof) or in vitro.

[0274] In another aspect, provided is an in vitro method of inhibiting the growth of a pathogen, the method comprising contacting an effective amount of a compound of the invention with a pathogen (e.g., a bacterium, virus, fungus, or parasite) in a cell culture.

[0275] In another aspect, provided is an in vitro method for inhibiting the growth of a pathogen, the method comprising contacting a pathogen (e.g., a bacterium, a virus, a fungus, or a parasite) with an effective amount of a compound of the present disclosure. In another aspect, provided is a method for inhibiting protein synthesis with an effective amount of a compound of the present disclosure (e.g., by binding to the 23s portion of the 50S subunit of bacterial ribosomes, thereby preventing protein synthesis and causing premature release of peptidyl-tRNA from the ribosome). In some embodiments, inhibiting protein synthesis comprises inhibiting bacterial ribosomes with an effective amount of a compound of the present disclosure. Protein synthesis may be inhibited in vivo or in vitro.

[0276] As used herein, "infectious disease" and "microbial infection" are used interchangeably and refer to an infection by a pathogen, such as a fungus, bacterium, virus, or parasite. In some embodiments, the infectious disease is caused by a fungus, bacterium, 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 multidrug-tolerant or multidrug-resistant pathogen, e.g., the infectious disease is caused by a pathogen that does not grow or die in the presence of or as a result of other treatments.

[0277] In some embodiments, the infectious disease is a bacterial infection. For example, in some embodiments, provided is a method of treating a bacterial infection, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the compound has a mean inhibitory concentration (MIC) with respect to a particular bacterium of 50 μg / mL or less, 25 μg / mL or less, 20 μg / mL or less, 10 μg / mL or less, 5 μg / mL or less, 1 μg / mL or less, 0.5 μg / mL or less, or 0.25 μg / mL or less.

[0279] In some embodiments, the bacteria are sensitive (e.g., responsive to) or resistant to known commercially available compounds such as azithromycin, lincomycin, clindamycin, tetrithromycin, erythromycin, spiramycin, etc. In some embodiments, the bacteria are resistant to known compounds. For example, in some embodiments, the bacteria are lincomycin-resistant or clindamycin-resistant.

[0280] In some embodiments, the bacterial infection is resistant to other antibiotic (e.g., non-compound) therapies. For example, in some embodiments, the pathogen is vancomycin-resistant (VR). In some embodiments, the pathogen is methicillin-resistant (MR), e.g., in some embodiments, the bacterial infection is a methicillin-resistant S. aureus infection (MRSA infection). In some embodiments, the pathogen is quinolone-resistant (QR). In some embodiments, the pathogen is fluoroquinolone-resistant (FR).

[0281] Exemplary bacterial infections include, but are not limited to, infections by gram-positive bacteria (e.g., those of the phyla Actinobacteria, Firmicutes, or Tenericutes); gram-negative bacteria (e.g., those of the phyla Aquificae, Deinococcus-Thermus, Fibrobacteres / Chlorobi / Bacteroides (FCB), Fusobacteria, Gemmatimonadest, Nitrospirae, Planctomycetes / Verrucomicrobia / Chlamydiae (PVC), Proteobacteria, Spirochaetes, or Synergistetes); or other bacteria (e.g., those of the phyla Acidobacteria, Chlroflexi, Chrysiogenetes, Cyanobacteria, Deferrubacteres, Dictyoglomi, Thermodesulfobacteria, or Thermotogae).

[0282] In some embodiments, the bacterial infection is an infection caused by a gram-positive bacterium.

[0283] In some embodiments, the Gram-positive bacterium is a bacterium of the phylum Firmicutes.

[0284] In some embodiments, the bacterium is a member of the phylum Firmicutes and the genus Enterococcus, i.e., the bacterial infection is an Enterococcus 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.

[0285] In some embodiments, the bacterium is a member of the phylum Firmicutes and genus Staphylococcus, ie, the bacterial infection is a Staphylococcus infection. Exemplary Staphylococcus bacteria include S. arlettae, S. aureus, S. auricularis, S. capitis, S. caprae, S. carnous, S. chromogenes, S. cohii, S. condimenti, S. croceolyticus, S. delphini, S. devriesei, S. epidermis, S. equorum, S. felis, S. fluroettii, S. gallinarum, S. haemolyticus, S. hominis, S. hyicus, S. intermedius, S. kloosii, S. leei, S. lenus, S. lugdunesis, S. lutrae, S. lyticans, S. massiliensis, S. microti, S. muscae, S. nepalensis, S. pasteuri, S. penttenkoferi, S. piscifermentans, S. Staphylococcus infections include, but are not limited to, S. psuedointermedius, S. psudolugdensis, S. pulvereri, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleiferi, S. sciuri, S. simiae, S. simulans, S. stepanovicii, S. succinus, S. vitulinus, S. warneri, and S. xylosus. In some embodiments, the Staphylococcus infection is a S. aureus infection.

[0286] In some embodiments, the S. aureus has an efflux genotype (e.g., mef, msr). Bacteria with an efflux genotype actively pump drugs out of the cell via efflux pumps.

[0287] In some embodiments, the S. aureus has a methylase (e.g., erm) genotype. In some embodiments, erm is a bacterial gene class that encodes erythromycin ribosomal methylases, which methylate a single adenine in the 23S rRNA, which is itself a component of the 50S rRNA.

[0288] In some embodiments, the bacterium is a member of the genus Bacillus of the phylum Firmicutes, ie, the bacterial infection is a Bacillus infection. Exemplary Bacillus bacteria include B. alcalophilus, B. alvei, B. aminovorans, B. amyloliquefaciens, B. aneurinolyticus, B. anthracis, B. aquaemaris, B. atrophaeus, B. boroniphilus, B. brevis, B. caldolyticus, B. centrosporus, B. cereus, B. circulans, B. coagulans, B. firmus, B. flavothermus, B. fusiformis, B. globigii, B. infernus, B. larvae, B. laterosporus, B. lentus, B. licheniformis, B. megaterium, B. mesentericus, B. mucilaginosus, B. mycoides, B. natto, B. pantothenticus, B. polymyxa, B. pseudoanthracis, B. pumilus, B. Bacillus infections include, but are not limited to, B. schlegelii, B. sphaericus, B. sporothermodurans, B. stearothermophilus, B. subtilis, B. thermoglucosidasius, B. thuringiensis, B. vulgatis, and B. weihenstephanensis. In some embodiments, the Bacillus infection is a B. subtilis infection. In some embodiments, the B. subtilis has an efflux (e.g., mef, msr) genotype. In some embodiments, the B. subtilis has a methylase (e.g., erm) genotype.

[0289] In some embodiments, the bacterium is a member of the phylum Firmicutes and the genus Streptococcus, i.e., the bacterial infection is a Streptococcus 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. peroris, S. pneumoniae, S. pyogenes, S. ratti, S. salivarius, S. thermophilus, S. sanguinis, S. sobrinus, S. suis, S. uberis, S. vestibularis, S. viridans, and S. zooepidemicus. In some embodiments, the Streptococcus infection is a S. pyogenes infection. In some embodiments, the Streptococcus infection is a S. pneumoniae infection. In some embodiments, the S. pneumoniae has an efflux (e.g., mef, msr) genotype. In some embodiments, the S. pneumoniae has a methylase (e.g., erm) genotype.

[0290] In some embodiments, the bacterium is a member of the phylum Firmicutes and genus Clostridium, i.e., the bacterial infection is a Clostridium infection. Exemplary Clostridium bacteria include, but are not limited to, C. botulinum, C. difficile, C. perfringens, C. tetani, and C. sordellii.

[0291] In some embodiments, the compounds of the present disclosure are a safer alternative to clindamycin due to a reduced incidence of pseudomembranous colitis. In some embodiments, the compounds of the present disclosure have increased activity against Clostridium difficile (C. difficile) compared to clindamycin. In some embodiments, the compounds have a mean inhibitory concentration (MIC) with respect to C. difficile of 50 μg / mL or less, 25 μg / mL or less, 20 μg / mL or less, 10 μg / mL or less, 5 μg / mL or less, 1 μg / mL or less, 0.5 μg / mL or less, or 0.25 μg / mL or less.

[0292] In some embodiments, the bacterial infection is an infection caused by a gram-negative bacterium.

[0293] In some embodiments, the gram-negative bacterium is a bacterium of the phylum Proteobacteria and the genus Escherichia, i.e., the bacterial infection is an Escherichia infection. Exemplary Escherichia bacteria include, but are not limited to, E. albertii, E. blattae, E. coli, E. fergusonii, E. hermannii, and E. vulneris. In some embodiments, the Escherichia infection is an E. coli infection.

[0294] In some embodiments, the Gram-negative bacteria are bacteria of the phylum Proteobacteria and the genus Haemophilus, i.e., the bacterial infection is a Haemophilus infection. Exemplary Haemophilus bacteria include, but are not limited to, H. aegyptius, H. aphrophilus, H. avium, H. ducreyi, H. felis, H. haemolyticus, H. influenzae, H. parainfluenzae, H. paracuniculus, H. parahaemolyticus, H. pittmaniae, Haemophilus segnis, and H. somnus. In some embodiments, the Haemophilus infection is an H. influenzae infection.

[0295] In some embodiments, the Gram-negative bacterium is a bacterium of the phylum Proteobacteria and the genus Acinetobacter, i.e., the bacterial infection is an Acinetobacter infection. Exemplary Acinetobacter bacteria include, but are not limited to, A. baumannii, A. haemolyticus, and A. lwoffii. In some embodiments, the Acinetobacter infection is an A. baumannii infection.

[0296] In some embodiments, the Gram-negative bacterium is a bacterium of the phylum Proteobacteria and the genus Klebsiella, i.e., the bacterial infection is a Klebsiella infection. Exemplary Klebsiella bacteria include, but are not limited to, K. granulomatis, K. oxytoca, K. michiganensis, K. pneumoniae, K. quasipneumoniae, and K. variicola. In some embodiments, the Klebsiella infection is a K. pneumoniae infection.

[0297] In some embodiments, the Gram-negative bacterium is a bacterium of the phylum Proteobacteria and the genus Pseudomonas, i.e., the bacterial infection is a Pseudomonas infection. Exemplary Pseudomonas bacteria include, but are not limited to, P. aeruginosa, P. oryzihabitans, P. plecoglissicida, P. syringae, P. putida, and P. fluorscens. In some embodiments, the Pseudomonas infection is a P. aeruginosa infection.

[0298] In some embodiments, the Gram-negative bacterium is a bacterium of the phylum Bacteroides and genus Bacteroides, i.e., the bacterial infection is a Bacteroides infection. Exemplary Bacteroides bacteria include, but are not limited to, B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, and B. vulgatus. In some embodiments, the Bacteroides infection is a B. fragilis infection.

[0299] In some embodiments, the bacterial infection being treated is a Staphylococcus infection, a Streptococcus infection, an Enterococcus infection, an Acinetobacter infection, a Clostridium infection, a Bacteroides infection, an Escherichia infection, a Pseudomonas infection, a Neisseria infection, a Klebsiella infection, or a Haemophilus infection. In some embodiments, the bacterial infection being treated is a Staphylococcus infection, a Streptococcus infection, an Enterococcus infection, an Acinetobacter infection, an Escherichia infection, a Pseudomonas infection, or a Klebsiella infection.

[0300] In some embodiments, the bacterial infection is a dental infection, an abdominal infection, an abscess, pelvic inflammatory disease, or an anaerobic infection.

[0301] In some embodiments, the compounds are useful for treating acne, toxic shock syndrome, malaria, and reducing the risk of premature birth in women with bacterial vaginosis. In some embodiments, the compounds are useful for treating methicillin-resistant S. aureus.

[0302] In some embodiments, the bacterium is an atypical bacterium, ie, neither gram-positive nor gram-negative.

[0303] In some embodiments, the infectious disease is a parasitic infection. Thus, in some embodiments, provided is a method of treating a parasitic infection, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0304] In some 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 for a particular parasite. 50 (uM).

[0305] Exemplary parasites include, but are not limited to, Trypanosoma species (e.g., Trypanosoma cruzi, Trypansosoma brucei), Leishmania species, Giardia species, Trichomonas species, Entamoeba species, Naegleria species, Acanthamoeba species, Schistosoma species, Plasmodium species (e.g., P. flaciparum), Crytosporidium species, Isospora species, Balantidium species, Pneumocystis species, Babesia, Loa Loa, Ascaris lumbricoides, Dirofilaria immitis, and Toxoplasma species (e.g., T. gondii).

[0306] As generally described herein, the present disclosure further provides a method for treating inflammatory conditions, the method comprising administering an effective amount of a compound of the present disclosure or its pharmaceutically acceptable salt to a subject in need thereof. Such a method can be carried out in vivo (i.e., by administering to a subject) or in vitro (e.g., by contacting with a pathogen, tissue, or cell culture). "Treating" as used herein encompasses therapeutic treatment and prophylactic treatment.

[0307] In some embodiments, the effective amount is a therapeutically effective amount. For example, in some embodiments, the method slows the progression of an inflammatory condition in a subject. In some embodiments, the method improves the condition of a subject suffering from an inflammatory condition. In some embodiments, the subject is suspected of having an inflammatory condition or has been confirmed to have an inflammatory condition.

[0308] In some embodiments, the effective amount is a prophylactically effective amount. For example, in some embodiments, the method prevents or reduces the likelihood of an inflammatory condition, e.g., in some embodiments, the method comprises administering a compound of the present invention to a subject in need thereof in an amount sufficient to prevent or reduce the likelihood of an inflammatory condition. In some embodiments, the subject is at risk for an inflammatory condition.

[0309] The term "inflammatory disease" refers to a disease, disorder, or condition characterized by signs of pain (dolor, from production of noxious substances and nerve irritation), heat (calor, from vasodilation), redness (rubor, from vasodilation and increased blood flow), swelling (from tumors, excessive inflow or restricted outflow of fluid), and / or loss of function (function laesa, which may be partial or complete, temporary or permanent). Inflammation takes many forms, including, but not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotizing, obstructive, parenchymal, plastic, proliferative, productive, proliferative, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation.

[0310] In some embodiments, the inflammatory condition is an acute inflammatory condition (e.g., inflammation resulting from an infection). In some embodiments, the inflammatory condition is a chronic inflammatory condition. In some embodiments, the inflammatory condition is inflammation associated with cancer.

[0311] definition chemical terms The definitions of specific functional groups and chemical terms are described in more detail below. Elements are identified according to the Periodic Table of the Elements, CAS version, on the inside cover of Handbook of Chemistry and Physics, 75th edition, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry, as well as specific functional groups and reactivity, are 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.

[0312] The peptides described herein may contain one or more asymmetric centers, and therefore can exist in various stereoisomeric forms, such as enantiomers and / or diastereomers.For example, the peptides described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched with one or more stereoisomers).Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; Alternatively, preferred isomers can 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, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0313] In the formula: [ka] is a single bond where the stereochemistry of the moiety directly attached to it is not specified (e.g., cis or trans alkene); [ka] is absent or a single bond, [ka] or [ka] is a single or double bond.

[0314] 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, the replacement of hydrogen with deuterium or tritium. 19 F 18 Replaced by F, or 12 C 13 C or 14 Compounds having the structures of the present invention, except for replacement by C, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0315] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It is intended to encompass alkyl.

[0316] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0317] The term "alkyl" refers to the radical of a straight-chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples 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-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional 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 (e.g., unsubstituted C 1-6Alkyl, e.g., —CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In some embodiments, the alkyl group is substituted C 1-10 Alkyl (e.g., substituted C 1-6 alkyl, for example, -CF3, Bn).

[0318] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodo. In certain embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 Examples of haloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl.

[0319] 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, located within the parent chain (i.e., inserted between adjacent carbon atoms thereof) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and one or more heteroatoms within the parent chain ("heteroC 1-10In some embodiments, heteroalkyl groups are saturated groups having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroalkyl"). C1-9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-8 In some embodiments, heteroalkyl groups are saturated groups having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroalkyl"). C1-7 In some embodiments, heteroalkyl groups are saturated groups having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroalkyl"). C1-6 In some embodiments, heteroalkyl groups are saturated groups having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-5 In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-4 In some embodiments, heteroalkyl groups are saturated groups having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-3 In some embodiments, heteroalkyl groups are saturated groups having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-2 In some embodiments, heteroalkyl groups are saturated groups having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, heteroalkyl groups are saturated groups having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-10 In some embodiments, the heteroalkyl group is a substituted heteroC 1-10 It is alkyl.

[0320] The term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has from 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). 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 alkenyl groups include the aforementioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In some embodiments, the alkenyl group is a substituted C 2-10In an alkenyl group, a C=C double bond about which the stereochemistry is not specified (e.g., -CH=CHCH3 or [ka] may be an (E)- or (Z)-double bond.

[0321] 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, located within the parent chain (i.e., inserted between adjacent carbon atoms thereof) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroalkenyl"). 2-10 In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 2-3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-10 In some embodiments, the heteroalkenyl group is a substituted heteroC 2-10 It is alkenyl.

[0322] The term "alkynyl" refers to a straight-chain or branched hydrocarbon radical having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., 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 alkenyl groups include the aforementioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In some embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0323] 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, located within the parent chain (i.e., inserted between adjacent carbon atoms thereof) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroalkynyl"). 2-10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-8In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2-3 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("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 some embodiments, the heteroalkynyl group is a substituted heteroC 2-10 It is alkynyl.

[0324] The term "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms ("C 3-14 refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include, without limitation, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. Exemplary C 3-8 The carbocyclyl group may be any of the aforementioned C 3-6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 The carbocyclyl group may be any of the aforementioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the above examples illustrate, in certain embodiments, carbocyclyl groups are either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing fused, bridged, or spiro ring systems, such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl"), and can be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring; in such cases, the number of carbons continues to designate the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, a carbocyclyl group is an unsubstituted C 3-14 In some embodiments, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0325] In certain embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-14 In some embodiments, the cycloalkyl group is a substituted C 3-14 It is cycloalkyl.

[0326] "Carbocyclylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a carbocyclyl group, where the point of attachment is on the alkyl portion.

[0327] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be on a carbon atom or on the nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic (a "monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as a bicyclic system (a "bicyclic heterocyclyl") or a tricyclic system (a "tricyclic heterocyclyl")) and can be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also encompasses 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 either the carbocyclyl ring or the heterocyclyl ring), or to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocyclyl ring); in such cases, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

[0328] In certain embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heterocyclyl"). In certain embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In certain embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In certain embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, a 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0329] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1, 4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]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.

[0330] "Heterocyclylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heterocyclyl group, where the point of attachment is on the alkyl portion.

[0331] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared among the ring array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl"; e.g., anthracyl). "Aryl" also encompasses ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring; in such cases, the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In some embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0332] "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.

[0333] The term "heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared among the cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. 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 with one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also encompasses ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, where the point of attachment is on either the aryl or heteroaryl ring; in such cases, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. For polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring containing the heteroatom (e.g., 2-indolyl) or on the ring without the heteroatom (e.g., 5-indolyl).

[0334] In certain embodiments, heteroaryl groups are 5-10 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In certain embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In certain embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In certain embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0335] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0336] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, where the point of attachment is on the alkyl portion.

[0337] The addition of the suffix "-ene" to a group indicates that the group is a divalent component, for example, alkylene is a divalent component of alkyl, alkenylene is a divalent component of alkenyl, alkynylene is a divalent component of alkynyl, heteroalkylene is a divalent component of heteroalkyl, heteroalkenylene is a divalent component of heteroalkenyl, heteroalkynylene is a divalent component of heteroalkynyl, carbocyclylene is a divalent component of carbocyclyl, heterocyclylene is a divalent component of heterocyclyl, arylene is a divalent component of aryl, and heteroarylene is a divalent component of heteroaryl.

[0338] Unless expressly specified otherwise, a group is optionally substituted. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to a group that may be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen atom present on a group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position is substituted in any given structure, the substituents are either the same or different at each position. The term "substituted" is intended to encompass substitution with all acceptable substituents of organic compounds and includes any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents, as described herein, that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The present invention is not intended to be limited in any way by the exemplary substituents described herein.

[0339] Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —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)Raa , -Si(R aa )3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR 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 Perhaloalkyl, 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 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14aryl, and 5- to 14-membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; Alternatively, two geminal hydrogens on a carbon atom can be bonded to the 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 has been replaced by; R aa Independently, for each case, C 1-10 Alkyl, C 1-10 Perhaloalkyl, 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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb In each case, independently, 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 Perhaloalkyl, 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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R cc In each case, independently, hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, 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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd In each case, independently, halogen, -CN, -NO 2、 -N 3、 -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(=NR ff )N(R ff )2, -NR ffSO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, 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 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg or substituted with two geminal R dd The substituents can be linked to form =O or =S; R ee Independently, for each case, C 1-6 Alkyl, C 1-6 Perhaloalkyl, 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 Carbocyclyl, C 6-10aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff In each case, independently, hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, 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 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, or two R ff The groups are linked to form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; and R gg In each case, 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 1-6alkyl), -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)(C 1-6 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(C1-6 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 Perhaloalkyl, 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 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents can be linked to form =O or =S; where X - is the counter ion.

[0340] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0341] The term "hydroxyl" or "hydroxy" refers to the group -OH. The term "substituted hydroxyl" or "substituted hydroxy" by extension refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen, such as -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(=NRbb )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 is as defined herein.

[0342] The term "amino" refers to the group -NH. The term "substituted amino" by extension refers to mono-, di-, or tri-substituted amino. In some embodiments, "substituted amino" is a mono- or di-substituted amino group.

[0343] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one non-hydrogen group, such as -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc )2, and -NHP(=O)(NR bb )2, where R aa , R bb , and R cc is as defined herein, and wherein —NH(R bb ) group R bb is not hydrogen.

[0344] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two groups other than hydrogen, -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 is as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not replaced with a hydrogen.

[0345] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with three groups, -N(R bb )3 and -N(R bb )3 + X - wherein R bb and X - is as defined herein.

[0346] The term "sulfonyl" refers to -SO2N(R bb )2, -SO2R aa , and -SO2OR aa where R aa and R bb is as defined herein.

[0347] The term "sulfinyl" refers to the group -S(=O)R aa where R aais as defined herein.

[0348] The term "acyl" refers to a group having the 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, and -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 unsubstituted, straight-chain or branched aliphatic; cyclic or acyclic, substituted or unsubstituted, straight-chain or branched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, straight-chain or branched alkyl; cyclic or acyclic, substituted or unsubstituted, straight-chain or branched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or diarylamino, or mono- or di-heteroarylamino; or two R X1The groups taken together form a 5- to 6-membered heterocycle. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), 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, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc.; each of which can be further substituted or unsubstituted).

[0349] The term "silyl" refers to the group -Si(R aa )3, where R aa is as defined herein.

[0350] The term "oxo" refers to the group =O and the term "thiooxo" refers to the group =S.

[0351] Nitrogen atoms may be substituted or unsubstituted depending on valence, 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 Perhaloalkyl, 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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Aryl, and 5- to 14-membered heteroaryl, or two R attached to the N atom cc The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group, where R aa , R bb , R cc and R dd is as defined above.

[0352] In certain embodiments, the substituent present on a 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)Raa , -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 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0353] For example, an amide group (e.g., —C(═O)R aaNitrogen protecting groups such as, but not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyl (oxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinamide, N-acetylmethionine derivatives, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

[0354] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as, but not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethylcarbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), 2,2,2-trichloroethylcarbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate mate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitribenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethyl methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacryl methylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoboryl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate methylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,6-trimethylbenzylcarbamate.

[0355] Sulfonamide groups (e.g., -S(=O)R aa Nitrogen protecting groups such as, but not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethyl benzenesulfonamide (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 phenacylsulfonamide.

[0356] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4, 4-Tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 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-pyridone) N-(4-Methoxyphenyl)diphenylmethylamine, ... N-methylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0357] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to: -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2, where R aa , Rbb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0358] Examples of oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxy Ethoxymethyl (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-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trimethyl ... methylethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl ) methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylsilyl isopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate ate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), 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-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-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, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate benzoate, 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, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0359] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to 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(Rbb )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 is as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0360] As used herein, "leaving group" (LG) is an art-recognized term that refers to a molecular fragment that departs with an electron pair in anisotropic bond cleavage, where 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 Edition (501-502). Exemplary leaving groups include, but are not limited to: halo (e.g., chloro, bromo, iodo), -OR, -CH, -CH� ... aa (where R aa is as defined herein), —O(C═O)R LG , or -O(SO)2RLG (e.g., tosyl, mesyl, besyl), where R LG is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, the leaving group is halogen. In some embodiments, the leaving group is I.

[0361] As used herein, use of the phrase "at least one instance" refers to 1, 2, 3, 4, or more instances, but also covers ranges such as 1-4, 1-3, 1-2, 2-4, 2-3, or 3-4 instances (inclusive).

[0362] A "non-hydrogen group" refers to any group defined for a particular variable that is not hydrogen.

[0363] The term "carbohydrate" or "sugar" refers to aldehyde or ketone derivatives of polyhydric alcohols. Carbohydrates encompass compounds with relatively small molecules (e.g., sugars) as well as macromolecular or polymeric substances (e.g., starch, glycogen, cellulose polysaccharides). The term "sugar" refers to monosaccharides, disaccharides, or polysaccharides. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed into smaller carbohydrates. Most monosaccharides have the general formula C y H 2y O y (e.g., CH 12 O6 (a hexose sugar such as glucose), where y is an integer greater than or equal to 3. Certain polyhydric alcohols not represented by the above general formula may also be considered monosaccharides. For example, deoxyribose has the chemical formula CH 10O4 and are monosaccharides. Monosaccharides usually consist of 5 or 6 carbon atoms and are called 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 may also consist of 3, 4, or 7 carbon atoms in the aldose or ketose form and are called trioses, tetroses, and heptoses, respectively. Glyceraldehyde and dihydroxyacetone are considered aldotriose and ketotriose sugars, respectively. Examples of aldotetrose sugars include erythrose and threose, and ketotetrose sugars include erythrulose. Aldopentose sugars include ribose, arabinose, xylose, and lyxose; ketopentose sugars include ribulose, arabulose, xylulose, and lyxulose. Examples of aldohexose sugars include glucose (e.g., dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose; ketohexose sugars include fructose, psicose, sorbose, and tagatose. Ketoheptose sugars include sedoheptulose. With the exception of the first and last carbons, each carbon atom in a monosaccharide bearing a hydroxyl group (-OH) is asymmetric, making it a stereocenter with two possible configurations (R or S). Because of this asymmetry, for any given monosaccharide formula, multiple isomers may exist. For example, the aldohexose d-glucose has the formula CH 12 O6, of which all but two of the six carbon atoms are stereogenic, which makes d-glucose a 16 (i.e., 2 4) to one of the possible stereoisomers of . The d or l assignment is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: if the hydroxyl group is on the right side in a standard Fischer projection, the molecule is a d sugar; otherwise, it is an l sugar. The aldehyde or ketone group of a linear monosaccharide can reversibly react with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between the two carbon atoms. Rings with five and six atoms, called furanose and pyranose forms, respectively, exist in equilibrium with the linear form. During the conversion from the linear to the cyclic form, the carbon atom containing the carbonyl oxygen, called the anomeric carbon, becomes a stereocenter with two possible configurations; the oxygen atom can be either above or below the plane of the ring. The resulting pair of possible stereoisomers is called anomers. In the α anomer, the -OH substituent on the anomeric carbon is on the opposite side of the ring from the -CHOH side chain (trans). The alternative form, in which the -CHOH substituent and the anomeric hydroxyl are on the same side of the plane of the ring (cis), is called the β anomer. Carbohydrates containing two or more linked monosaccharide units are called disaccharides or polysaccharides (e.g., trisaccharides), respectively. Two or more monosaccharide units joined by a covalent bond known as a glycosidic linkage, formed by a dehydration reaction, result in the loss of a hydrogen atom from one monosaccharide and a hydroxyl group from the other monosaccharide. 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, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, and kestose. The term carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.

[0364] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary recitation of substituents.

[0365] Other definitions As used herein, the term "salt" refers to any and all salts and encompasses pharmaceutically acceptable salts.

[0366] The term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic responses, etc., and that 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 bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts derived from appropriate bases include lactobionate, lactate, laurate, lauryl sulfate, 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-methyl-N ... + (C 1~4 Alkyl)4 -Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0367] The term "solvate" refers to a compound or its salt form associated with a solvent, usually through solvolysis. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein may be prepared, for example, in crystalline form, or may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric and non-stoichiometric solvates. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate may be isolated. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0368] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R×H2O, where R is a compound and X is a number greater than 0. A given compound may form more than one type of hydrate, including, for example, a monohydrate (X is 1), a lower hydrate (X is greater than 0 and less than 1, e.g., a hemihydrate (RO.5H2O)), and a polyhydrate (X is greater than 1, e.g., a dihydrate (R2H2O) and a hexahydrate (R6H2O)).

[0369] The term "tautomer" or "tautomer" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction providing a pair of tautomers) can be catalyzed by acid or base. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0370] It should also be understood that compounds that have the same molecular formula but that 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."

[0371] Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the R and S ordering rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, and are designated as dextrorotatory or levorotatory ((+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0372] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvents, rate of crystallization, storage temperature, and other factors may cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0373] The term "prodrug" refers to a compound having a cleavable group that becomes a compound described herein (which becomes pharmaceutically active in vivo) upon solvolysis or under physiological conditions. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both the acid and acid-derivative forms, but often offer advantages of solubility, tissue compatibility, or delayed release in mammals in the acid-sensitive form (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare double ester prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, aryl, C 7-12 Substituted aryl, and C7-C 12Aryl alkyl esters may be preferred.

[0374] The terms "composition" and "formulation" are used interchangeably.

[0375] A "subject" to which administration is contemplated refers to a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, or adolescent), or an adult subject (e.g., a young adult, middle-aged adult, or elderly adult)), or a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird (e.g., a commercially relevant bird such as a chicken, duck, goose, or turkey)). In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic or genetically engineered animal. "Disease," "disorder," and "condition" are used interchangeably herein.

[0376] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a peptide described herein or a composition thereof into or onto a subject.

[0377] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is suffering from a particular infectious disease or inflammatory condition, which reduce the severity of the infectious disease or inflammatory condition or delay or slow the progression of the infectious disease or inflammatory condition ("therapeutic treatment"), and also contemplate actions that occur before a subject begins to suffer from a particular infectious disease or inflammatory condition ("prophylactic treatment").

[0378] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response.As will be understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health and condition of the subject.The effective amount covers both therapeutic and prophylactic treatment.

[0379] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of an infectious disease or inflammatory condition, or to delay or minimize one or more symptoms associated with an infectious disease or inflammatory condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of an infectious disease or inflammatory condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of an infectious disease or inflammatory condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0380] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of an infectious disease or inflammatory condition, or one or more symptoms associated with an infectious disease or inflammatory condition. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a prophylactic benefit in the prevention of an infectious disease or inflammatory condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0381] example In order that the invention described herein may be more fully understood, the following examples are set forth: The synthetic and biological examples described herein are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0382] Synthesis of Lincosamide Analogues General Experimental Procedures: Unless otherwise noted, all reactions were carried out in flame-dried round-bottom flasks equipped with rubber septa under positive nitrogen pressure. Air- and moisture-sensitive liquids were transferred via syringe or stainless steel cannula. Organic solutions were concentrated by rotary evaporation (house vacuum, approximately 25-40 Torr) at room temperature unless otherwise noted. Analytical thin-layer chromatography (TLC) was performed using glass plates (0.25 mm, 60 Å pore size, 230-400 mesh, Merck KGA) pre-coated with silica gel impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to UV light and then stained with either ammonium cerium molybdate (CAM) in aqueous sulfuric acid, 2,4-dinitrophenylhydrazine (DNP) in ethanolic sulfuric acid, or potassium permanganate (KMnO) in aqueous sodium hydroxide-potassium carbonate, followed by brief heating using a heat gun. Flash column chromatography was performed using silica gel (60 Å, 15-40 μM, EMD Millipore Corp.) as described by Still et al. (Still, WC; Khan, M.; Mitra AJ Org. Chem. 1978, 43, 2923-2925).

[0383] Materials: Commercially available reagents and solvents were used as received.

[0384] Measurement equipment: Proton magnetic resonance ( 1H 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, δ scale) and are referenced to residual protium in the NMR solvent (CHCl3, δ 7.26; CD3OD, δ 3.31). Data are expressed as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, pent = pentent, m = multiplet and / or multiple resonances, br = broad, app = apparent), integral, and coupling constant (J) in Hertz (Hz). Carbon nuclear magnetic resonance spectra ( 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 (CDCl, δ 77.16, CDOD, δ 49.00). Multiplicities are 13 C signals are magnetically active nuclei (e.g., 19 F) is reported only when coupled with fluorine nuclear magnetic resonance spectrum ( 19 F NMR was 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 expressed as follows: frequency of absorption (cm -1 ), and absorption intensity (s = strong, m = medium, w = weak, br = broad). High-resolution mass spectra were obtained via electrospray ionization (ESI) using a Thermo Q Exactive Plus Orbitrap mass spectrometer at the Harvard University Mass Spectrometry Facility or a Bruker Compact qTOF mass spectrometer at Harvard's Laukien-Purcell Instrumentation Center. High-performance liquid chromatography purification was performed using an Agilent Technologies 1200 Series Preparative HPLC system.

[0385] Synthesis of FSA1507013, FSA1507066, FSA1507068, FSA1508001, and FSA1508003

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[0387]

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[0388]

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[0389]

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[0390]

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[0391]

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[0392]

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[0393]

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[0394]

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[0395]

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[0396] R-AA: 1H NMR (400 MHz, CDCl3) δ 8.15 - 8.08 (m, 2H), 8.00 - 7.93 (m, 2H), 7.80 - 7.73 (m, 2H), 7.66 - 7.57 (m, 1H), 7.56 - 7.46 (m, 3H), 7.44 - 7.34 (m, 3H), 7.23 (t, J = 7.8 Hz, 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, 1.5 Hz, 1H), 5.11 (dt, J = 17.3, 1.6 Hz, 1H), 5.04 - 4.93 (m, 2H), 4.71 - 4.62 (m, 1H), 3.58 - 3.50 (m, 2H), 2.90 (pent, J = 6.9 Hz, 1H), 2.78 - 2.62 (m, 2H), 2.44 - 2.26 (m, 2H), 1.14 (s, 9H), 1.12 (d, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.96, 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, 128.78, 128.56, 128.26, 116.68, 116.62, 83.97, 70.49, 69.70, 69.36, 69.10, 60.01, 57.12, 37.80, 33.88, 30.57, 23.03, 16.64. HRMS (ESI+, m / z): C 39 H 45 NO8S2についての[M+H] + Calculated value, 720.2659; Measured value, 720.2655.

[0397] S-AA: 1H NMR (400 MHz, CDCl3) δ 8.15 - 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 = 3.2 Hz, 1H), 6.04 (d, J = 5.8 Hz, 1H), 5.89 - 5.71 (m, 3H), 5.67 (dd, J = 10.8, 3.2 Hz, 1H), 5.22 - 5.11 (m, 2H), 5.10 - 4.94 (m, 2H), 4.74 (d, J = 6.9 Hz, 1H), 3.71 (d, J = 5.9 Hz, 1H), 3.60 - 3.51 (m, 1H), 2.79 - 2.59 (m, 3H), 2.46 - 2.29 (m, 2H), 1.13 (d, J = 7.6 Hz, 3H), 1.09 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 165.85, 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, 128.85, 128.57, 128.32, 116.70, 116.14, 83.91, 69.71, 69.13, 68.96, 68.92, 60.07, 56.82, 39.98, 33.90, 30.39, 22.94, 16.05. HRMS (ESI+, m / z): C 39 H 45 NO8S2についての[M+H] + Calculated value, 720.2659; Measured value, 720.2653.

[0398]

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[0399]

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[0400]

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[0401] FSA1507066·HCOOH was prepared and isolated as a single diastereomer. The C-7 methyl group was assigned as the R stereocenter. Furthermore, those skilled in the art will recognize that the synthetic routes described herein can provide compounds with either an R or S stereocenter at the C-7 methyl group.

[0402]

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[0403] FSA1508001·HCOOH was prepared and isolated as a single diastereomer. The C-7 methyl group was assigned as the R stereocenter. Furthermore, those skilled in the art will recognize that the synthetic route described herein can provide compounds with either an R or S stereocenter at the C-7 methyl group.

[0404]

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[0405]

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[0406]

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[0407] FSA1507068·HCOOH was prepared and isolated as a single diastereomer. The C-7 methyl group was assigned as the S stereocenter. Furthermore, those skilled in the art will recognize that the synthetic route described herein can provide compounds with either an R or S stereocenter at the C-7 methyl group.

[0408] Synthesis of FSA1503054, FSA1503055, and FSA1503058

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[0409]

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[0410]

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[0411]

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[0412]

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[0413]

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[0414]

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[0415]

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[0416] FSA1503054·HCOOH: 1 H NMR (400 MHz, MeOD) δ 8.44 (br s, 1H), δ 5.78 (d, J = 5.3 Hz, 1H), 5.54 - 5.32 (m, 2H), 4.69 - 4.55 (m, 2H), 4.32 (d, J = 5.3 Hz, 2H), 4.20 (d, J = 10.3 Hz, 1H), 4.05 - 3.90 (m, 2H), 3.82 - 3.72 (m, 2H), 3.56 (dd, J = 11.2, 7.2 Hz, 1H), 3.45 - 3.34 (m, 1H), 3.16 (d, J = 13.9 Hz, 1H), 2.85 (t, J = 11.7 Hz, 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 = 6.5 Hz, 6H). HRMS (ESI+, m / z): C 24 H 40 [M+H] for N2O6S + Calculated value: 485.2680; Measured value: 485.2682.

[0417] FSA1503055·HCOOH: 1 H NMR (400 MHz, MeOD) δ 8.41 (br s, 1H), 5.56 (br s, 2H), 5.46 (q, J = 9.8, 9.3 Hz, 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, 3.0 Hz, 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 HRMS (ESI+, m / z): C 24 H 40 [M+H] for N2O6S + Calculated value: 485.2680; Measured value: 485.2684.

[0418]

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[0419] Synthesis of FSA1504066A, FSA1504066B, and FSA1504068

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[0420]

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[0421]

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[0422] FSA1504066A·HCOOH: 1H NMR (400 MHz, MeOD) δ 8.42 (br s, 1H), 5.80 (d, J = 5.3 Hz, 1H), 5.72 (t, J = 12.3 Hz, 1H), 5.58 (t, J = 12.4 Hz, 1H), 4.43 - 4.24 (m, 3H), 4.22 (d, J = 9.6 Hz, 1H), 4.02 - 3.90 (m, 2H), 3.78 (td, J = 11.2, 10.7, 3.5 Hz, 1H), 3.73 - 3.63 (m, 2H), 3.58 (dd, J = 11.3, 7.6 Hz, 1H), 3.42 (t, J = 12.1 Hz, 1H), 3.20 - 3.12 (m, 1H), 2.88 (t, J = 11.7 Hz, 1H), 2.35 - 2.20 (m, 2H), 2.00 (d, J = 13.3 Hz, 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 = 6.6 Hz, 6H). 13 C NMR (101 MHz, MeOD) δ 168.77, 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): C 26 H 44 [M+H] for N2O6S + Calculated value: 513.2993; Measured value: 513.2992.

[0423] FSA1504066B·HCOOH was found by NMR to exist as a mixture of two equilibrium atropisomers, for which the coalescence temperature was close to ambient temperature. 1H and 13 In both spectra of C, the peaks belonging to the amino sugar moiety were significantly broadened and / or reduced in visibility; this can be resolved by VT-NMR at -60 °C. For ease of comparison, peaks corresponding to the spectrum obtained at 23 °C are represented. 1 H NMR (400 MHz, MeOD) δ 8.31 (br s, 1H), 5.77 (br s, 1H), 5.53 (pent, J = 9.3 Hz, 1H), 4.46 - 4.26 (m, 3H), 4.15 (br s, 1H), 4.00 (dt, J = 12.2, 4.1 Hz, 1H), 3.96 (br s, 1H), 3.87 - 3.79 (m, 1H), 3.76 (br s, 1H), 3.64 (dd, J = 8.6, 2.8 Hz, 1H), 3.59 (dd, J = 11.4, 7.7 Hz, 1H), 2.88 (t, J = 11.7 Hz, 1H), 2.30 - 2.15 (m, 1H), 2.00 (d, J = 13.5 Hz, 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 = 6.6 Hz, 6H). 13 C NMR (101 MHz, MeOD) δ 167.42, 81.18, 71.03, 69.19, 62.00, 49.54, 48.11, 43.45, 38.82, 37.41, 36.16, 36.02, 26.29, 25.67, 23.15, 22.93. HRMS (ESI+, m / z): C 26 H 44 [M+H] for N2O6S + Calculated value: 513.2993; Measured value: 513.2991.

[0424]

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[0425] Synthesis of FSA1503085

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[0426]

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[0427]

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[0428] After concentration under reduced pressure, 1 M HCl in MeOH (1 mL, 1.00 mmol, 52.6 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 in HO containing 0.1% HCOOH over 30 min) gave the product FSA1503085·HCOOH (0.633 mg, 0.00119 mmol, 6% yield over three steps) as a thin, clear film. 1 H NMR (400 MHz, MeOD) δ 8.50 (br s, 1H), 5.65 (br s, 1H), 5.58 - 5.33 (m, 2H), 4.43 (br s, 1H), 4.27 (t, J = 9.2 Hz, 1H), 4.12 (d, J = 9.0 Hz, 1H), 4.02 - 3.76 (m, 5H), 3.70 (s, 1H), 3.54 - 3.42 (m, 1H), 3.40 - 3.35 (m, 1H), 3.22 (dd, J = 13.3, 3.9 Hz, 1H), 2.75 (t, J = 11.4 Hz, 1H), 2.27 (dt, J = HRMS (ESI+, m / z): C 26 H 44 [M+H] for N2O6S + Calculated value: 513.2993; Measured value: 513.2995.

[0429] formula:

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[0430] formula:

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[0431] Additional exemplary compounds were prepared as described below.

[0432]

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[0433]

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[0434]

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[0435]

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[0436]

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[0437]

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[0438]

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[0440]

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[0441]

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[0442]

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[0443]

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[0444]

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[0445]

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[0446]

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[0447]

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[0448]

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[0450]

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[0460]

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[0461]

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Claims

1. Equation (I): 【Chemistry 1】 A compound of which, in the formula: Each P occurrence is independently a hydrogen or oxygen protecting group; A is a substituted or unsubstituted heteroaliphatic, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heteroaralkyl; R ７ is hydrogen or an unsubstituted alkyl; R is a heterocycline; R ２ Each occurrence of R, independently, is 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 carbocyclic, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic, 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 ), -SR ２ , -CN, -SCN, -C(=NR Ａ )R, -C(=NR Ａ )OR, -C(=NR Ａ )N(R, -C(=O)R Ａ )R, -C(=O)OR Ａ )R, -C(=O)N(R Ａ )R, -NO Ａ )R, -NR ２ )RC(=O)R Ａ )R, -C(=O)OR Ａ )R, -C(=O)N(R Ａ )R, -NO ２ )R, -NR ２ )RC(=O)R Ａ )R, -NR Ａ )RC(=O)OR Ａ )R, -NR Ａ )RC(=O)N(R Ａ )R, -NR Ａ )RC(=NR ２ )R, -NR Ａ )RC(=NR Ａ )R, -OC(=O)R Ａ )R , -OC(=O)OR ２ )R, -OC(=O)N(R Ａ )R, -NR Ａ )RS(O Ａ )R, -OS(O ２ )R, or -S(O Ａ )R ２ )R Ａ )R, or -OS(O ２ )R Ａ )R, or -S(O ２ )R Ａ )R, or two Rs ２ )R Ａ )R[[ID=We]] Ａ )R ８ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R ２ )R Ａ )R Ａ )R Ａ )R ２ )R ２ )R Ａ )R ９ )R [[ID=Sub]] Ａ )R Ａ )R ２ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R ２ )R Ａ )R Ａ )R Ａ )R ２ )R ２ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R ２ )R Ａ )R Ａ )R Ａ )R ２ )R Ａ )R Ａ )R Ａ )R ２ )R Ａ )R ２ )R Ａ )R ２ )R Ａ )R ２ )R Ａ )R ８ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R ２ )R Ａ )R Ａ )R Ａ )R ２ )R ２ )R Ａ )R ９ )R Ａ )R Ａ )R ２ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R ２ )R Ａ )R Ａ )R Ａ )R ２ )R ２ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R Ａ )R ２ )R Ａ )R Ａ )R Ａ )R ２ )R Ａ )R Ａ )R Ａ )R ２ )R Ａ )R ２ )R [[ID=The groups are linked together 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 between 0 and 12; and R Ａ Each appearance is independently either hydrogen, a substituted or unsubstituted acyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroaliphatic, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted carbocyclylalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a nitrogen protecting group if bonded to a nitrogen atom, an oxygen protecting group if bonded to an oxygen atom, or a sulfur protecting group if bonded to a sulfur atom, or two R Ａ The groups are linked together to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring. The aforementioned compound, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

2. (a) A is a substituted or unsubstituted heteroaliphatic; (b) A is a substituted or unsubstituted heterocyclyl; (c) A is a substituted or unsubstituted 4- to 8-membered monocyclic heterocyclyl, or a substituted or unsubstituted condensed bicyclic heterocyclyl; (d) A is a substituted or unsubstituted 4- to 8-membered monocyclic heterocycline; (e) A is given by the formula: 【Chemistry 2】 It is of the form, and in the formula: n is 1, 2, or 3; R ８ This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaliphatic, -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) ２ R Ａ , or a nitrogen protecting group; R ９ Each occurrence of R is, independently, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, 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 ), -SR ２ , -CN, -SCN, -C(=NR Ａ ), -C(=NR Ａ )OR Ａ , -C(=NR Ａ )OR Ａ , -C(=NR Ａ )(R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ p is between 0 and 4; Arbitrarily, A is given by the formula: 【Transformation 3】 or 【Chemistry 4】 It belongs to; (f) A is a substituted or unsubstituted condensed bicyclic heterocycline; (g) A is given by the formula: 【Transformation 5】 It is of the form, and in the formula: B is either a carbocyclyl or a heterocyclyl; R ８ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaliphatic, -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) ２ R Ａ , or a nitrogen protecting group; R ９ Each occurrence is 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 , -NO ２ , -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) ２ R Ａ , -OS(O) ２ R Ａ , or -S(O) ２ R Ａ is it; or two R's ９ The groups are linked to form substituted or unsubstituted heterocyclyl rings, or substituted or unsubstituted carbocyclyl rings; and p is between 0 and 4; Arbitrarily, A is given by the formula: 【Transformation 6】 It is of the form, and in the formula: X is O, S, NR ９ , or C(R ９ ) ２ And; Y is O, S, N, NR ９ , C(R ９ ) ２ CR ９ ,CH ２ , or CH; n is either 0 or 1; p is 0 to 4; and 【Transformation 7】 represents a single bond or a double bond; Arbitrarily, A is given by the formula: 【Transformation 8】 It is; Arbitrarily, A is given by the formula: 【Chemistry 9】 It is; Arbitrarily, A is given by the formula: 【Chemistry 10】 It belongs to; or A is the formula: 【Chemistry 11】 It is; Arbitrarily, A is given by the formula: 【Chemistry 12】 It is; Arbitrarily, A is given by the formula: 【Chemistry 13】 It is; Arbitrarily, A is given by the formula: 【Chemistry 14】 It belongs to; or, (h) A is given by the formula: 【Chemistry 15】 It is; Arbitrarily, A is given by the formula: 【Chemistry 16】 It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

3. R ７ However, it is hydrogen. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

4. R ８ but, (a) Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or -C(=O)R Ａ It is; (b) hydrogen or substituted or unsubstituted alkyl; (c) hydrogen or methyl; (d) hydrogen; or (e) It is methyl, The compound described in claim 2, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

5. R ９ but, (a) It is a substituted or unsubstituted alkyl group; (b) Substitutive or non-substitutive C １－６ It is alkyl. (c)-CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ ien-CH ２ CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ CH (CH ３ ) ２ , or -CH(CH ３ ) ３ is; or (d)-CH ２ CH (CH ３ ) ２ That is, The compound described in claim 2, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

6. Each P is a hydrogen atom. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

7. (a) R is a heterocyclyl with 6 to 14 members; R is an 8- to 12-membered heterocycline; R is a heterocycline with 9 to 12 members; R is a heterocyclyl with 9 to 11 members; R is an 11-member heterocyclyl; or R is a 10-membered heterocycline; and / or (b) R contains at least one unsaturated bond in its ring; and / or (c) R contains at least one unsaturated carbon-carbon bond in its ring; and / or (d) R contains at least one heteroatom in addition to oxygen in its ring; and / or (e) R contains at least one sulfur atom in its ring; and / or (f) R contains one sulfur atom in its ring; and / or (g) R is given by the formula: 【Chemistry 17】 It is a heterocycline, In the formula, R １ -NR ２ It is -, -O-, or -S-; R is expressed in the formula: [Chemistry 18] It is a heterocycline of; R is expressed in the formula: 【Chemistry 19】 It is a heterocycline, In the formula, each R １ Independently, combined, -CR ２ R ２ -, -CR ２ -, C, N, -NR ２ It is -, -O-, or -S-; q ​​is 3 to 6; R is expressed in the formula: 【Chemistry 20】 It is a heterocycline, During the ceremony: Each R １ These are, independently, combined or -CR ２ R ２ - and; and 【Chemistry 21】 represents a single bond or a double bond; R is expressed in the formula: 【Chemistry 22】 It is a heterocycline, During the ceremony: Each R １ These are, independently, combined or -CR ２ R ２ - is; R is expressed in the formula: 【Chemistry 23】 It is a heterocycline, During the ceremony: Each R １ These are, independently, combined or -CR ２ R ２ - is; R is expressed in the formula: 【Chemistry 24】 It is a heterocycline, During the ceremony: Each R １ These are, independently, combined or -CR ２ R ２ - is; R is expressed in the formula: 【Chemistry 25】 It is a heterocycline, During the ceremony: Each R １ These are, independently, combined or -CR ２ R ２ - is; R is the formula: 【Chemistry 26】 It is a heterocycline of; R is the formula: 【Chemistry 27】 It is a heterocycline of; R is the formula: 【Chemistry 28】 It is a heterocycline of; R is the formula: 【Chemistry 29】 It is a heterocycline of; R is the formula: 【Transformation 30】 It is a heterocycline of; R is the formula: 【Chemistry 31】 It is a heterocycline of; or R is the formula: 【Chemistry 32】 It is a heterocycline of The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

8. (a) R ２ Each occurrence is 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 together 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; (b) R ２ Each occurrence is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, nitrogen protecting group if bonded to a nitrogen atom, -OR Ａ , -N(R Ａ ) ２ , -SR Ａ , or -CN; or two R ２ The groups are linked together 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; (c) R ２ Each occurrence is independently hydrogen, halogen, substituted or unsubstituted alkyl, -OR Ａ , -N(R Ａ ) ２ , or -SR Ａ is; or two R ２ The groups are linked together to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heterocyclyl ring; (d) R ２ Each occurrence is independently a halogen, a substituted or unsubstituted alkyl, or -OR Ａ is it; or two R's ２ The groups are linked together to form a substituted or unsubstituted carbocyclyl ring, a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heterocyclyl ring; (e) R ２ Each occurrence independently represents a halogen, a substituted or unsubstituted alkyl, or -OR Ａ That is, (f) R ２ Each occurrence is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (g) R ２ Each occurrence is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (h)R ２ Each occurrence is independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl; (i) R ２ Each occurrence is independently a halogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroaryl; (j) Caution ２ Each occurrence is independently either a substituted or unsubstituted alkyl group; or (k)R ２ Each occurrence is independently an unsubstituted alkyl. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

9. (a) t is between 0 and 4; (b) t is between 0 and 2; (c) t is 0 or 1; (d) t is 0; or (e) t is 1 or 2, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

10. (a) The compound is of formula (I-a): 【Transformation 33】 (I-a) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (b) The compound is of formula (I-b): 【Transformation 34】 (I-b) It is, In the formula: R １ -NR ２ -, -O-, or -S- The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (c) Compound is of formula (I-c): 【Chemistry 35】 (I-c) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (d) Compound is of formula (I-d): 【Transformation 36】 (I-d) It is of the form, and in the formula: Each R １ Independently, combined, -CR ２ R ２ -, -CR ２ -, C, N, -NR ２ -, -O-, or -S-; q ​​is 3 to 6. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (e) The compound is of formula (I-e): 【Chemistry 37】 (I-e) It is of the form, and in the formula: Each R １ These are, independently, combined or -CR ２ R ２ - and; and 【Transformation 38】 This represents a single bond or a double bond. A compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-e-1): 【Chemistry 39】 (I-e-1) It is of the form, and in the formula: Each R １ These are, independently, combined or -CR ２ R ２ - is, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (f) The compound is of formula (I-f): 【Chemistry 40】 (I-f) It is of the form, and in the formula: Each R １ These are, independently, combined or -CR ２ R ２ - and; and 【Chemistry 41】 This represents a single bond or a double bond. A compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-f-1): 【Chemistry 42】 (I-f-1) It is of the form, and in the formula: Each R １ These are, independently, combined or -CR ２ R ２ - is, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound is of formula (I-f-2): 【Chemistry 43】 (I-f-2) It is of the form, and in the formula: Each R １ These are, independently, combined or -CR ２ R ２ - is, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (g) Compound is of formula (I-g): 【Chemistry 44】 (I-g) It is of the form, and in the formula: Each R １ These are, independently, combined or -CR ２ R ２ - and; and 【Chemistry 45】 This represents a single bond or a double bond. A compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-g-1): 【Chemistry 46】 (I-g-1) It is of the form, and in the formula: Each R １ These are, independently, combined or -CR ２ R ２ - is, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound is of formula (I-g-2): 【Chemistry 47】 (I-g-2) It is of the form, and in the formula: Each R １ These are, independently, combined or -CR ２ R ２ - is, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (h) Compound is of formula (I-h): 【Chemistry 48】 (I-h) It belongs to A compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-h-1): 【Chemistry 49】 (I-h-1) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or, Arbitrarily, the compound is of formula (I-h-2): [Transformation 50] (I-h-2) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (i) The compound is of formula (I-i): 【Chemistry 51】 (I-i) It belongs to A compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is given by formula (I-i-1): 【Chemistry 52】 (I-i-1) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound is given by formula (I-i-2): 【Chemistry 53】 (I-i-2) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound is given by formula (I-i-3): 【Chemistry 54】 (I-i-3) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound is given by formula (I-i-4): 【Transformation 55】 (I-i-4) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound is given by formula (I-i-5): 【Transformation 56】 (I-i-5) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound is given by formula (I-i-6): 【Chemistry 57】 (I-i-6) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound is given by formula (I-i-7): 【Transformation 58】 (I-i-7) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound is given by formula (I-i-8): 【Chemistry 59】 (I-i-8) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (j) Compound is of formula (I-j): 【Transformation 60】 (I-j) It belongs to A compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-j-1): 【Chemistry 61】 (I-j-1) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (k) Compound is given by formula (I-k): 【Transformation 62】 (I-k) It belongs to A compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is given by formula (I-k-1): 【Transformation 63】 (I-k-1) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (l) Compound is of formula (I-l): 【Chemistry 64】 (I-l) It belongs to A compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-l-1): 【Transformation 65】 (I-l-1) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-l-2): 【Chemical Formula 66】 (I-l-2) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-l-3): 【Transformation 67】 (I-l-3) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound Formula (I-l-4): 【Transformation 68】 (I-l-4) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; (m) Compound is given by formula (I-m): 【Transformation 69】 (I-m) It belongs to A compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-m-1): 【Transformation 70】 (I-m-1) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-m-2): 【Chemistry 71】 (I-m-2) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-m-3): 【Chemistry 72】 (I-m-3) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-m-4): 【Transformation 73】 (I-m-4) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound is given by formula (I-m-5): 【Chemistry 74】 (I-m-5) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or (n) Compound is of formula (I-n): 【Chemistry 75】 (I-n) It belongs to A compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-n-1): 【Transformation 76】 (I-n-1) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-n-2): 【Chemical Formula 77】 (I-n-2) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-n-3): 【Transformation 78】 (I-n-3) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is given by formula (I-n-4): 【Transformation 79】 (I-n-4) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is given by formula (I-n-5): 【Chemistry 80】 (I-n-5) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-n-6): 【Chemistry 81】 (I-n-6) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-n-7): 【Chemistry 82】 (I-n-7) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-n-8): 【Chemistry 83】 (I-n-8) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-n-9): 【Chemical 84】 (I-n-9) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-n-10): 【Chemical 85】 (I-n-10) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-n-11): 【Chemical 86】 (I-n-11) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-n-12): 【Chemistry 87】 (I-n-12) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; Arbitrarily, the compound is of formula (I-n-13): 【Chemical 88】 (I-n-13) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or Arbitrarily, the compound is given by formula (I-n-14): 【Chemistry 89】 (I-n-14) It belongs to The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

11. The compound is given by the following formula: 【Chemistry 90-1】 【Chemistry 90-2】 【Chemistry 90-3】 【Chemistry 90-4】 【Chemistry 90-5】 【Chemistry 90-6】 【Chemistry 90-7】 【Chemistry 90-8】 The compound described in claim 1, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug, and a pharmaceutically acceptable excipient, The pharmaceutical composition optionally comprises a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug.

13. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug, Instructions for administering the compound, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof, or the pharmaceutical composition to a subject requiring it, and A kit that includes this.

14. The pharmaceutical composition according to claim 12 for use in treating infectious diseases in subjects requiring such treatment.

15. Infectious diseases are bacterial infections, Optionally, A bacterial infection is an infection caused by Gram-positive bacteria; or A bacterial infection is an infection caused by Gram-negative bacteria; or Bacterial infections include Staphylococcus infection, Streptococcus infection, Enterococcus infection, Acinetobacter infection, Clostridium infection, Bacteroides infection, Escherichia infection, Pseudomonas infection, Neisseria infection, Klebsiella infection, or Haemophilus infection; or The bacterial infection is either a C. difficile infection or a B. fragilis infection; or Infectious diseases are parasitic infections. A pharmaceutical composition for use according to claim 14.

16. An in vitro method for killing or inhibiting the growth of microorganisms, Microorganisms, A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug; or an effective amount of a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug, and a pharmaceutically acceptable excipient, Including contact, The aforementioned method.

17. An in vitro method for inhibiting the proliferation of pathogens, A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or an effective amount of a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug, and a pharmaceutically acceptable excipient. Contact with pathogens, or, Pathogens, Contacting the compound, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof, or an effective amount of the pharmaceutical composition. The method, including the method described above.

18. An in vitro method for inhibiting protein synthesis, A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug thereof; or, in an effective amount of a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative or prodrug, and a pharmaceutically acceptable excipient, Inhibiting bacterial ribosomes The method, including the method described above.

19. The pharmaceutical composition according to claim 12, for use in killing or inhibiting the growth of microorganisms in a subject where such action is required.

20. The pharmaceutical composition according to claim 12 for use in inhibiting protein synthesis.

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