C10-alkylene substituted 13-membered macrolides and uses thereof

Abstract

To provide a novel antibiotic that is effective against drug-resistant bacteria, especially gram-negative bacteria.SOLUTION: Provided is a pharmaceutical composition comprising a 13-membered macrolide represented by the following formula. The 13-membered macrolide described herein is an azaketolide. Also provided are methods for preparing the 13-membered macrolides and methods for treating infectious diseases, particularly diseases caused by gram-negative bacteria, using the disclosed macrolides.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 769,383, filed November 19, 2018. The disclosure of this prior application is considered part of the disclosure of this application and is incorporated by reference in its entirety herein. [Background technology]

[0002] Newly emerged resistance to existing antibiotics is rapidly developing as a global crisis, especially for infections resulting from drug-resistant Gram-negative bacteria. Pathogenic bacteria can transmit genes encoding antibiotic resistance both vertically (to their progeny) and horizontally (to neighboring bacteria of different lineages), and as a result, antibiotic resistance can spread rapidly, especially in nosocomial (hospital) environments. See, e.g., Wright, Chem. Commun. (2011) 47:4055-4061. More than 99,000 people die annually in the United States from healthcare-associated infections, more than all deaths from car accidents, HIV, and breast cancer combined, and it is estimated that the 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 reduction in research into the development of new antibiotics by most major pharmaceutical companies. See, e.g., Projan, Curr. Opin. Microbiol. (2003) 6:427-430. The current rate of introduction of new antibiotics is not adequate to address the rise in resistance, and with the ease of international travel and increasing population densities, the need for innovation in this field has never been greater.

[0003] Macrolides are one of the few major classes of clinically important antibiotics to which the only practical access has been gained through semisynthesis or chemical engineering of structurally complex fermentation products in up to 16-step pathways. See, e.g., Paterson, Tetrahedron (1985) 41:3569-3624; Omura, Ed., Macrolide Antibiotics: Chemistry, Biology, and Practice, Second Edition; Academic Press, 2002. The macrolide class of antibiotics has proven safe and effective in combating pathogenic bacteria since the discovery of erythromycin more than 60 years ago; see, e.g., Wu et al., Curr. Med. Chem. (2001) 8:1727-1758. Erythromycin exhibits a spectrum of antibacterial activity against gram-positive bacteria similar to penicillin, but has a lower propensity to induce allergic interactions, and is routinely prescribed for upper and lower respiratory tract infections as well as genitourinary tract infections. See, e.g., Washington et al., Mayo. Clin. Proc. (1985) 60:189-203, Washington et al., Mayo. Clin. Proc. (1985) 60:271-278. However, erythromycin is known to undergo acid-promoted internal ketization (cyclization of the C6 and C12 hydroxyl groups to a C9 ketone) in the gastrointestinal tract, which leads to adverse gastrointestinal events. See, e.g., Kurath et al., Experientia (1971) 27:362. The second generation macrolide antibiotics clarithromycin and azithromycin addressed the problem of acid instability and were prepared semisynthetically in 4-6 steps from readily available erythromycin by large-scale fermentation.For example, Ma et al.,Curr.Med.Chem.(2011)18:1993-2015;Wu et al.,Curr.Pharm.Des.(2000)6:181-223;Ma et al.,Mini-Rev.Med.Chem.(2010)10:272-286;Asaka et al. al.,Curr.Top.Med.Chem.(Sharjah,United Arab Emirates)(2003)3:961-989;Morimoto et al.,J.Antibiot.(1990)43:286-294;Morimoto et al.,J.Antibiot.(1984)37:187-189;Watanabe et al. See, e.g., et al., J. Antibiot. (1993) 46:1163-1167; Watanabe et al., J. Antibiot. (1993) 46:647-660; Bright et al., J. Antibiot. (1988) 41:1029-1047; Djokic et al., J. Antibiot. (1987) 40:1006-1015; Mutak et al., J. Antibiot. (2007) 60:85-122; and Retsema et al., Antimicrob. Agents Chemother. (1987) 31:1939-1947. Azithromycin has been shown to exhibit significantly improved efficacy against gram-negative organisms, and has a longer half-life and higher tissue distribution than other macrolide antibiotics, which may be correlated with its 15-membered ring containing a tertiary amine. See, for example, Ferwerda et al., J. Antimicrob. Chemother. (2001) 47:441-446; Girard et al., Antimicrob. Agents Chemother. (1987) 31:1948-1954. The natural product tyrosine, a 16-membered macrolide used in veterinary medicine, has been shown by X-ray crystallography to occupy the same binding pocket as erythromycin and azithromycin, suggesting a high tolerance to variability in the ring size and composition of the macrocycle.

[0004] The three main causes of resistance to macrolides in bacterial organisms are ribosomal methylation, mutations in ribosomal RNA or peptides encoded by erm genes, and cellular efflux mediated by mef and msr genes. For example, Leclercq et al., Antimicrob.Agents Chemother.(1991)35:1273-1276;Leclercq et al.,Antimicrob.Agents Chemother.(1991)35:1267-1272;Weisblum, Antimicrob.Agents Chemother.(1995)39:577-585;Vester et al. al.,Antimicrob.Agents Chemother.(2001)45:1-12;Prunier et al.,Antimicrob.Agents Chemother.(2002)46:3054-3056;Li et al.,J.Antimicrob.Chemother.(2011)66:1983-1986;Sutcliffe et al.,Antimicrob.Agents Chemother. (1996) 40:1817-1824; Wondrack et al., Antimicrob. Agents Chemother. (1996) 40:992-998. Ketolides such as telithromycin and solithromycin are believed to subvert the resistant efflux mechanism by replacing the C3 cladinose sugar with a carbonyl group (hence the name "ketolide") and exhibit greatly increased binding due to favorable interactions between the novel aryl-alkyl side chains and the ribosome. See, e.g., Ma et al., Curr. Med. Chem. (2011) 18:1993-2015; Ma et al., Mini-Rev. Med. Chem. (2010) 10:272-286. Despite significant improvements in ribosome binding, ketolides such as telithromycin and solithromycin do not address some of the more recent forms of macrolide resistance that have evolved in the nosocomial setting, particularly ribosomal methylation and RNA point mutations. Thus, the discovery and development of new antibiotics that are effective against drug-resistant bacteria, particularly Gram-negative bacteria, represents a currently unmet medical need. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Wright,Chem.Commun.(2011)47:4055-4061 [Non-Patent Document 2] Klevens et al.,Public Health Rep(2007)122:160-166 [Non-Patent Document 3] Projan,Curr.Opin.Microbiol.(2003)6:427-430 [Non-Patent Document 4] Wu et al.,Curr.Med.Chem.(2001)8:1727-1758 [Non-Patent Document 5] Washington et al., Mayo. Clin. Proc. (1985)60:189-203 [Non-Patent Document 6] Washington et al., Mayo. Clin. Proc. (1985) 60:271-278 [Non-Patent Document 7] Kurath et al.,Experientia(1971)27:362 [Non-Patent Document 8] Ma et al.,Curr.Med.Chem.(2011)18:1993-2015 [Non-Patent Document 9] Wu et al.,Curr.Pharm.Des.(2000)6:181-223 [Non-Patent Document 10] Ma et al.,Mini-Rev.Med.Chem.(2010)10:272-286 [Non-Patent Document 11] Asaka et al., Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) (2003) 3:961-989 [Non-Patent Document 12] Morimoto et al., J. Antibiot. (1990) 43:286-294 [Non-Patent Document 13] Morimoto et al., J. Antibiot. (1984) 37:187-189 [Non-Patent Document 14] Watanabe et al., J. Antibiot. (1993) 46:1163-1167 [Non-Patent Document 15] Watanabe et al., J. Antibiot. (1993) 46:647-660 [Non-Patent Document 16] Bright et al., J. Antibiot. (1988) 41:1029-1047 [Non-Patent Document 17] Djokic et al., J. Antibiot. (1987) 40:1006-1015 [Non-Patent Document 18] Mutak et al., J. Antibiot. (2007) 60:85-122 [Non-Patent Document 19] Retsema et al., Antimicrob. Agents Chemother. (1987) 31:1939-1947 [Non-Patent Document 20] Ferwerda et al., J. Antimicrob. Chemother. (2001) 47:441-446 [Non-Patent Document 21] Girard et al., Antimicrob. Agents Chemother. (1987) 31:1948-1954 [Summary of the Invention] [Means for Solving the Problems]

[0006] Disclosed herein are novel, synthetically accessible 13-membered macrolide compounds that are novel antibiotics with unexpectedly potent antibacterial activity.

[0007] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 2a and R 2b One of the groups is H, halo, or optionally substituted C 1~10 Alkyl, optionally substituted C 1~10 Alkoxy and optionally substituted C 1~10 alkenyl, 1~10 Alkyl, C 1~10 Alkoxy and C 1~10 the alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R 2a and R 2b The other of these is halo, optionally substituted C 1~10 Alkyl, optionally substituted C 1~10 Alkoxy and optionally substituted C 1~10 alkenyl, 1~10 Alkyl, C 1~10 Alkoxy and C 1~10 the alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, substituted amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R 4a and R 4b each independently represents H and optionally substituted C 1~10 is selected from the group consisting of alkyl, R 5 is H, an oxygen protecting group, and [ka] and selected from the group consisting of " [ka] " indicates the point of attachment, R 6a is an arbitrarily substituted C 1~10 is alkyl, R 6b , H, C 1~10 Alkyl, C 1~10 hydroxyalkyl, aryl, haloalkyl, aryl, heteroalkenyl, heterocycloalkyl, or heteroaryl, any of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R 8a and R 8b are each independently H and optionally substituted C 1~10 is selected from the group consisting of alkyl, R 9a is H, optionally substituted C 1~10 Alkyl, hydroxyalkyl, optionally substituted C 1~10 Alkylene-NR T R T’ , optionally substituted C 1~10 Alkylene-Cycloalkyl-NR T R T’ and optionally substituted alkoxyalkyl, wherein R T and R T’ are each independently H, optionally substituted alkyl, and optionally substituted C 1~10 alkylene-heterocycloalkyl; R 10a and R 10b One of the groups is H, optionally substituted C 1~10 Alkyl, optionally substituted C 1~10 alkoxy; R 10a and R 10b The other is -CO 2H, -CO 2 -optionally substituted alkyl, -CON(R z’ )(R z’’ ), optionally substituted C 1~10 Alkylene-R 101 , optionally substituted C 2~10 Alkenylene-R 101 , and optionally substituted C 2~10 Alkynylene-R 101 wherein: R 101 is H, (C 1~6 Alkyl)-S-, (C 1~6 Alkyl)-SO-, (C 1~6 Alkyl)-SO 2 -, -OH, optionally substituted -O-(C 1~6 alkyl), -NR x R x’ Selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R z’ and R z’’ are each independently H or optionally substituted alkyl; R x and R x’ are each independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y’ )(R y’’ ) wherein R y’ and R y’’ are each independently H or optionally substituted alkyl; R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2, N.R. y , and N.C. 1 ~C 10 forming an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of alkyl, Each R y are independently -H and optionally substituted C 1~10 is selected from the group consisting of alkyl, R 11a and R 11b each independently represents -H and optionally substituted C 1~10 alkyl.

[0008] The disclosed compounds have antimicrobial activity and can be used to treat and / or prevent infectious diseases. Pharmaceutical compositions of the compounds and therapeutic and prophylactic methods using the compounds or compositions thereof 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, Acinetobacter, Klebsiella, Escherichia, and Pseudomonas species.

[0009] Methods for preparing the compounds are also provided herein. The present disclosure also provides intermediates in the preparation of the compounds described herein.

[0010] Details of certain embodiments of the invention are set forth in the detailed description set forth below. Other features, objects, and advantages of the invention will become apparent from the definition, drawings, examples, and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The compounds disclosed herein include 13-membered azaketolides. The disclosed compounds can have reduced structural complexity than known macrolides, providing compounds that can be accessed by synthetic routes that are less demanding than those required for other macrolides. Despite the reduced structural complexity, the disclosed 13-membered azaketolides provide unexpected and potent activity against a variety of microorganisms, including gram-negative bacteria. Methods for preparing the compounds, pharmaceutical compositions containing the compounds, and methods for using the compounds (e.g., for treating infectious diseases) are also disclosed.

[0012] In certain embodiments, a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 2a and R 2b One of the groups is H, halo, or optionally substituted C 1~10 Alkyl, optionally substituted C 1~10 Alkoxy and optionally substituted C 1~10 alkenyl, 1~10 Alkyl, C 1~10 Alkoxy and C 1~10 the alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R 2a and R 2b The other of these is halo, optionally substituted C 1~10 Alkyl, optionally substituted C 1~10 Alkoxy and optionally substituted C 1~10 alkenyl, 1~10 Alkyl, C 1~10 Alkoxy and C 1~10 the alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, substituted amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R 4a and R 4b each independently represents H and optionally substituted C 1~10 is selected from the group consisting of alkyl, R 5 is H, an oxygen protecting group, and [ka] and selected from the group consisting of " [ka] " indicates the point of attachment, R 6a is an arbitrarily substituted C 1~10 is alkyl, R 6b , H, C 1~10 Alkyl, C 1~10 hydroxyalkyl, aryl, haloalkyl, aryl, heteroalkenyl, heterocycloalkyl, or heteroaryl, any of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R 8a and R 8b are each independently H and optionally substituted C 1~10 is selected from the group consisting of alkyl, R 9a is H, optionally substituted C 1~10 Alkyl, hydroxyalkyl, optionally substituted C 1~10 Alkylene-NR T R T’ , optionally substituted C 1~10 Alkylene-Cycloalkyl-NR T R T’ and optionally substituted alkoxyalkyl, wherein R T and R T’ are each independently H, optionally substituted alkyl, and optionally substituted C 1~10 alkylene-heterocycloalkyl; R 10a and R 10b One of the groups is H, optionally substituted C 1~10 alkyl, (optionally substituted), R 10a and R 10b The other is -CO 2 H, -CO 2 -optionally substituted alkyl, -CON(R z’ )(R z’’ ), optionally substituted C 1 ~ 10 Alkylene-R 101 , optionally substituted C 2 ~ 10 Alkenylene-R 101 , and optionally substituted C 2 ~ 10 Alkynylene-R 101 wherein: R 101 is H,(C 1~6 Alkyl)-S-, (C 1~6 Alkyl)-SO-, (C 1~6 Alkyl)-SO 2 -, -OH, optionally substituted -O-(C 1~6 alkyl), -NR x R x’ , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R z’ and R z’’ are each independently H or optionally substituted alkyl; R x and R x’ are each independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(Ry’ )(R y’’ ) wherein R y’ and R y’’ are each independently H or optionally substituted alkyl; R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 forming an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of alkyl, Each R y are independently -H and optionally substituted C 1~10 is selected from the group consisting of alkyl, R 11a and R 11b each independently represents -H and optionally substituted C 1~10 alkyl.

[0013] In certain embodiments, a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 2a and R 2b One of the groups is H, halo, or optionally substituted C 1~10 Alkyl, optionally substituted C 1~10 Alkoxy and optionally substituted C 1~10 alkenyl, 1~10 Alkyl, C 1~10 Alkoxy and C 1~10 the alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R 2a and R 2b The other of these is halo, optionally substituted C 1~10Alkyl, optionally substituted C 1~10 Alkoxy and optionally substituted C 1~10 alkenyl, 1~10 Alkyl, C 1~10 Alkoxy and C 1~10 the alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R 4a and R 4b each independently represents H and optionally substituted C 1~10 is selected from the group consisting of alkyl, R 5 is H, an oxygen protecting group, and [ka] and selected from the group consisting of " [ka] " indicates the point of attachment, R 6a is an arbitrarily substituted C 1~10 is alkyl, R 6b , H, C 1~10 Alkyl, C 1~10 hydroxyalkyl, aryl, haloalkyl, aryl, heteroalkenyl, heterocycloalkyl, or heteroaryl, any of which is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; R 8a and R 8b are each independently H and optionally substituted C 1~10 is selected from the group consisting of alkyl, R 9a is H, optionally substituted C 1~10 selected from the group consisting of alkyl, hydroxyalkyl, and optionally substituted alkoxyalkyl; R10a and R 10b One of the groups is H, optionally substituted C 1~10 alkyl, (optionally substituted), R 10a and R 10b The other is -CO 2 H, -CO 2 -optionally substituted alkyl, -CON(R z’ )(R z’’ ), optionally substituted C 1~10 Alkylene-R 101 , optionally substituted C 2~10 Alkenylene-R 101 , and optionally substituted C 2~10 Alkynylene-R 101 wherein: R 101 is H,(C 1~6 Alkyl)-S-, (C 1~6 Alkyl)-SO-, (C 1~6 Alkyl)-SO 2 -, -OH, optionally substituted -O-(C 1~6 alkyl), -NR x R x’ , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R z’ and R z’’ are each independently H or optionally substituted alkyl; R x and R x’ are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y’ )(R y’’ ) wherein R y’and R y’’ are each independently H or optionally substituted alkyl; R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 forming a 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of alkyl, Each R y are independently -H and optionally substituted C 1~10 is selected from the group consisting of alkyl, R 11a and R 11b each independently represents -H and optionally substituted C 1~10 alkyl.

[0014] One embodiment of the compound of formula I is a compound of formula IA: [ka]

[0015] Another embodiment of the compounds of formula I and IA is the compound of formula IB. [ka]

[0016] In certain embodiments of compounds of formula I, IA, and IB, R 5 teeth, [ka] It is.

[0017] Another embodiment of the compounds of formula I, IA, and IB is a compound of formula IC. [ka]

[0018] Another embodiment of the compounds of formula I, IA, IB, and IC is a compound of formula ID. [ka]

[0019] In another embodiment of the compounds of formula I, IA, IB, IC, and ID, R 6b is -H, optionally substituted C 1 ~C 10 Alkyl, optionally substituted C 1 ~C 10 It is selected from the group consisting of hydroxyalkyl, and allyl.

[0020] In another embodiment of the compounds of formula I, IA, IB, IC, and ID, R 6b is methyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, -CH 2 CHOHCH 2 OH, and allyl.

[0021] Another embodiment of the compounds of formula I, IA, IB, IC, and ID is the compound of formula IE. [ka]

[0022] Another embodiment of the compounds of formula I, IA, IB, IC, ID, and IE is the compound of formula IF. [ka]

[0023] Another embodiment of the compounds of formula I, IA, IB, IC, ID, IE, and IF is the compound of formula IG. [ka]

[0024] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 9a is -H or optionally substituted C 1~4 It is an alkyl.

[0025] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In another embodiment of the compounds of formula I, IA, IB, IC, ID, IE, IF, and IG, R 9a is -H or methyl.

[0026] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 11a and R 11b is -H.

[0027] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 11a and R 11b one of which is -H and the other is optionally substituted C 1~10 It is an alkyl.

[0028] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 11a and R 11b One of these is -H and the other is methyl.

[0029] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 11a and R 11b each independently represents an optionally substituted C 1~10 It is an alkyl.

[0030] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 11a and R 11b are each methyl.

[0031] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 2a and R 2b One of them is an arbitrarily substituted C 1~10 It is an alkyl.

[0032] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 2a and R 2b is an optionally substituted aminoalkyl.

[0033] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 2a and R 2b One of them is an arbitrarily substituted C 1~10 is alkyl, R 2a and R 2b The other of these is H.

[0034] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 2a and R 2b Both of these can be expressed as C 1~10 It is an alkyl.

[0035] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 2a and R 2b One of the groups is methyl.

[0036] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 2a and R 2b One of the groups is methyl, and R 2a and R 2b The other of these is H.

[0037] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 2a and R2b Both of are methyl.

[0038] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 2a and R 2b One of is methyl and the other is halo. In a further embodiment, halo is selected from the group consisting of F and Cl.

[0039] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 2a and R 2b one of which is methyl and the other is an optionally substituted C 1~10 It is an alkyl.

[0040] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, or IG, R 2a and R 2b one of which is methyl and the other is an optionally substituted C 1~10 Alkyl, optionally substituted C 1~10 Alkoxy and optionally substituted C 1~10 alkenyl, 1~10 Alkyl, C 1~10 Alkoxy and C 1~10 The alkenyl is optionally substituted with one or more groups selected from halo, aryl, and heteroaryl.

[0041] Another embodiment of a compound of formula I, IA, IB, IC, ID, IE, IF, or IG is a compound of formula IG-1. [ka]

[0042] Another embodiment of a compound of formula I, IA, IB, IC, ID, IE, IF, or IG is a compound of formula IH-1. [ka]

[0043] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, IG, IG-1, or IH, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In another embodiment of the compounds of formula I, IA, IB, IC, ID, IE, IF, and IG, R 9a is -H or methyl.

[0044] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, IG, IG-1, or IH, R 10a and R 10b One of the groups is H or optionally substituted C 1~10 It is an alkyl.

[0045] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, IG, IG-1, or IH, R 10a and R 10b One of them is H.

[0046] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, IG, IG-1, or IH, R 10a and R 10b One of them is an arbitrarily substituted C 1~10 It is an alkyl.

[0047] In another embodiment of the compound of formula I, IA, IB, IC, ID, IE, IF, IG, IG-1, or IH, R 10a and R 10b One of the groups is methyl.

[0048] Another embodiment of a compound of formula I, IA, IB, IC, ID, IE, IF, IG, or IH is a compound of formula IIA, IIB, IIC, or IID, [ka] In the formula, R 10a and R 10bOne of the groups is H and optionally substituted C 1~10 is selected from the group consisting of alkyl, R 10a and R 10b The other is -CO 2 H, and -CO 2 -alkyl, optionally substituted C 1 ~ 10 Alkylene-R 101 , C 2 ~ 10 Alkenylene-R 101 , and C 2 ~ 10 Alkynylene-R 101 wherein: R 101 is H, (C 1~6 Alkyl)-S-, (C 1~6 Alkyl)-SO-, (C 1~6 Alkyl)-SO 2 -, -OH, -O-alkyl, -NR x R x’ , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R x and R x’ are each independently selected from -H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y’ )(R y’’ ) or R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10forming an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of alkyl, Each R y are independently H and optionally substituted C 1~10 alkyl.

[0049] Another embodiment of a compound of formula I, IA, IB, IC, ID, IE, IF, IG, or IH is a compound of formula IIA, IIB, IIC, or IID, [ka] In the formula, R 10a and R 10b One of the groups is H and optionally substituted C 1~10 is selected from the group consisting of alkyl, R 10a and R 10b The other is -CO 2 H, and -CO 2 -alkyl, optionally substituted C 1 ~ 10 Alkylene-R 101 , C 2 ~ 10 Alkenylene-R 101 , and C 2 ~ 10 Alkynylene-R 101 wherein: R 101 is H, (C 1~6 Alkyl)-S-, (C 1~6 Alkyl)-SO-, (C 1~6 Alkyl)-SO 2 -, -OH, -O-alkyl, -NR x R x’ , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R x and R x’are each independently selected from -H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y’ )(R y’’ ) or R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 forming a 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of alkyl, Each R y are independently H and optionally substituted C 1~10 alkyl.

[0050] In one embodiment of the compounds of formula IIA, IIB, IIC, and IID, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In another embodiment of the compounds of formula IIA, IIB, IIC, and IID, R 9a is -H or methyl.

[0051] Another embodiment of the compounds of formula IIA, IIB, IIC, and IID is a compound of formula IIA-1, IIA-2, IIB-1, IIB-2, IIC-1, IIC-2, IID-1, or IID-2. [ka] [ka]

[0052] In one embodiment of the compound of formula IIA-1, IIA-2, IIB-1, IIB-2, IIC-1, IIC-2, IID-1, or IID-2, R 9a In another embodiment of the compound of formula IIA-1, IIA-2, IIB-1, IIB-2, IIC-1, IIC-2, IID-1, or IID-2, R 9a is -H or methyl.

[0053] Another embodiment of the compounds of formula IIA, IIB, IIC, and IID is a compound of formula IIA-1a, IIA-2a, IIB-1a, IIB-2a, IIC-1a, IIC-2a, IID-1a, or IID-2a. [ka] [ka]

[0054] In one embodiment of the compound of formula IIA-1a, IIA-2a, IIB-1a, IIB-2a, IIC-1a, IIC-2a, IID-1a, or IID-2a, R 9a In another embodiment of the compound of formula IIA-1a, IIA-2a, IIB-1a, IIB-2a, IIC-1a, IIC-2a, IID-1a, or IID-2a, R 9a is -H or methyl.

[0055] Another embodiment of the compounds of formula IIA, IIB, IIC, and IID is a compound of formula IIA-1b, IIA-2b, IIB-1b, IIB-2b, IIC-1b, IIC-2b, IID-1b, or IID-2b. [ka] [ka]

[0056] In one embodiment of the compound of formula IIA-1b, IIA-2b, IIB-1b, IIB-2b, IIC-1b, IIC-2b, IID-1b, or IID-2b, R 9a In another embodiment of the compound of formula IIA-1b, IIA-2b, IIB-1b, IIB-2b, IIC-1b, IIC-2b, IID-1b, or IID-2b, R 9a is -H or methyl.

[0057] In one embodiment of a compound of formula IIA, IIB, IIC, IID, IIA-1a, IIA-2a, IIB-1a, IIB-2a, IIC-1a, IIC-2a, IID-1a, IID-2a, IIA-1b, IIA-2b, IIB-1b, IIB-2b, IIC-1b, IIC-2b, IID-1b, or IID-2b, R 10a -C 1 ~C 10 Alkylene-R 101a and R 101a -H, (C 1~6 Alkyl)-S-, (C 1~6 Alkyl)-SO-, (C 1~6 Alkyl)-SO 2 -, -OH, -O-alkyl, (C 1~6 Alkyl)-S-, (C 1~6 Alkyl)-SO-, (C 1~6 Alkyl)-SO 2 -, -NR x R x’ , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R x and R x’are each independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y’ )(R y’’ ), or R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 alkyl, wherein each R y are independently -H and optionally substituted C 1~10 alkyl.

[0058] In another embodiment, R 10a is an arbitrarily substituted C 3 Alkylene-R 101a and R 101a is -H, -OH, -O-alkyl, (C 1~6 Alkyl)-S-, (C 1~6 Alkyl)-SO-, (C 1~6 Alkyl)-SO 2 -, -NR x R x’ , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R x and R x’are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y’ )(R y’’ ), or R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 alkyl, wherein each R y are independently -H and optionally substituted C 1~10 alkyl.

[0059] In another embodiment, R 10a is an arbitrarily substituted R 101a -CH 2 CH 2 CH 2 -, R 101a -CH 2 CH 2 CH(OH)- and R 101a -CH 2 CH 2 CH(OMe)-, R 101a is -H, -OH, -O-optionally substituted alkyl, -N(Me)(Et), -N(Me) 2 , -N(Me)(t-Bu), -N(Me)(iPr), -NH(Me), -NH(iPr), -N(Et) 2, -N(Me)(cyclopropyl), -NH(cyclopropyl), -N(Me)(cyclobutyl), -NH(cyclobutyl), -N(Me)(cyclopentyl), -NH(cyclopentyl), -N(Me)(cyclohexyl), -NH(cyclohexyl), optionally substituted aziridinyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted piperazinyl-2-one, optionally substituted tetrahydroisoquinolinyl, optionally substituted indolinyl, and optionally substituted isoindolinyl.

[0060] In another embodiment, R 10a is an arbitrarily substituted R 101a -CH 2 CH 2 CH 2 -, R 101a -CH 2 CH 2 CH(OH)- and R 101a -CH 2 CH 2 CH(OMe)-, R 101a is NR x R x’ where R x and R x’ is H, methyl, or ethyl, and R x and R x’ the other is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, or -CH 2 C(CH 3 ) 3 In another embodiment, R x and R x’ is H, methyl, or ethyl, and R x and R x’ The other is -C(=O)-CH 2 -N(R y’ )(R y’’ ) in which R y’ and Ry’’ are each independently H or methyl. In another embodiment, R x and R x’ is H, methyl, or ethyl, and R x and R x’ The other is -C(=O)-CH 2 -N(R y’ )(R y’’ ) in which R y’ and R y’’ is H or methyl, and R y’ and R y’’ the other is H, methyl, cyclopropyl, or -CH 2 In a further embodiment, NR x R x’ -N(Me)(Et), -N(Me) 2 , -N(Me)(t-Bu), -N(Me)(iPr), -NH(Me), -NH(iPr), -N(Et) 2 , -N(Me)(cyclopropyl), -NH(cyclopropyl), -N(Me)(cyclobutyl), -NH(cyclobutyl), -N(Me)(cyclopentyl), -NH(cyclopentyl), -N(Me)(cyclohexyl), and -NH(cyclohexyl).

[0061] In a further embodiment, R 10a teeth, [ka] [ka] wherein the formula is selected from the group consisting of: [ka] " indicates the point of attachment.

[0062] In another embodiment of the compound of formula IIA, IIB, IIC, or IID, R 10a is an optionally substituted -C 2Alkylene-R 101a1 and R 101a1 is H, (C 1~6 Alkyl)-S-, (C 1~6 Alkyl)-SO-, (C 1~6 Alkyl)-SO 2 -, -OH, -O-optionally substituted alkyl, -NR x R x’ , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R x and R x’ are each independently selected from -H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y’ )(R y’’ ), or R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 alkyl, wherein each R y are independently -H and optionally substituted C 1~10 alkyl.

[0063] In another embodiment, R 10a is an arbitrarily substituted R 101a1 -CH 2 CH 2 -It is.

[0064] In a further embodiment, R 101a1is -S(Me), -SO(Me), or -SO 2 (Me).

[0065] In another embodiment, R 10a is MeSCH 2 CH 2 -, MeSOCH 2 CH 2 - or MeSO 2 CH 2 CH 2 -It is.

[0066] In a further embodiment, R 101a1 is an optionally substituted heterocycloalkyl.

[0067] In another embodiment, R 10a teeth, [ka] wherein the formula is selected from the group consisting of: [ka] " indicates the point of attachment.

[0068] In another embodiment of the compounds of formula IIA, IIB, IIC, and IID, R 10a is an arbitrarily substituted C 1 Alkylene-R 101a2 and R 101a2 is -H, -OH, -O-alkyl, -NR x R x’ , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R x and R x’are each independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y’ )(R y’’ ), or R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 alkyl, wherein each R y are independently H and optionally substituted C 1~10 alkyl.

[0069] In another embodiment, R 10a is an arbitrarily substituted R 101a2 -CH 2 -, R 101a2 -CH(OH)-, R 101a2 -CH(OMe)-, [ka] or R 101a2 -C(=O)-, wherein [ka] " indicates the point of attachment, R 101a2 is -H, -OH, -O-alkyl, -NR x R x’, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R x and R x’ are each independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y’ )(R y’’ ), or R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 alkyl, wherein each R y are independently H and optionally substituted C 1~10 alkyl.

[0070] In another embodiment, R 10a is R 101a2 -CH 2 - and R 101a2 is NR x R x’ where R x and R x’are each independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, and optionally substituted alkylene-heteroaryl groups, as well as -C(=O)-alkylene-N(R y’ )(R y’’ ).

[0071] In a further embodiment, R 10a is an arbitrarily substituted R 101a2 -CH 2 - and R 101a2 -NHR z , and -NMeR z wherein: R z is an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted -CH 2 -cycloalkyl, optionally substituted -CH 2 -heterocycloalkyl, optionally substituted -CH 2 -aryl, optionally substituted -CH 2 -heteroaryl, -(C=O)-cycloalkyl, or -(C=O)-alkylene-NR z’ R z’’ where R z’ and R z’’ are each independently H or alkyl; R z is an optionally substituted alkylene-R 101a2’ where R 101a2’ is an optionally substituted heteroaryl.

[0072] In a further embodiment, R 101a2 -CH 2 - is -(CH 2 ) 6-heteroaryl. In another embodiment, R 101c -CH 2 - is -(CH 2 ) 6 -triazolyl.

[0073] In a further embodiment, R 101a2 -CH 2 -, -CH 2 NHMe, -CH 2 N(Me) 2 , -CH 2 N(Me)(cyclopropyl), -CH 2 NH(oxetanyl), -CH 2 NHCH 2 (cyclopropyl), or - [ka] In the formula, [ka] " indicates the point of attachment.

[0074] In a further embodiment, R 10a is an arbitrarily substituted R 101a2 -CH 2 - and R 101a2 is -(C=O)-cycloalkyl or -(C=O)-alkylene-NR z’ R z’’ where R z’ and R z’’ are each independently -H or alkyl.

[0075] In a further embodiment, R 10a is an arbitrarily substituted R 101a2 -CH 2 - and R 101a2 is -(C=O)-CH 2 -NR z’ R z’’ where R z’ and Rz’’ are each independently -H or alkyl.

[0076] In a further embodiment, R 10a is an arbitrarily substituted R 101a2 -CH 2 - and R 101a2 is -(C=O)-CH 2 -NH 2 , -(C=O)-CH 2 -NHMe, or -(C=O)-CH 2 -N(Me) 2 It is.

[0077] In another embodiment, R 10a is R 101a2 -CH 2 - and R 101a2 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0078] In another embodiment, R 10a is R 101a2 -CH 2 - and R 101a2 is selected from the group consisting of optionally substituted cyclobutyl, optionally substituted azetinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, and optionally substituted triazolyl.

[0079] In another embodiment, R 10a is R 101a2 -CH 2 - and R 101a2is selected from the group consisting of optionally substituted cyclobutyl, optionally substituted azetinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, and optionally substituted triazolyl.

[0080] In another embodiment, R 10a is an arbitrarily substituted R 101a2 -CH 2 -, R 101a2 -CH(OH)-, R 101a2 -CH(OMe)-, [ka] or R 101a2 -C(=O)-, wherein [ka] " indicates the point of attachment, R 101a2’ is an optionally substituted piperidinyl or an optionally substituted piperidinyl.

[0081] In another embodiment, R 10a is an arbitrarily substituted R 101a2 -CH 2 -, R 101a2 -CH(OH)-, R 101a2 -CH(OMe)-, [ka] or R 101a2 -C(=O)-, wherein [ka] " indicates the point of attachment, R 101a2’ is arbitrarily replaced [ka] or optionally substituted [ka] where R 101a2’ is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, -C(=O)-H, -C(=O)-optionally substituted cycloalkyl, -C(=O)-optionally substituted alkylene-R 101a2’’ or optionally substituted alkylene-R 101a2’’ where R 101a2’’ is selected from the group consisting of H, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkenyl, [ka] " indicates the point of attachment.

[0082] In another embodiment, R 10a is R 101a2 -CH 2 -, R 101a2 -CH(OH)-, R 101a2 -CH(OMe)-, [ka] or R 101a2 -C(=O)-, R 101a2 teeth, [ka] where R 101a2’ is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, -C(=O)-H, -C(=O)-optionally substituted cycloalkyl, -C(=O)-optionally substituted alkylene-R 101a2’’or optionally substituted alkylene-R 101a2’’ where R 101a2’’ is selected from the group consisting of H, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkenyl, [ka] " indicates the point of attachment.

[0083] In another embodiment, [ka] teeth, [ka] and R 101a2’ is selected from the group consisting of -alkylene-OH and -alkyleneO-alkyl. 101a is -(CH 2 ) 3 -OH, -(CH 2 ) 3 -OMe, -(CH 2 ) 2 -OH and -(CH 2 ) 2 -OMe, wherein [ka] " indicates the point of attachment.

[0084] In another embodiment, [ka] teeth, [ka] and R 101a2’is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, CH 2 (Me) 3 hexyl, and heptyl, [ka] " indicates the point of attachment.

[0085] In another embodiment, [ka] teeth, [ka] and R 101a2’ is alkenyl. In a further embodiment, R 101a teeth, [ka] In the formula, [ka] " indicates the point of attachment.

[0086] In another embodiment, [ka] teeth, [ka] and R 101a2’ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, [ka] " indicates the point of attachment.

[0087] In another embodiment, [ka] teeth, [ka] and R 101a2’ is an optionally substituted alkylene-cycloalkyl. In a further embodiment, R 101a is an optionally substituted -CH 2 -cycloalkyl. In a further embodiment, R 101a is an optionally substituted -CH 2 -cyclopropyl, optionally substituted -CH 2 -cyclobutyl, optionally substituted -CH 2 -cyclopentyl, and optionally substituted -CH 2 -cyclohexyl, [ka] " indicates the point of attachment.

[0088] In another embodiment, [ka] teeth, [ka] and R 101a2’ is -C(=O)-cycloalkyl.

[0089] In another embodiment, [ka] teeth, [ka] and R 101a2’is -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, or -C(=O)-cyclohexyl, [ka] " indicates the point of attachment.

[0090] In another embodiment, [ka] teeth, [ka] and R 101a2’ is an optionally substituted alkylene-aryl or an optionally substituted -CH 2 -aryl. In a further embodiment, R 101a is -CH 2 -phenyl, -CH 2 -Furanyl, -CH 2 -pyridyl, optionally substituted -CH 2 -cyclobutyl, optionally substituted -CH 2 -cyclopentyl, or optionally substituted -CH 2 -cyclohexyl, [ka] " indicates the point of attachment.

[0091] In another embodiment, R 10a teeth, [ka] [ka] wherein the formula is selected from the group consisting of: [ka] " indicates the point of attachment.

[0092] In another embodiment, R 10a is R 101a2 -CH 2 -, R 101a2 -CH(OH)-, R 101a2 -CH(OMe)-, [ka] or R 101a2 -C(=O)-, R 101a2 teeth, [ka] where R 101a2’ is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, -C(=O)-H, -C(=O)-optionally substituted cycloalkyl, -C(=O)-optionally substituted alkylene-R 101a2’’ or optionally substituted alkylene-R 101a2’’ where R 101a2’’ is selected from the group consisting of H, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkenyl, [ka] " indicates the point of attachment.

[0093] In another embodiment, R 10a teeth, [ka] and R 101a2’ is selected from the group consisting of -alkylene-OH and -alkyleneO-alkyl.

[0094] In a further embodiment, R 10a teeth, [ka] and R 101a2’ is -(CH 2 ) 3 -OH, -(CH 2 ) 3 -OMe, -(CH 2 ) 2 -OH and -(CH 2 ) 2 -OMe.

[0095] In another embodiment, R 10a teeth, [ka] and R 101a2’ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, CH 2 (Me) 3 hexyl, and heptyl, [ka] " indicates the point of attachment.

[0096] In another embodiment, R 10a teeth, [ka] and R 101a2’ is alkenyl.

[0097] In another embodiment, R 10a teeth, [ka] and R101a2’ teeth, [ka] In the formula, [ka] " indicates the point of attachment.

[0098] In another embodiment, R 10a teeth, [ka] and R 101a2’ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, [ka] " indicates the point of attachment.

[0099] In another embodiment, R 10a teeth, [ka] and R 101ca2’ is an optionally substituted alkylene-cycloalkyl.

[0100] In another embodiment, R 10a teeth, [ka] and R 101a2’ is an optionally substituted -CH 2 -cyclopropyl, optionally substituted -CH 2 -cyclobutyl, optionally substituted -CH 2 -cyclopentyl, or optionally substituted -CH 2-cyclohexyl, [ka] " indicates the point of attachment.

[0101] In another embodiment, R 10a teeth, [ka] and R 101ca2’ is -C(=O)-cycloalkyl. In another embodiment, R 101a is -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, or -C(=O)-cyclohexyl, [ka] " indicates the point of attachment.

[0102] In another embodiment, R 10a teeth, [ka] and R 101a2’ is an optionally substituted alkylene-aryl or an optionally substituted -CH 2 -aryl. In a further embodiment, R 101a is -CH 2 -phenyl, -CH 2 -Furanyl, -CH 2 -pyridyl, optionally substituted -CH 2 -cyclobutyl, optionally substituted -CH 2 -cyclopentyl, or optionally substituted -CH 2 -cyclohexyl, [ka] " indicates the point of attachment, [ka] " indicates the point of attachment.

[0103] In another embodiment, R 10a teeth, [ka] wherein the formula is selected from the group consisting of: [ka] " indicates the point of attachment.

[0104] In another embodiment, R 10a is R 101a3 -CH 2 -, R 101a3 -CH(OH)-, R 101a3 -CH(OMe)-, [ka] or R 101a3 -C(=O)-, R 101a3 is an optionally substituted azetidinyl.

[0105] In another embodiment, R 10a teeth, [ka] wherein the formula is selected from the group consisting of: [ka] " indicates the point of attachment.

[0106] In another embodiment, R 10a is R 101a4 -CH 2 -, R 101a4 -CH(OH)-, R 101a4 -CH(OMe)-, [ka] or R 101a4 -C(=O)-, R 101a5 is optionally substituted cyclobutyl.

[0107] In another embodiment, R 10a teeth [ka] wherein the formula is selected from the group consisting of: [ka] " indicates the point of attachment.

[0108] In another embodiment, R 10a is R 101a5 -CH 2 -, R 101a5 -CH(OH)-, R 101a5 -CH(OMe)-, [ka] or R 101a5 -C(=O)-, R 101a5 is an optionally substituted triazolyl.

[0109] In another embodiment, R 10a teeth, [ka] In the formula, [ka] " indicates the point of attachment.

[0110] In another embodiment, R 10a is an arbitrarily substituted C 2~10 Alkenylene-R 101 where R 101 is -H, -OH, -O-alkyl, -NR x R x’, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R x and R x’ are each independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y’ )(R y’’ ) or R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 forming an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of alkyl, Each R y are independently -H and optionally substituted C 1~10 alkyl.

[0111] In another embodiment, R 10a teeth, [ka] Optionally substituted C selected from the group consisting of 2~5 Alkenylene-R 101e where: R 101e is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and NR x R x’ Selected from Rx and R x’ are each independently H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y’ )(R y’’ ) or R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 forming an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of alkyl, Each R y are independently -H and optionally substituted C 1~10 is selected from the group consisting of alkyl, During the ceremony, `` [ka] " indicates the point of attachment.

[0112] In another embodiment, R 10a teeth, [ka] Optionally substituted C selected from the group consisting of 2~5 Alkenylene-R 101 In the formula, [ka] " indicates the point of attachment.

[0113] In another embodiment, R 10ais an optionally substituted alkenylene-R 101 [ka] where A is an optionally substituted cycloalkyl or heterocycloalkyl; R 101e is H, halo, alkyl, haloalkyl and -NR x R x’ wherein R x and R x’ are each independently selected from the group consisting of H and optionally substituted alkyl, [ka] " indicates the point of attachment.

[0114] In another embodiment, R 10a teeth, [ka] Optionally substituted alkenylene-R is selected from the group consisting of 101 [ka] It is.

[0115] Another embodiment of the compound of formula I is a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof, R 101b is H, optionally substituted alkyl or alkoxy; R 10b is -H or alkyl; R 11a and R 11b is independently selected from the group consisting of H and methyl; R x and R x’are each independently selected from -H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y ) 2 or selected from the group consisting of: R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 forming an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of alkyl, Each R y are independently H and optionally substituted C 1~10 alkyl.

[0116] In some embodiments of Formula III, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In some embodiments of III, R 9a is -H or methyl, R 10b is H or methyl. In some embodiments, R 11a and R 11b are each independently H or methyl. In some embodiments, R 10b is H and R 11a and R 11b are each independently H.

[0117] In one embodiment, R 101b is H, methyl, or methoxy.

[0118] In one embodiment of Formula III, NR x R x’ -N(Me)(Et), -N(Me) 2 , -N(Me)(t-Bu), -N(Me)(iPr), -NH(Me), -NH(iPr), -N(Et) 2 , -N(Me)(cyclopropyl), -NH(cyclopropyl), -N(Me)(cyclobutyl), -NH(cyclobutyl), -N(Me)(cyclopentyl), -NH(cyclopentyl), -N(Me)(cyclohexyl), and -NH(cyclohexyl).

[0119] Another embodiment of the compound of formula I is a compound of formula IV: [ka] or a pharma- ceutically acceptable salt thereof, R 101b is H, optionally substituted alkyl or alkoxy; R 11a and R 11b is independently selected from the group consisting of: -H and methyl; [ka] is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0120] In one embodiment of Formula IV, R 101b is H, methyl, or methoxy; [ka] is selected from the group consisting of optionally substituted aziridinyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted piperazinyl-2-one, optionally substituted tetrahydroisoquinolinyl, optionally substituted indolinyl, and optionally substituted isoindolinyl.

[0121] In some embodiments of Formula IV, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In some embodiments of IV, R 9a is -H or methyl, and R 10b is H or methyl. In some embodiments, R 11a and R 11b are each independently H or methyl. In some embodiments, R 10b is H and R 11a and R 11b are each independently H.

[0122] Another embodiment of the compound of formula I is a compound of formula V: [ka] or a pharma- ceutically acceptable salt thereof, R 101b is H, optionally substituted alkyl or alkoxy; R 11a and R 11b is independently selected from the group consisting of: -H and methyl; [ka] is an optionally substituted heterocycloalkyl.

[0123] In one embodiment of Formula V, R 10b is H or optionally substituted alkyl; [ka] is optionally substituted piperidinyl.

[0124] In some embodiments of Formula V, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In some embodiments of V, R 9a is -H or methyl, and R 10b is H or methyl. In some embodiments, R 11a and R 11b are each independently H or methyl. In some embodiments, R 10b is H and R 11a and R 11b are each independently H.

[0125] Another embodiment of the compound of formula I is a compound of formula VI: [ka] or a pharma- ceutically acceptable salt thereof, R 101b is H, R 10b is H or alkyl, R 11a and R 11b is independently selected from the group consisting of: -H and methyl; R x and R x’ are each independently selected from -H, optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl, and -C(=O)-alkylene-N(R y ) 2 or selected from the group consisting of: R x and R x’ together with the atoms to which they are attached, optionally O, S, SO, SO 2 , N.R. y , and N.C. 1 ~C 10 forming an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of alkyl, Each R y are independently -H and optionally substituted C 1~10 alkyl; R x and R x’ One of the groups is -H or alkyl, and the other is R z where: R z is -(C=O)-cycloalkyl or -(C=O)-alkylene-NR z’’ R z’’’ where R z’’ and R z’’’ are each independently -H or alkyl; R z is -alkylene-R 101a where R 101a is an optionally substituted heteroaryl.

[0126] In some embodiments of Formula VI, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In some embodiments of VI, R 9a is -H or methyl, and R 10b is H or methyl. In some embodiments, R 11a and R 11b are each independently H or methyl. In some embodiments, R 10b is H and R 11a and R 11b are each independently H.

[0127] Another embodiment of the compound of formula I is a compound of formula VII: [ka] or a pharma- ceutically acceptable salt thereof, R 101c is H, R 101b is -H, -OH, -OMe, or -OCH 2 OMe or R 101b and R 101c forms =O, R 10b is -H or optionally substituted alkyl; R 11a and R 11b is independently selected from the group consisting of: -H and methyl; [ka] is selected from the group consisting of optionally substituted cyclobutyl, optionally substituted azetinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, and optionally substituted triazolyl.

[0128] In some embodiments of Formula VII, R 9a is -H, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In some embodiments of VII, R 9a is -H or methyl, and R 10b is H or methyl. In some embodiments, R 11a and R 11b are each independently H or methyl. In some embodiments, R 10b is H and R 11a and R 11b are each independently H.

[0129] In another embodiment, the compound of Formula I, II, III, IV, V, VI, or VII is selected from Table A, or a pharma- ceutically acceptable salt thereof.

Table A-1

Table A-2

Table A-3

Table A-4

Table A-5

Table A-6

Table A-7

Table A-8

Table A-9

Table A-10

Table A-11

Table A-12

Table A-13

Table A-14

Table A-15

Table A-16

Table A-17

Table A-18

Table A-19

Table A-20

Table A-21

Table A-22

Table A-23

Table A-24

Table A-25

Table A-26

Table A-27

Table A-28

Table A-29

Table A-30

Table A-31

Table A-32

Table A-33

Table A-34

Table A-35

Table A-36

Table A-37

Table A-38

Table A-39

Table A-40

Table A-41

Table A-42

Table A-43

Table A-44

Table A-45

Table A-46

[0130] Unless otherwise stated, any formula described herein is also meant to include its salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives. In certain embodiments, the compounds provided are salts of any of the formulas described herein. In certain embodiments, the compounds provided are pharma- ceutically acceptable salts of any of the formulas described herein. In certain embodiments, the compounds provided are solvates of any of the formulas described herein. In certain embodiments, the compounds provided are hydrates of any of the formulas described herein. In certain embodiments, the compounds provided are polymorphs of any of the formulas described herein. In certain embodiments, the compounds provided are co-crystals of any of the formulas described herein. In certain embodiments, the compounds provided are tautomers of any of the formulas described herein. In certain embodiments, the compounds provided are stereoisomers of any of the formulas described herein. In certain embodiments, the compounds provided are isotopically labeled forms of any of the formulas described herein. For example, replacement of hydrogen with deuterium or tritium, 19 F 18 Replace with F, or 13 C or 14 By C 12 Compounds having this structure, except for the replacement of 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.

[0131] Additional Expressions Provided herein are certain intermediates that can be prepared during the preparation of the macrolides described herein.

[0132] In one aspect, the present disclosure provides a macrolide right half intermediate of formula (M): [ka] or a salt thereof, wherein R 3 , R 4a , R4b , R 5 , R 6a , R 6b , R 8a , and R 8b is as described herein; G 4 is of the following formula: [ka] R 15 Each instance of is independently silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or two R 15 the groups are joined to form an optionally substituted heterocyclyl or heteroaryl ring; R 16a Each instance of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0133] In another aspect, the present disclosure provides a non-cyclized macrolide intermediate of formula (N): [ka] or a salt thereof, wherein PG is a protecting group, R 4a , R 4b , R 5 , R 6a , R 6b , R 8a , and R 8b is as described herein; G 4 is of the following formula: [ka] R 15Each instance of is independently silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or two R 15 the groups are linked to form an optionally substituted heterocyclyl or heteroaryl ring; R 16a Each instance of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0134] In some embodiments, -OPG is -OBz.

[0135] In certain embodiments, the compound of formula (N) is a compound of formula (Na): [ka] or a salt thereof, in which the variables are as defined herein.

[0136] Preparation by coupling and macrolactonization In certain embodiments, the macrolide of the present disclosure is R s is a sugar residue [ka] where PG is a protecting group and [ka] " indicates the point of attachment, with a compound of formula (N-1) (left half) to provide the uncyclized macrolide precursor of formula (Na) as shown in Scheme 1.

[0137] Scheme 1. [ka] Formula (Na) is cyclized to form a sugar residue [ka] After deprotection of the above, the macrolide of formula (I) is obtained as shown in Scheme 2.

[0138] Scheme 2. [ka] Alternatively, a macrolide precursor of formula (Na) can be cyclized to give a macrolide of formula (P), i.e., a compound of formula (I), 9a is hydrogen), which can undergo reductive amination to provide compounds of formula (I) as shown in Scheme 3, 9a is other than H, as otherwise defined for formula I.

[0139] Scheme 3. [ka] R 2b Later resolution of the group can be achieved by reacting a base and a suitable electrophilic group (e.g., a halogenating agent or R 2 This can be achieved through treatment of a compound of formula (A) prepared to provide R 2a or R 2b These compounds can be prepared in the same manner as the compounds of formula (I) shown in Schemes 2 and 3, except that one of is hydrogen.

[0140] Scheme 4. [ka] Exemplary methods that may be used in the preparation of the macrolides of the present disclosure are described below and should not be construed as limiting. Further description of right and left half preparation methods, half coupling, macrocyclization, and other methods for the various steps in the preparation of the macrolides herein are described in PCT Publication Nos. WO2014 / 165792 and WO2016 / 154591, both of which are incorporated herein by reference in their entireties. The macrolides herein may be prepared by other synthetic methods known in the art, and the procedures described herein may be modified or combined with other known methods.

[0141] For all intermediates, the variables are as defined herein for compounds of formula (I).

[0142] The other variables displayed for the intermediates and precursors are defined as follows: R 2a is other than H as defined for formula I, and is selected from halo, optionally substituted C 1~10 Alkyl, optionally substituted C 1~10 Alkoxy and optionally substituted C 1~10 alkenyl, 1~10 Alkyl, C 1~10 Alkoxy and C 1~10 the alkenyl is optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; LG is a leaving group, G 4 is of the following formula: [ka] R 15Each instance of is independently silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or two R 15 the groups are linked to form an optionally substituted heterocyclyl or heteroaryl ring; R 16a Each instance of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0143] R 5 is the sugar part [ka] In some embodiments, the sugar moiety is typically attached to the macrolide framework during synthesis of the right half, but may be attached at other stages of the preparation. The sugar moiety may be attached by a chemical or enzymatic glycosylation reaction between the hydroxyl group at the C5 position and a glycosyl donor. In certain embodiments, the sugar moiety is attached to the macrolide framework as a thioglycoside. In certain embodiments, the substituents of the sugar moiety are modified after glycosylation of the macrolide or macrolide precursor (e.g., the right half).

[0144] Pharmaceutical Compositions and Administration The present disclosure provides a pharmaceutical composition comprising a macrolide described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0145] Pharmaceutically acceptable excipients include any and all solvents, diluents, or other liquid vehicles, dispersants, suspending aids, surface active agents, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., appropriate for the particular dosage form desired. General considerations in the manufacture of formulations and / or pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0146] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such methods include the step of bringing into association a macrolide of the present invention with the carrier and / or one or more other accessory ingredients and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multi-dosage unit.

[0147] The pharmaceutical compositions may be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of a macrolide of the invention. The amount of macrolide is generally equal to the dosage of the macrolide that would be administered to a subject, and / or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.

[0148] The relative amounts of the macrolide, pharma- ceutically acceptable excipient, and / or any additional components in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as depending further on the route by which the composition is administered. By way of example, the composition may contain from 0.1% to 100% (w / w) of the macrolide.

[0149] Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents 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 perfuming agents may also be present in the composition.

[0150] Liquid dosage forms for oral and parenteral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the macrolide, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and 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 aromatics. In certain embodiments for parenteral administration, the conjugate of the present invention is mixed with a solubilizer, and mixtures thereof.

[0151] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing 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, for example, as solutions in 1,3-butanediol.Among acceptable vehicles and solvents that can be employed are water, Ringer's solution, USP, and isotonic sodium chloride injection.In addition, sterile solidified oils are conventionally used as solvents or suspending media.

[0152] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the macrolide is mixed with at least one inert, pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) wetting agents, such as glycerol, d) disintegrants, such as agar, calcium carbonate, and / or glycerol. In the case of capsules, tablets, and pills, the dosage form may contain buffering agents.

[0153] Dosage forms for topical and / or transdermal administration of the macrolides of the invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and / or patches. Generally, the macrolide is admixed under sterile conditions with a pharma- ceutically acceptable carrier and / or any needed preservatives and / or buffers as may be required.

[0154] Although the description of pharmaceutical compositions provided herein is primarily directed 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. Modifications of pharmaceutical compositions to render them suitable for administration to a variety of animals are well understood, and veterinary pharmacologists of skill in the art can design and / or perform such modifications with routine experimentation.

[0155] The macrolides provided herein are typically formulated in unit dosage form for ease of administration and uniformity of dosage. However, it will be understood that the total daily dose of the macrolide will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend on a variety of factors, including the disease, disorder, or condition being treated, as well as the severity of the disorder; the activity of the specific macrolide used; the specific composition used; the age, weight, general health, sex, and diet of the subject; the administration time, route of administration, and excretion rate of the specific macrolide used; the duration of treatment; drugs used in combination or simultaneously with the specific macrolide used; and similar factors well known in the medical arts.

[0156] The macrolides and compositions provided herein may be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intraspinal, intrathecal, subcutaneous, intracerebroventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (by powder, ointment, cream, and / or infusion), mucosal, nasal, buccal, sublingual, by intratracheal instillation, bronchial instillation, and / or by inhalation, and / or as oral spray, nasal spray, and / or aerosol. In general, the most appropriate route of administration will depend on a variety of factors, including the nature of the agent, the treatment regimen, and / or the condition of the subject. Oral administration is the preferred mode of administration. However, in certain embodiments, the subject may not be in a condition to tolerate oral administration, and therefore intravenous, intramuscular, and / or rectal administration are also preferred alternative modes of administration.

[0157] An effective amount can be contained in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses).In certain embodiments, when multiple doses are administered to a subject or applied to tissue or cells, any two doses of the multiple doses contain different or substantially the same amount of the compound described herein.In certain embodiments, when multiple doses are administered to a subject or applied to tissue or cells, the frequency of administering multiple doses to a subject or applying multiple doses to tissue or cells is 3 times a day, 2 times a day, 1 time a day, 1 time every other day, 1 time every 3 days, 1 time a week, 1 time every 2 weeks, 1 time every 3 weeks, or 1 time every 4 weeks. In certain embodiments, the doses described herein (e.g., a single dose, or any of the multiple doses) independently comprise between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.

[0158] It will also be understood that the macrolides or compositions described herein can be administered in combination with one or more additional therapeutically active agents. The macrolides or compositions can be administered simultaneously with, prior to, or after 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 further be understood that the additional therapeutically active agents utilized in the combination can be administered together in a single composition or administered separately in different compositions. The particular combination to be used in the regimen will take into account the compatibility of the macrolides of the present invention with the additional therapeutically active agents and / or the desired therapeutic effect to be achieved. In general, it is expected that the additional therapeutically active agents utilized in combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In certain embodiments, the levels utilized in combination will be lower than the levels utilized individually.

[0159] Exemplary additional therapeutically active agents include, but are not limited to, antibiotics, antivirals, anesthetics, anticoagulants, enzyme inhibitors, steroids, 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 by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0160] In certain embodiments, the additional therapeutically active agent is an antibiotic. Exemplary antibiotics include penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g., cephalexin), macrolides (e.g., erythromycin, clarithromycin, azithromycin, troleandomycin), fluoroquinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin), sulfonamides (e.g., cotrimoxazole, trimethoprim), tetracyclines (e.g., tetracycline, chlortetracycline, oxytetracycline, demeclomycin, methacycline, sancycline, doxycline (doxycycline), tetracycline, ... oxycline), 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 / dalfoprisin (Syndercid™).

[0161] The present invention also encompasses kits (e.g., pharmaceutical packs). The kits provided may include a pharmaceutical composition or macrolide 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 certain embodiments, the kits provided may optionally further include a second container, which includes a pharmaceutical additive for diluting or suspending the pharmaceutical composition or macrolide of the present invention. In certain embodiments, the pharmaceutical composition or macrolide of the present invention provided in a container and the second container are combined to form a unit dosage form.

[0162] Treatment Methods and Uses The present disclosure contemplates the use of the macrolides of the present invention for the treatment of infectious diseases, e.g., fungal, bacterial, viral, or parasitic infections, and for the treatment of inflammatory conditions. Ketolides are known to exhibit antibacterial as well as antiparasitic activity. See, e.g., Clark et al., Bioorganic & Medicinal Chemistry Letters (2000) 10:815-819 (antibacterial activity) and Lee et al., J. Med. Chem. (2011) 54:2792-2804 (antibacterial and antiparasitic activity). Ketolides are also known to exhibit anti-inflammatory effects. See, e.g., Amsden, Journal of Antimicrobial Chemotherapy (2005) 55:10-21 (chronic pulmonary inflammatory syndrome).

[0163] Thus, as generally described herein, there is provided a method of treating an infectious disease, comprising administering to a subject in need thereof an effective amount of a macrolide of the present disclosure, or a pharma- ceutically acceptable salt thereof. Such a method may be performed in vivo (i.e., by administration to a subject) or in vitro (e.g., by contact with a pathogen, tissue, or cell culture). As used herein, treatment includes therapeutic and prophylactic treatment.

[0164] In certain embodiments, the effective amount is a therapeutically effective amount.For example, in certain embodiments, the method slows down the progression of infectious disease in the subject.In certain embodiments, the method improves the condition of the subject suffering from infectious disease.In certain embodiments, the subject has suspected or confirmed infectious disease.

[0165] In certain embodiments, the effective amount is a prophylactically effective amount. For example, in certain embodiments, the method prevents or reduces the likelihood of an infectious disease, for example, in certain embodiments, the method comprises administering to a subject in need thereof a macrolide of the present invention in an amount sufficient to prevent or reduce the likelihood of an infectious disease. In certain embodiments, the subject is at risk for an infectious disease (e.g., has been exposed to another subject with suspected or confirmed infectious disease, or has been exposed or is believed to have been exposed to a pathogen).

[0166] In another aspect, an in vitro method of inhibiting pathogen growth is provided, the method comprising contacting an effective amount of a macrolide of the invention with a pathogen (e.g., a bacterium, virus, fungus, or parasite) in cell culture.

[0167] As used herein, "infectious disease" and "microbial infection" are used interchangeably and refer to an infection by a pathogen, such as a fungus, bacteria, virus, or parasite. In certain embodiments, the infectious disease is caused by a pathogen that is resistant to other treatments. In certain embodiments, the infectious disease is caused by a pathogen that is multi-drug tolerant or resistant, e.g., the infectious disease is caused by a pathogen that does not grow or die in the presence or as a result of other treatments.

[0168] In certain embodiments, the infectious disease is a bacterial infection. For example, in certain embodiments, a method of treating a bacterial infection is provided, the method comprising administering to a subject in need thereof an effective amount of a macrolide of the present invention, or a pharma- ceutically acceptable salt thereof.

[0169] In certain embodiments, the macrolide has a mean inhibitory concentration (MIC) for a particular bacterial isolate of less than 50 μg / mL, less than 25 μg / mL, less than 20 μg / mL, less than 10 μg / mL, less than 5 μg / mL, or less than 1 μg / mL.

[0170] In certain embodiments, the bacterial isolates are susceptible (e.g., responsive) or resistant to known commercially available macrolides, such as azithromycin, clindamycin, telithromycin, erythromycin, spiramycin, etc. In certain embodiments, the bacterial isolates are resistant to known macrolides. For example, in certain embodiments, the bacteria are erythromycin-resistant (ER). In certain other embodiments, the bacteria are azithromycin-resistant (AR).

[0171] In certain embodiments, the bacterial infection is resistant to other antibiotic (e.g., non-macrolide) therapies. For example, in certain embodiments, the pathogen is vancomycin-resistant (VR). In certain embodiments, the pathogen is methicillin-resistant (MR), for example, in certain embodiments, the bacterial infection is a methicillin-resistant S. aureus infection (MRSA infection). In certain embodiments, the pathogen is quinolone-resistant (QR). In certain embodiments, the pathogen is fluoroquinolone-resistant (FR).

[0172] In certain embodiments, the bacterial isolate has an efflux (e.g., mef, msr) genotype. In certain embodiments, the bacteria has a methylase (e.g., erm) genotype. In certain embodiments, the bacterial isolate has a constitutive genotype. In certain embodiments, the bacterial isolate has an inducible genotype.

[0173] Exemplary bacterial infections include, but are not limited to, infections with gram-positive bacteria (e.g., Actinobacteria, Firmicutes, or Tenericutes), gram-negative bacteria (e.g., Aquificae, Deinococcus-Thermus, Fibrobacteres / Chlorobi / Bacteroidetes (FCB), Fusobacteria, Gemmatimonadest, Ntrospirae, Planctomycetes / Verrucomicrobia / Chlamydiae (PVC), Proteobacteria, Spirochaetes, or Synergistetes), or other bacteria (e.g., Acidobacteria, Chlroflexi, Chrystiogenetes, Cyanobacteria, Deferrubacteres, Dictyoglomi, Thermodesulfobacteria, or Thermotogae).

[0174] In certain embodiments, the bacterial infection is an infection with a gram-positive bacteria.

[0175] In certain embodiments, the Gram-positive bacterium is a bacterium of the phylum Firmicutes.

[0176] In certain embodiments, the bacterium is a member of the phylum Firmicutes and the genus Enterococcus, i.e., the bacterial infection is an Enterococcus infection. Exemplary Enterococci bacteria include, but are not limited to, E. avium, E. durans, E. faecalis, E. faecium, E. gallinarum, E. solitarius, E. casseliflavus, and E. raffinosus.

[0177] In certain embodiments, the bacterium is a member of the phylum Firmicutes and the genus Staphylococcus, i.e., the bacterial infection is a Staphylococcus infection. Exemplary Staphylococci 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. Staphylococcus infections include, but are not limited to, Staphylococcus aureus, Staphylococcus spp. ...

[0178] In certain embodiments, the bacterium is a member of the phylum Firmicutes and the genus Bacillus, i.e., 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. lentis ... Bacillus infections include, but are not limited to, B. tus, B. licheniformis, B. megaterium, B. mesentericus, B. mucilaginosus, B. mycoides, B. natto, B. pantothenticus, B. polymyxa, B. pseudoanthracis, B. pumilus, B. schlegelii, B. sphaericus, B. sporothermodurans, B. stearothermophilus, B. subtilis, B. thermoglucosidasius, B. thuringiensis, B. vulgatis, and B. weihenstephanensis. In certain embodiments, the Bacillus infection is a B. subtilis infection. In certain embodiments, the B. subtilis has an efflux (e.g., mef, msr) genotype. In certain embodiments, the B. subtilis has a methylase (e.g., erm) genotype.

[0179] In certain embodiments, the bacterium is a member of the phylum Firmicutes and the genus Streptococcus, i.e., the bacterial infection is a Strepococcus infection. Exemplary Strepococcus bacteria include, but are not limited to, S. agalactiae, S. angiosus, 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 certain embodiments, the Strepococcus infection is a S. pyogenes infection. In certain embodiments, the Strepococcus infection is a S. pneumoniae infection. In certain embodiments, the S. pneumoniae has an efflux (e.g., mef, msr) genotype. In certain embodiments, the S. pneumoniae has a methylase (e.g., erm) genotype.

[0180] In certain embodiments, the bacterium is a member of the phylum Actinobacteria and the genus Mycobacterium, i.e., the bacterial infection is a Mycobacterium infection. Exemplary Mycobacteriaceae bacteria include, but are not limited to, M. tuberculosis, M. avium, M. gordonae, M. kansasi, M. nonchromogenicum, M. terrae, M. ulcerans, M. simiae, M. leprae, M. abscessus, M. chelonae, M. fortuitum, M. mucogenicum, M. parafortuitum, and M. vaccae.

[0181] In certain embodiments, the bacterial infection is an infection with a gram-negative bacterium.

[0182] In certain 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 certain embodiments, the Escherichia infection is an E. coli infection.

[0183] In certain embodiments, the gram-negative bacteria is a bacterium of the phylum Proteobacteria and the genus Haemophilus. That is, 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 certain embodiments, the Haemophilus infection is an H. influenzae infection.

[0184] In certain 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. baumanii, A. haemolyticus, and A. lwoffii. In certain embodiments, the Acinetobacter infection is an A. baumanii infection.

[0185] In certain 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 certain embodiments, the Klebsiella infection is a K. pneumoniae infection.

[0186] In certain 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. fluoroscens. In certain embodiments, the Pseudomonas infection is a P. aeruginosa infection.

[0187] In certain embodiments, the bacteria is an atypical bacteria, i.e., neither gram positive nor gram negative.

[0188] In certain embodiments, the infectious disease is an infection involving a parasitic infection. Thus, in certain embodiments, a method of treating a parasitic infection is provided, the method comprising administering to a subject in need thereof an effective amount of a macrolide of the invention or a pharmaceutically acceptable salt thereof.

[0189] In certain embodiments, the macrolide 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).

[0190] 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, Loa Loa, Ascaris lumbricoides, Dirofilaria immitis, and Toxoplasma species (e.g., T. gondii).

[0191] As outlined herein, the present disclosure further provides a method of treating an inflammatory condition, comprising administering to a subject in need thereof an effective amount of a macrolide of the present disclosure, or a pharma- ceutically acceptable salt thereof. Such a method can be performed in vivo (i.e., by administration to a subject) or in vitro (e.g., by contact with a pathogen, tissue, or cell culture). As used herein, treatment includes therapeutic and prophylactic treatment.

[0192] In certain embodiments, the effective amount is a therapeutically effective amount.For example, in certain embodiments, the method slows down the progression of an inflammatory condition in a subject.In certain embodiments, the method improves the condition of a subject suffering from an inflammatory condition.In certain embodiments, the subject has a suspected or confirmed inflammatory condition.

[0193] In certain embodiments, the effective amount is a prophylactically effective amount. For example, in certain embodiments, the method prevents an inflammatory condition or reduces the likelihood of an inflammatory condition, for example, in certain embodiments, the method comprises administering to a subject in need thereof a macrolide of the present invention in an amount sufficient to prevent or reduce the likelihood of an inflammatory condition. In certain embodiments, the subject is at risk for an inflammatory condition.

[0194] In another aspect, there is provided an in vitro method of treating an inflammatory condition, the method comprising contacting an effective amount of a macrolide of the invention with an inflammatory cell culture.

[0195] The term "inflammatory condition" refers to a disease, disorder, or condition that is characterized by symptoms of pain (dolor, due to production of noxious substances and irritation of nerves), heat (calor, due to vasodilation), redness (rubor, due to vasodilation and increased blood flow), swelling (tumor, due to excessive inflow or restricted outflow of fluid), and / or loss of function (functio laesa, which can be partial or complete, transient or persistent). Inflammation takes many forms, including, but not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, scattered, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obstructive, parenchymal, plastic, productive, proliferous, pseudomembranous, suppurative, sclerosing, serous-fibrous, serous, simple, idiosyncratic, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation.

[0196] Exemplary inflammatory conditions include, but are not limited to, chronic pulmonary inflammatory syndromes (eg, diffuse panbronchiolitis, cystic fibrosis, asthma, bronchiectasis, and chronic obstructive pulmonary disease).

[0197] In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., inflammation resulting from an infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition. In certain embodiments, the inflammatory condition is inflammation associated with cancer.

[0198] definition chemical terms Definitions of specific functional groups and chemical terms are described in detail below. Chemical elements are defined in accordance with the Handbook of Chemistry and Physics, 75 thThe elements are identified in accordance with the CAS version of the Periodic Table of the Elements, Ed. inside cover, and specific functional groups are generally defined as described therein. In addition, the general rules of organic chemistry, as well as specific functional moieties and reactivities, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999, Smith and March March's Advanced Organic Chemistry, 5 th 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.

[0199] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers.For example, the compounds 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 in one or more stereoisomers.Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention encompasses the compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0200] During the ceremony, [ka] is a single bond that does not specify the stereochemistry of the moiety immediately attached to it, [ka] is absent or a single bond, [ka] is a single or double bond. When a variable is defined generally with many possible substituents, each individual radical can be defined with or without a bond. For example, R zz can be hydrogen, this means that R zz In the definition of, it may be shown as "-H" or "H".

[0201] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen with deuterium or tritium. 19 F 18 Replace with F, or 12 C 13 C or 14 Compounds having this structure, except for the replacement with C, are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0202] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~10 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , 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 The range is intended to include alkyl, e.g., C 1~10 or C 1~ C 10 can be written as

[0203] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0204] The term "alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1~10 In certain embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In certain embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In certain embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7 In certain embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In certain embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In certain embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In certain embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In certain embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In certain embodiments, an alkyl group has one carbon atom ("C 1 In certain embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2~6 "Alkyl"). C 1~6 Examples of alkyl groups include methyl (C 1 ), ethyl (C 2 ), Propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C 5 ) (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 (C 7 ), n-octyl (C 8 Unless otherwise indicated, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogens such as F) ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (e.g., unsubstituted C 1~6 Alkyl, e.g., -CH 3 (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 certain embodiments, the alkyl group is a substituted C 1~10 Alkyl (substituted C 1~6 Alkyl, e.g., -CF 3 , Bn, etc.).

[0205] 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 certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1~6 In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1~4 In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1~3 In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1~2 An example of a haloalkyl group is -CF 3 , -CF 2 CF3 , -CF 2 CF 2 CF 3 , -CCl 3 , -CFCl 2 , -CF 2 Cl, etc.

[0206] The term "alkoxy" refers to a moiety of the formula -OR', where R' is defined herein (C 1 ~C 6 ) alkyl moiety. n~m Alkoxy" or (C n ~C m ) The term alkoxy refers to an alkoxy group whose alkyl group has n to m carbons. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0207] The term "hydroxyalkyl" refers to a moiety of formula HOR', where R' is defined herein (C 1 ~C 6 ) alkyl moiety. n~m Alkoxy" or (C n ~C m ) The term alkoxy refers to an alkoxy group whose alkyl group has n to m carbons. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0208] 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 within the parent chain (i.e., inserted between adjacent carbon atoms in the main chain) 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 in the parent chain ("heteroC 1~10 In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroC1~9 In certain 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 certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~7 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~6 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~5 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~3 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~2 In certain embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC 1 In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless otherwise indicated, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is an alkyl.

[0209] The term "alkenyl" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In certain embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 In certain embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 In certain embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2~6 In certain embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~5 In certain embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2~4 In certain embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In certain embodiments, an alkenyl group has two carbon atoms ("C 2 The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2~4 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups, as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8Unless otherwise indicated, each instance of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents. In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 Alkenyl. In an alkenyl group, there is a C=C double bond with no specified stereochemistry (e.g., -CH=CHCH 3 or [ka] ) can be an (E)- or a (Z)-double bond.

[0210] The term "heteroalkenyl" refers to an alkenyl group that further comprises at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., inserted between adjacent carbon atoms in the main chain) and / or located 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 ("heteroC 2~10 In certain 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 certain 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 certain 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 certain embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~6In certain 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 certain embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In certain 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 certain 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 indicated, each instance of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted ("substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0211] The term "alkynyl" refers to the radical of a straight-chain or branched-chain hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (see "C 2~10 In certain embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In certain embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In certain embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In certain embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In certain embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5In certain embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In certain embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 In certain embodiments, an alkynyl group has two carbon atoms ("C 2 The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ) etc. 2~6 Examples of alkynyl groups include the above-mentioned C 2~4 Alkynyl groups, as well as pentynyl (C 5 ), Hexynyl (C 6 Additional examples of alkynyl include heptynyl (C 7 ), Octynyl (C 8 Unless otherwise indicated, each instance of an alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted ("substituted alkynyl") with one or more substituents. In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0212] The term "heteroalkynyl" refers to an alkynyl group that further comprises at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., inserted between adjacent carbon atoms in the main chain) and / or located 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 in the parent chain ("heteroalkynyl group"). 2~10In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 In certain embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~8 In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~7 In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~6 In certain 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 certain 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 certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2~3 In certain 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 indicated, each instance of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted ("substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0213] The term "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms ("C 3~14 In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3~10 In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4~6 In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C 5~6 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and others. 3~8 The carbocyclyl group may be any of the above-mentioned C 3~6 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ) and others. 3~10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")), may be saturated, or may contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continues to designate the number of carbons in the carbocyclic ring system. Unless otherwise indicated, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~14 In certain embodiments, the carbocyclyl group is a substituted C 3~14 It is a carbocyclyl.

[0214] In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3~14 In certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3~10In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In certain embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4~6 In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 "Cycloalkyl"). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ) are listed. C 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups, as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ) are listed. C 3~8 Examples of cycloalkyl groups are the aforementioned C 3~6 Cycloalkyl groups, as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 Unless otherwise indicated, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3~14 In certain embodiments, the cycloalkyl group is a substituted C 3~14 It is cycloalkyl.

[0215] The term "heterocycloalkyl" or "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 14-membered saturated or partially unsaturated but non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl") or tricyclic systems ("tricyclic heterocyclyl")), may be saturated or may contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring defined above is fused with one or more carbocyclyl groups and the point of attachment is on the carbocyclyl or heterocyclyl ring, or in which the heterocyclyl ring defined above is fused with one or more aryl or heteroaryl groups and the point of attachment is on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. Unless otherwise indicated, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0216] In certain embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("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 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("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 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In certain embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0217] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiecanyl.Exemplary bicyclic heterocyclyl groups include 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.

[0218] 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 in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system (see "C 6~14 In certain embodiments, an aryl group has six ring carbon atoms ("C 6 aryl"; e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In certain embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring, in which case the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Unless otherwise indicated, 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 certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0219] "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.

[0220] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valence permits. Heteroaryl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring as defined above is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring, and in such instances 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., the ring bearing a heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl).

[0221] In certain embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In certain embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In certain embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In certain embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, 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.

[0222] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0223] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein, where the point of attachment is on the alkyl portion.

[0224] The addition of the suffix "ene" to the base indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of an alkyl, alkenylene is a divalent moiety of an alkenyl, alkynylene is a divalent moiety of an alkynyl, heteroalkylene is a divalent moiety of a heteroalkyl, heteroalkenylene is a divalent moiety of a heteroalkenyl, heteroalkynylene is a divalent moiety of a heteroalkynyl, carbocyclylene is a divalent moiety of a carbocyclyl, heterocyclylene is a divalent moiety of a heterocyclyl, arylene is a divalent moiety of an aryl, and heteroarylene is a divalent moiety of a heteroaryl.

[0225] A group is optionally substituted unless expressly provided otherwise. The term "optionally substituted" refers to being 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., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present in the 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 stated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position of any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all acceptable substituents of organic compounds, including any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates any and all such combinations to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents 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 manner by the exemplary substituents described herein.

[0226] Exemplary carbon atom substituents include halogen (halo), -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 、-CO 2 H、-CHO、-C(OR cc ) 2 、-CO 2 R aa 、-OC(=O)R aa 、-OCO 2 R aa 、-C(=O)N(R bb ) 2 、-OC(=O)N(R bb ) 2 、-NR bb C(=O)R aa 、-NR bb CO 2 R 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 SO 2 R aa 、-NRbb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa ) 3 、-OSi(R aa ) 3 -C(=S)N(R bb ) 2 、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O) 2 R aa 、-OP(=O) 2 R aa 、-P(=O)(R aa ) 2 、-OP(=O)(R aa ) 2 、-OP(=O)(OR cc ) 2 、-P(=O) 2 N(R bb ) 2 、-OP(=O) 2 N(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, 3-14 membered heterocyclyl, C 6~14 Each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd or or two geminal hydrogens on a carbon atom are 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) 2 R aa , =NR bb , or =NOR cc is replaced by R aa Each instance of 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 3~10Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(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 C1~10 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 groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R cc Each instance of is 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 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd Each example is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 、-CO 2 H、-CO 2 R ee 、-OC(=O)R ee 、-OCO 2 R ee 、-C(=O)N(R ff ) 2 、-OC(=O)N(R ff ) 2 、-NR ff C(=O)R ee 、-NR ff CO 2 R 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 ff SO 2 R ee 、-SO 2 N(R ff ) 2 、-SO 2 R ee 、-SO 2 OR ee 、-OSO 2 R ee 、-S(=O)R ee 、-Si(R ee ) 3 、-OSi(R ee ) 3 、-C(=S)N(Rff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O) 2 R 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, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently selected from 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd the substituents may link to form =O or =S; R ee Each instance of 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, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently selected from 0, 1, 2, 3, 4, or 5 Rgg is substituted with a group, R ff Each instance of is 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 groups are linked to form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R gg Each example is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 - , -NH 2 (C 1~6 Alkyl) + X - , -NH 3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 Alkyl), -CO 2 H, -CO 2 (C 1~6 alkyl), -OC(=O)(C 1~6 Alkyl), -OCO 2 (C 1~6 alkyl), -C(=O)NH 2 , -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), -NHCO 2 (C 1~6 alkyl), -NHC(=O)N(C 1~6 Alkyl) 2 , -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH 2 , -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)NH 2 , -OC(=NH)N(C 1~6 Alkyl) 2 , -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1~6 Alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1~6 Alkyl), -SO 2 N(C 1~6 Alkyl) 2 , -SO 2 NH(C 1~6 Alkyl), -SO 2 NH 2, -SO 2 C 1~6 Alkyl, -SO 2 O.C. 1~6 Alkyl, -OSO 2 C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 Alkyl) 3 , -OSi(C 1~6 Alkyl) 3 -C(=S)N(C 1~6 Alkyl) 2 , C(=S)NH(C 1~6 alkyl), C(=S)NH 2 , -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 may be linked to form =O or =S, and X - is the counter ion.

[0227] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0228] The term "hydroxyl" or "hydroxy" refers to an -OH group. The term "substituted hydroxyl" or "substituted hydroxyl" refers, by extension, to an oxygen atom directly attached to the parent molecule that 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 , -OCO 2 R aa , -OC(=O)N(R bb ) 2 , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb ) 2 , -OS(=O)R aa , -OSO 2 R aa , -OSi(R aa ) 3 , -OP(R cc ) 2 , -OP(R cc ) 3 , -OP(=O) 2 R aa , -OP(=O)(R aa ) 2 ,-OP(=O)(OR cc ) 2 , -OP(=O) 2 N(R bb ) 2 , and -OP(=O)(NR bb ) 2 R aa , R bb , and R cc is as defined herein.

[0229] The term "amino" means -NH 2 The term "substituted amino" refers to a mono-, di-, or tri-substituted amino group. In certain embodiments, a "substituted amino" is a mono- or di-substituted amino group.

[0230] 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, -NH(R bb ), -NHC(=O)R aa , -NHCO 2 R aa , -NHC(=O)N(R bb ) 2 , -NHC(=NR bb )N(R bb ) 2 , -NHSO 2 R aa , -NHP(=O)(OR cc ) 2 , and -NHP(=O)(NR bb ) 2 and R aa , R bb , and R cc is as defined herein and the group -NH(R bb )R bb is not hydrogen.

[0231] 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 CO 2 R aa , -NR bb C(=O)N(R bb ) 2 , -NR bb C(=NR bb )N(R bb ) 2 , -NR bb SO 2 R aa , -NR bb P(=O)(OR cc ) 2 , and -NR bb P(=O)(NR bb ) 2 R aa , R bb, and R cc is as defined herein, except that the nitrogen atom directly attached to the parent molecule is not replaced by hydrogen.

[0232] 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 - refers to an amino group, as defined herein.

[0233] As used herein, the term "aminoalkyl" refers to an amino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. A "substituted aminoalkyl" includes a mono-, di-, or tri-substituted amino group, as defined herein, appended to the parent molecular moiety through an alkyl group. The alkyl portion of the group can be substituted or unsubstituted.

[0234] The term "sulfonyl" means -SO 2 N(R bb ) 2 , -SO 2 R aa , and -SO 2 OR aa R aa and R bb is as defined herein.

[0235] The term "sulfinyl" refers to the group -S(=O)R aa In the formula, R aa is as defined herein.

[0236] 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)SRX1 , -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 In the formula, R X1 is hydrogen, halogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted thiol, substituted or unsubstituted amino, substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic, cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic, cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched 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, monoaliphatic or dialiphatic amino, monoheteroaliphatic or diheteroaliphatic amino, monoalkyl or dialkylamino, monoheteroalkyl or diheteroalkylamino, monoarylamino- or diarylamino, or monoheteroarylamino- or diheteroarylamino-; or two R X1 The groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO 2H), 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 may be further substituted or unsubstituted).

[0237] The term "silyl" means -Si(R aa ) 3 R aa is as defined herein.

[0238] The term "oxo" refers to the group =O and the term "thioxo" refers to the group =S.

[0239] Nitrogen atoms may be substituted or unsubstituted, where valence permits, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR. aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc ) ORaa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(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 5-14 membered heteroaryl; or two R cc groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a R aa , R bb , R cc , and R dd is as defined above.

[0240] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -OR aa , -N(R cc ) 2 , -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR 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 and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd is substituted with a R aa , R bb , R cc , and R ddis as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3, incorporated herein by reference. rd This includes those described in detail in the following publication, John Wiley & Sons, 1999.

[0241] For example, nitrogen protecting groups, such as amide groups (e.g., -C(=O)R aa ) include, but are 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'-dithiobenzyloxyacylamino)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.

[0242] Nitrogen protecting groups, such as carbamate groups (e.g., -C(=O)OR aa), methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilyl ether Teocyl 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 (t-Bumeo c), 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, albamate, Kyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrilebenzyl 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-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzoisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonyl 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, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethyoxybenzyl carbamate, xyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isoborynnylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate , 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzyl carbamate.

[0243] Nitrogen protecting groups, such as sulfonamide groups (e.g. -S(=O) 2 R aa ) are p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6 -dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0244] Other nitrogen protecting groups include 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, and N-1,1,4,4-tetramethyldisilylazacyclopentane derivatives. Additive (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-pyroolin-3-yl)amine, Quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1- Dimethylthiomethyleneamine, 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-diphenylboronic 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, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0245] 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 -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R 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 , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 , -P(=O) 2 R aa , -P(=O)(R aa )2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , and -P(=O)(NR bb ) 2 These include, but are not limited to, R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3, incorporated herein by reference. rd This includes those described in detail in the following publication, John Wiley & Sons, 1999.

[0246] Exemplary oxygen protecting groups include methyl, methoxylmethyl (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-methoxyethoxymethyl (MEM), and the like. ), 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-trichloroethoxyethyl, ethyl, 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, 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), dimethylisopropyl Pyrsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formic acid, benzoyl formate, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methoxyacetic acid, triphenylmethoxyacetic acid, phenoxy Acetic acid, p-chlorophenoxyacetic acid, 3-phenylpropionic acid, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonic acid, 4-methoxycrotonic acid, benzoic acid, p-phenylbenzoic acid, 2,4,6-trimethylbenzoic acid (mesitoic acid), 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-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoic acid, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoic acid, 2-formyl These include, but are not limited to, benzenesulfonic acid, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyric acid, 2-(methylthiomethoxymethyl)benzoic acid, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, chlorodiphenylacetic acid, isobutyric acid, monosuccinoate, (E)-2-methyl-2-butenoic acid, o-(methoxyacyl)benzoic acid, α-naphthoic acid, nitric acid, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, boric acid, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenic acid, sulfuric acid, methanesulfonic acid (mesylate), benzylsulfonic acid, and tosylic acid (Ts). ,

[0247] 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 -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R 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 , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , and -P(=O)(NR bb ) 2 These include, but are not limited to, R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd Edition, incorporated herein by reference. rd This includes those described in detail in the following publication, John Wiley & Sons, 1999.

[0248] As used herein, "leaving group" (LG) is an art-recognized term that refers to a molecular fragment that carries a pair of electrons with it in a heterolytic bond cleavage, the molecular fragment being an anion or a neutral molecule. As used herein, a leaving group can be an atom or group that can be displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include halo (e.g., chloro, bromo, iodo), -OR, -CH, -CH- ... aa (When bonded to a carbonyl group, R aa is as defined herein), -O(C=O)R LG , or -O(SO) 2 R LG (e.g., tosyl, mesyl, besyl), but are not limited to these. LG is an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. In certain embodiments, the leaving group is a halogen. In certain embodiments, the leaving group is I.

[0249] As used herein, use of the phrase "at least one instance" refers to 1, 2, 3, 4 or more instances, but also encompasses ranges including, for example, 1-4, 1-3, 1-2, 2-4, 2-3, or 3-4 instances (inclusive).

[0250] A "non-hydrogen group" refers to any group defined for a particular variable that is not hydrogen.

[0251] The term "carbohydrate" or "saccharide" refers to an aldehyde or ketone derivative of a polyhydric alcohol. Carbohydrates include compounds with relatively small molecules (e.g., sugars) as well as macromolecular or polymeric substances (e.g., starch, glycogen, and cellulose polysaccharides). The term "saccharide" refers to a monosaccharide, disaccharide, or polysaccharide. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed into smaller carbohydrates. Most monosaccharides have the general formula C yH 2y O y (For example, C 6 H 12 O 6 (hexose, such as glucose), where y is an integer equal to or greater than 3. Certain polyhydric alcohols not represented by the general formula above may also be considered monosaccharides. For example, deoxyribose can be represented by the formula C 5 H 10 O 4 and are monosaccharides. Monosaccharides usually consist of 5 or 6 carbon atoms and are receptively referred to as pentoses and hexoses. If a monosaccharide contains an aldehyde, it is called an aldose, and 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 to be 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, and ketopentose sugars include ribulose, arabulose, xylulose, and lyxose. Examples of aldohexose sugars include glucose (e.g., dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose, while ketohexose sugars include fructose, psicose, sorbose, and tagatose. Ketoheptose sugars include sedoheptulose. With the exception of the first and last carbons, each carbon atom of a monosaccharide bearing a hydroxyl group (-OH) is asymmetric, making the carbon atom a stereocenter with two possible configurations (R or S). Due to this asymmetry, several isomers can exist for any given monosaccharide formula. Aldohexose d-glucose, for example, has the formula C 6 H 12 O 6All but two of its six carbon atoms are stereogenic, making d-glucose a 16-carbon (i.e., 4 The assignment of d or l is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection, if the hydroxyl group is on the right, the molecule is a d sugar, otherwise it is an l sugar. The aldehyde or ketone group of a linear monosaccharide can react reversibly with hydroxyl groups on different carbon atoms to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between the two carbon atoms. Rings with 5 and 6 atoms, called the furanose and pyranose forms, respectively, exist in equilibrium with the linear form. During the conversion from the linear form to the cyclic form, the carbon atom containing the carbonyl oxygen, called the anomeric carbon, becomes a stereocenter with two possible configurations. That is, the oxygen atom may take a position either above or below the plane of the ring. The pair of possible resulting stereoisomers are called anomers. In the α anomer, the -OH substituent on the anomeric carbon is replaced by -CH 2 It is on the opposite side (trans) of the ring from the OH branch. -CH 2 The alternative form in which the OH 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 linked together by a covalent bond known as a glycosidic bond formed via a dehydration reaction results in the loss of a hydrogen atom from one monosaccharide and a hydroxyl group from another 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.

[0252] These and other exemplary substituents are described in further detail in the detailed description, examples, and claims. The invention is not intended to be limited in any manner by the above exemplary recitation of substituents.

[0253] Other definitions As used herein, the term "salt" refers to any and all salts, including pharma- ceutically acceptable salts.

[0254] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals, within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and 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 other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-type salts such as 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. + (C 1~4 Alkyl) 4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0255] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, usually by a solvent decomposition reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form and solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0256] The term "hydrate" refers to a compound that is associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in a certain ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may be, for example, a compound of the general formula R xH 2 O, where R is a compound and x is a number greater than 0. A given compound may be present in any number of forms, such as a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, such as a hemihydrate (R 0.5H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R 2H 2 O), and hexahydrate (R 6H 2 O)) may form more than one type of hydrate.

[0257] The term "tautomer" or "tautomeric" 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 that provides a tautomeric pair) 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.

[0258] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0259] Stereoisomers that are not mirror images of each other are called "diastereoisomers" and those that are non-superimposable mirror images of each other are called "enantiomers". For example, if a compound has an asymmetric center, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures of these. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0260] The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may govern one crystalline form. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0261] The term "prodrug" refers to a compound having a cleavable group that, upon dissolution or under physiological conditions, becomes a compound described herein that is pharmacologic in vivo. Such 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 their acid and acid derivative forms, but the acid-sensitive forms offer many advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (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, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of 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 acid groups pendant on the compounds described herein are particular prodrugs. In some cases, it is desirable to prepare double ester type 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 C 7 ~C 12 Aryl alkyl esters may be preferred.

[0262] The terms "composition" and "formulation" are used interchangeably.

[0263] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, or adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) or a non-human animal. In certain 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 certain 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, and "diseases," "disorders," and "conditions" are used interchangeably herein.

[0264] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into or onto a subject.

[0265] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is suffering from a specified infectious disease or inflammatory condition and that reduce the severity of, or delay or slow the progression of, an infectious disease or inflammatory condition ("therapeutic treatment"), and also contemplate actions that occur before a subject begins to suffer from a specified infectious disease or inflammatory condition ("prophylactic treatment").

[0266] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response.It is understood by those skilled in the art that the effective amount of the compound of the present invention may 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 includes therapeutic and prophylactic treatment.

[0267] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic effect in treating an infectious disease or inflammatory condition, or to delay or minimize one or more symptoms associated with an infectious disease or inflammatory condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic effect in treating an infectious disease or inflammatory condition. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or prevents the symptoms or causes of an infectious disease or inflammatory condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0268] As used herein, and 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 refers to an amount of a therapeutic agent that alone or in combination with other agents provides a prophylactic benefit in the prevention of an infectious disease or inflammatory condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0269] The term "inflammatory disease" refers to a disease caused by, resulting from, or resulting in inflammation. The term "inflammatory disease" may also refer to a dysregulated inflammatory response that causes an exaggerated response by macrophages, granulocytes, and / or T lymphocytes resulting in abnormal tissue damage and / or cell death. Inflammatory diseases may be either acute or chronic inflammatory conditions and may result from infectious or non-infectious causes.Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune diseases, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, synovitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes mellitus (e.g., type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' syndrome, and other conditions. Vs' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory dermatitis, usual interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, beryllium pulmonary disease, talc pneumoconiosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (episodic arteritis and polyarteritis nodosa), inflammatory dermatitis , hepatitis, delayed hypersensitivity reactions (e.g., toxic ivy dermatitis), pneumonia, respiratory inflammation, adult respiratory distress syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hay fever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host graft rejection, appendicitis, arteritis, appendicitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorionitis, dacryoadenitis, endocarditis, endometritis, enteritis, small intestine colitis, epicondyle Inflammatory conditions include, but are not limited to, inflammation of the eye, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, ovariitis, orchitis, osteitis, otitis media, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. Inflammatory conditions of the eye include, but are not limited to, postoperative inflammation. EXAMPLES

[0270] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0271] Table 1 lists the intermediates used in the preparation of the example compounds. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0272] Intermediate scheme 1. [ka] [ka] tert-Butyl 4-(((benzyloxy)carbonyl)-D-threonyl)piperazine-1-carboxylate (IS1-1) To a solution of (2R,3S)-2-{[(benzyloxy)carbonyl]amino}-3-hydroxybutanoic acid (3 g, 11.8 mmol) in EtOAc (50 mL) was added DIEA (1.8 mL, 10.3 mmol) and tert-butylpiperazine (2 g, 10.7 mmol). 1-Propanephosphonic anhydride (T3P®) (8.63 g of a 50% w / w solution in dichloromethane) was added via pipette over 2 minutes (min) with stirring and the reaction mixture was stirred for 6.5 hours (h). The reaction mixture was diluted with EtOAc (40 mL) and washed with 1 M aqueous HCl (aq.) (120 mL), water (50 mL), saturated NaHCO 3 (80 mL), followed by washing with Na2 SO 4 It was dried over, filtered, concentrated, and reconcentrated from dichloromethane / MBTE to give an off-white foam. The crude product was purified by silica gel chromatography eluting with EtOAc / dichloromethane (0-70% gradient) to give a white solid (1.70 g). 1 H NMR (400 MHz, chloroform-d) δ 7.38-7.25(m, 5H), 6.03(d, 1H), 5.09(s, 2H), 4.49(d, 1H), 4.15-3.99(m, 2H), 3.77-3.58(m, 2H), 3.45(tt, 4H), 3.36-3.21(m, 2H), 1.46(s, 9H), 1.15(d, 3H). [ka]

[0273] tert-Butyl 4-(D-threonyl)piperazine-1-carboxylate (I4). IS1-1 (766 mg, 1.03 mmol) was dissolved in anhydrous EtOH (12 mL) and the reaction mixture was evacuated and backfilled with nitrogen (3 times). 5% Pd / C (109 mg, 0.05 mmol) was added and the reaction mixture was evacuated and backfilled with nitrogen (3 times). The reaction mixture was then evacuated and backfilled with hydrogen (3 times) and stirred under a hydrogen atmosphere (balloon) at room temperature (rt) for 1.5 h. The reaction mixture was evacuated and backfilled with nitrogen (5 times). Diatomaceous earth (Celite®) was added to the reaction mixture, which was stirred for 5 min, filtered through a MeOH-wet pad of Celite®, rinsed with MeOH, and concentrated. The crude material was dissolved in dichloromethane and filtered through a syringe filter to provide the crude product. MS (ESI+) m / z: 288.03 [M+H ]+、 1H NMR (400 MHz, chloroform-d) δ 3.86 (td, 1H), 3.79 (s, 10H), 1.47 (s, 9H), 1.18 (d, 3H). [ka]

[0274] tert-Butyl 4-((2S,3S)-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutyl)piperazine-1-carboxylate (IS1-2). In an oven-dried 3-neck flask equipped with a reflux condenser, IS1-1 (1.25 g, 2.96 mmol) was dissolved in dry THF (29 mL, 0.1 M) and cooled to 0 °C under nitrogen. 1 M borane·THF complex (8.8 mL, 8.8 mmol) was added dropwise over 11.5 min, maintaining the temperature below 3.5 °C. Slight evolution of gas was observed. The reaction mixture was stirred for 6 min, the ice bath was removed, and the reaction mixture was then warmed to 16.5 °C and then heated to 65 °C for 2 h. The reaction mixture was cooled in an ice bath and quenched slowly by the addition of MeOH (7 mL). The reaction mixture was diluted with additional MeOH and concentrated (3 times). The residue was dissolved in MeOH (50 mL), heated for approximately 1 h, and concentrated. The crude product was purified by elution with 20% MeOH + 0.5% NH in dichloromethane. 4 OH / CH 2 Cl 2 Purification by silica gel chromatography eluting with (0-60% gradient) gave a white foam (766 mg). MS (ESI+) m / z: 408.13 [M+H] + , 1 H NMR (400 MHz, chloroform-d) δ 7.44-7.29(m, 5H), 5.24(d, 1H), 5.11(s, 2H), 4.05(qd, 1H), 3.65(d, 1H), 3.48-3.31(m, 4H), 2.71(dd, 1H), 2.56-2.46(m, 3H), 2.42(dt, 2H), 1.45(s, 9H), 1.18(d, 3H). [ka]

[0275] tert-Butyl 4-((2S,3S)-2-amino)-3-hydroxybutyl)piperazine-1-carboxylate (I5). IS1-2 (766 mg, 1.87 mmol) was dissolved in anhydrous EtOH (20 mL) and the reaction mixture was evacuated and backfilled with nitrogen (3 times). 5% Pd / C (200 mg, 0.94) was added and the reaction mixture was evacuated and backfilled with nitrogen (3 times). The reaction mixture was evacuated and backfilled with hydrogen (3 times), stirred at room temperature under a hydrogen atmosphere (balloon) for 1.5 h and heated to 45° C. for 1 h. The reaction mixture was cooled to room temperature and backfilled with nitrogen (5 times). Celite® was added to the reaction mixture, which was stirred for 5 min, filtered through a MeOH-wet pad of Celite®, rinsed with MeOH, and concentrated to give the crude product as an off-white solid. MS (ESI+) m / z: 274.08 [M+H] + ,1H NMR (400 MHz, chloroform-d) δ 7.41-7.33 (m, 0H), 3.56 (qd, 1H), 3.50-3.34 (m, 4H), 2.93-2.78 (m, 1H), 2.48 (d, 3H), 2.43-2.28 (m, 3H), 1.45 (s, 10H), 1.17 (d, 3H).

[0276] Intermediate scheme 2. [ka] [ka] (R)-2-((tert-butoxycarbonyl)amino)-3-(piperidin-4-yl)propanoic acid (IS2-2). An oven dried flask was evacuated and backfilled with nitrogen (twice) and then cooled to room temperature. 10% Pd / C (50% wet, 7.96 g, 3.74 mmol) was added to the flask and the flask was evacuated and backfilled with nitrogen (twice). Glacial acetic acid (32 mL) was added to the reaction and the reaction was evacuated and backfilled with nitrogen (twice). N-Boc-D-pyridylalanine (5 g, 18.7 mmol) was added followed by glacial acetic acid (5 mL). The reaction was evacuated and backfilled with nitrogen (twice), then evacuated and backfilled with hydrogen (four times). The reaction mixture was heated to 60° C. and stirred under a hydrogen balloon for 15 hours. The reaction mixture was cooled to room temperature, evacuated and backfilled with nitrogen (four times). Celite® was added and the reaction mixture was stirred for about 15 minutes and then filtered through a pad of Celite® rinsing with MeOH. The reaction mixture was concentrated and then reconcentrated from MTBE to give a clear gum. The material was used without further purification. MS(ESI+) m / z: 273.07[M+H] + . [ka]

[0277] (R)-3-(1-((benzyloxy)carbonyl)piperidin-4-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (IS2-3). Crude IS2-2 (4.15 g, 15.2 mmol) was dissolved in THF (30 mL) and added with saturated NaHCO 3 (20 mL) aqueous solution was added. The reaction mixture was cooled to 0 °C and N-(benzyloxycarbonyloxy)succinimide (4.16 g, 16.7 mmol) was added. The reaction mixture was stirred for 11 min, the ice bath was removed and the reaction mixture was stirred at room temperature. Upon completion, the reaction mixture was cooled in an ice bath and 1 N HCl (~50 mL) was added slowly until bubbling ceased and the solution was pH 2-3. The reaction mixture was extracted with MTBE (25 mL x 3). The combined extracts were washed with 1 N HCl (20 mL x 2), water (40 mL), and brine (40 mL) and diluted with MgSO 4After drying over 100° C., the mixture was filtered and concentrated. The material was purified on 80 g of silica gel (dichloromethane / EtOAc+1% AcOH gradient: 0-100%) to give the title compound (2.3 g, 37%, 2 steps). MS (ESI+) m / z: 429.09 [M+Na] + . 1 H NMR (400 MHz, chloroform-d) δ 7.42-7.28(m, 5H), 5.14(s, 2H), 4.95(d, 1H), 4.44-4.32(m, 1H), 4.30-4.07(m, 2H), 2.89-2.66(m, 2H), 1.91-1.51(m, 5H), 1.46(s, 9H), 1.27-1.06(m, 2H). [ka]

[0278] Benzyl (R)-4-(2-amino-3-hydroxypropyl)piperidine-1-carboxylate (I7). The crude IS2-3 (2.3 g, 5.65 mmol) was concentrated from dry toluene (10 mL) in an oven-dried flask and cooled to 37° C. 2The mixture was dissolved in dry THF (12 mL) under reduced pressure and cooled to 0° C. Trimethyl borate (1.37 mL, 12.4 mmol) was added and the reaction mixture was stirred for about 7 minutes. Borane dimethyl sulfide complex (0.80 mL, 8.47 mmol) was added dropwise via syringe over about 4 minutes such that the temperature did not exceed 3° C. The reaction mixture was stirred for 10 minutes, the ice bath was removed, and the reaction mixture was stirred at room temperature for 5.5 hours. The reaction mixture was cooled to 0° C., additional trimethyl borate (0.7 mL) and borane dimethyl sulfide (0.4 mL) were added, and the reaction mixture was allowed to warm slowly to room temperature over 1.5 hours. The reaction mixture was cooled to 0° C., and methanol (10 mL) was added dropwise over 15 minutes while maintaining the temperature below 10° C. The ice bath was removed, and the reaction mixture was stirred for 30 minutes and concentrated. The resulting clear oil was redissolved in methanol (about 50 mL), concentrated (twice), and then placed on high vacuum for about 20 minutes. The residue was partitioned between 1N HCl (30 mL) and MTBE (25 mL). The aqueous layer was extracted with MTBE (25 mL x 2). The aqueous layer was washed with saturated NaHCO 3 The mixture was basified with EtOAc (pH about 8.5) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with Na 2 SO 4 It was dried over ice, filtered and concentrated. MS(ESI+)m / z:293.01[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.31-7.24 (m, 2H), 7.24-7.20 (m, 1H), 7.20-7.11 (m, 1H), 7.11-7.01 (m, 1H), 5.03 (s, 2H), 4.18-3.96 (m, 2H), 3.47 (dd, 1H), 3.16 (ddd, 1H), 2.84 (tt, 1H), 2.78-2.57 (m, 2H), 1.67-1.41 (m, 3H), 1.27-0.88 (m, 4H).

[0279] Intermediate scheme 3. [ka] [ka] tert-Butyl ((1R,3R)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclobutyl)carbamate (IS3-2). To a solution of 2-((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)acetic acid (1.1 g, 4.8 mmol) in dichloromethane (20 mL) was added methoxyl(methyl)amine hydrochloride (0.70 g, 7.2 mmol), N,N-diisopropylethylamine (4.15 mL, 24.0 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (2.73 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into 1 M MeOH and stirred vigorously for 10 min. The organic layer was separated and washed with 2N HCl (2 times), water (1 time), and brine (1 time). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography (80 g silica gel column, 0-50% EtOAc / Hex) to give the title compound as a white powder (1.19 g, 4.4 mmol, 92%). MS (ESI+) m / z: [M+Na] + 295.2. [ka]

[0280] tert-Butyl ((1R,3R)-3-((E)-2-(((R)-tert-butylsulfinyl)imino)propyl)cyclobutyl)carbamate (IS3-4). IS3-2 (1.19 g, 4.4 mmol) in THF (20 mL) was cooled to -40°C and Red-Al (1.83 mL, 70 wt% in toluene, 5.7 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Ethyl acetate and saturated aqueous potassium sodium tartrate (Rochelle's salt) were added and the mixture was stirred vigorously for 2 h. The organic layer was separated, washed with brine (1x), dried over sodium sulfate, filtered and concentrated to give the aldehyde IS3-3 as a clear oil. IS3-3 (0.96 g, 4.5 mmol) was dissolved in toluene (9 mL) and (S)-2-methylpropane-2-sulfinamide (0.545 g, 4.5 mmol) was added followed by copper(II) sulfate (2.15 g, 13.5 mmol). The reaction mixture was stirred at room temperature for 18 h and filtered through Celite® eluting with ethyl acetate. The filtrate was concentrated and purified by column chromatography on silica gel (24 g, 0-70% EtOAc / Hex) to afford the title compound as a white solid (0.53 g, 1.67 mmol, 37%). 1 H NMR (400 MHz, chloroform-d) δ 7.99(t, 1H), 4.71(s, 1H), 4.24(s, 1H), 2.70(dd, 2H), 2.65-2.51(m, 1H), 2.23-1.98(m, 4H), 1.43(d, 10H), 1.18(d, 9H). [ka]

[0281] tert-Butyl ((1S,3R)-3-((R)-2-(((S)-tert-butylsulfinyl)amino)but-3-en-1-yl)cyclobutyl)carbamate (IS3-5). ZnCl 2A solution of (2.63 mL, 1.9 M in MeTHF, 5.01 mmol) was added to dry THF (3.34 mL) and cooled to -78 °C. A solution of methyllithium (3.22 mL, 3.1 M in DME, 10 mmol) was added slowly while maintaining the internal reaction temperature below -65 °C. The mixture was stirred for 10 min and a solution of vinylmagnesium chloride (3.22 mL, 1.6 M in THF, 3.13 mmol) was added slowly while maintaining the internal reaction temperature below -65 °C. The mixture was stirred for 5 min. A solution of IS3-4 (0.53 g, 1.67 mmol) in THF (1 mL) was added dropwise and the reaction mixture was stirred for 30 min. Acetic acid (0.5 mL) was added slowly, the bath was removed and the reaction mixture was allowed to warm to room temperature over 20 min. Half-saturated (sat.) NH 4 Aqueous Cl was added, followed by MTBE. The layers were separated and the aqueous layer was extracted with MBTE (2x) and the combined extracts were washed with Na 2 SO 4 It was dried over, filtered and concentrated. The crude material was purified by column chromatography (12 g silica gel column, 0-50% EtOAc / Hex) to give the title compound as a white powder (0.366 g, 1.06 mmol, 64%). 1 H NMR(400 MHz, chloroform-d) δ 5.61 (dddd, 1H), 5.22-5.08 (m, 2H), 4.73 (s, 1H), 4.10 (s, 1H), 3.76-3.67 (m, 1H), 3.06 (d, 1H), 2.41-2.26 (m, 1H), 2.13-1.92 (m, 4H), 1.74 (td, 2H), 1.42 (s, 9H), 1.19 (d, 9H). [ka]

[0282] Benzyl ((R)-1-((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclobutyl)but-3-en-2-yl)carbamate (IS3-7) Concentrated HCl (0.1 mL, 1.27 mmol) was added to a solution of IS3-5 (0.366 g, 1.06 mmol) in THF / water (5:2, 2.8 mL) and the reaction mixture was stirred at room temperature for 18 h. 3 (3 mL) aqueous solution was added, followed by N-(benzyloxycarbonyloxy)succinimide (0.276 g, 1.11 mmol). The reaction mixture was stirred at room temperature for 1 h and extracted with EtOAc (2x). The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The material was purified by column chromatography (12 g silica gel column, 0-70% EtOAc / Hex) to give the title compound as a white powder (0.31 g, 0.83 mmol, 78%). MS (ESI+) m / z: 397.31 [M+Na] + ; 1 H NMR (400 MHz, chloroform-d) δ 7.40-7.30(m, 5H), 5.73(ddd, 1H), 5.18-5.04(m, 4H), 4.63(d, 2H), 4.12(s, 2H), 2.28(s, 1H), 2.06(s, 2H), 1.97(s, 2H), 1.74-1.59(m, 2H), 1.43(s, 9H). [ka]

[0283] Benzyl ((R)-1-((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclobutyl)-3-hydroxypropan-2-yl)carbamate (IS3-8). IS3-7 (0.31 g, 0.827 mmol) was dissolved in methanol (16.5 mL) and cooled to -78°C. A stream of ozone (7 PSI, 2 LPM) was bubbled through the reaction mixture for 8 minutes, at which point a slight blue coloration was observed. The ozone stream was removed and nitrogen was bubbled through the solution for 5 minutes (blue color disappeared). Sodium borohydride (77.1 mg, 2.04 mmol) was added and the reaction mixture was removed from the bath and allowed to warm to room temperature for 30 minutes. The reaction was purified with saturated NH 4 The mixture was quenched with aqueous Cl and extracted with dichloromethane (3 times).2 SO 4 The mixture was dried over hexane, filtered and concentrated in vacuo. The material was purified by column chromatography on silica gel (12 g, 0-70% EtOAc / Hex) to give the title compound as a white foam (0.265 g, 0.7 mmol, 85%). MS (ESI+) m / z: 401.09 [M+Na] + ; 1 H NMR (400 MHz, chloroform-d) δ 7.44-7.30(m, 5H), 5.09(s, 2H), 4.82(s, 1H), 4.69(s, 1H), 4.22-4.09(m, 1H), 3.67(s, 2H), 3.55(s, 1H), 2.28(s, 1H), 2.06(d, 2H), 1.99(s, 3H), 1.74-1.60(m, 2H), 1.43(s, 9H). [ka]

[0284] tert-Butyl ((1S,3R)-3-((R)-2-amino-3-hydroxypropyl)cyclobutyl)carbamate (I8). A solution of IS3-8 (265 mg, 0.7 mmol) was dissolved in methanol (3 mL) and Pd / C (74.3 mg, 5 wt% on charcoal, 0.5 mol%) was added. A balloon of hydrogen was bubbled through the reaction mixture for 0.5 h. The reaction mixture was filtered through Celite®, eluted with methanol, and the filtrate was concentrated under vacuum to give I8 as a clear oil (171 mg, 0.7 mmol, 100%). MS (ESI+) m / z: 245.08 [M+Na] + ; 1 H NMR (400 MHz, methanol-d 4 )δ 4.13-4.01(m,1H),3.64(dd,1H),3.42(dd,1H),2.97(dt,1H),2.39-2.23(m,1H),2.16-1.95(m,4H),1.69(ddt,2H),1.43(s,9H).

[0285] Intermediate scheme 4. [ka] A solution of di-tert-butyl dicarbonate (34.2 mmol, 1.05 equiv.) in 1,4-dioxane (20 mL) and 1N aqueous sodium hydroxide (35.8 mmol, 1.1 equiv.) were added simultaneously slowly to an ice-cooled mixture of 4-piperidone hydrochloride monohydrate (32.6 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL). The reaction was kept under stirring overnight (12 h), at which point TLC showed complete protection of the starting material. The 1,4-dioxane was then removed under reduced pressure and the residue was extracted twice with ethyl acetate (2×30 mL). The combined organic layers were washed successively with 5% aqueous potassium hydrogen sulfate (20 mL), water (20 mL) and brine (20 mL) and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give tert-butyl 4-oxopiperidine-1-carboxylate as a white solid (6.10 g, 94%). [ka]

[0286] To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (25.09 mmol, 1.0 equiv.) and triphenylphosphine (100.36 mmol, 4.0 equiv.) in acetonitrile (60 mL) at 0° C. under argon atmosphere, tetrabromomethane (50.18 mmol, 2.0 equiv.) was added in small portions. The reaction mixture was stirred at 0° C. for 15 min, then warmed to room temperature and kept under stirring for an additional 2 h. The precipitate formed was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. After purification of the filtrate by column chromatography (hexane / AcOEt: 100:0 to 85:15), tert-butyl 4-(dibromomethylene)piperidine-1-carboxylate was obtained as a white solid (7.63 g, 86%). [ka]

[0287] To a stirred solution of tert-butyl 4-(dibromomethylene)piperidine-1-carboxylate (12.67 mmol, 1.0 equiv) in a 1:2 mixture of THF / MeOH (55 mL) at 0° C. under an argon atmosphere, ammonium chloride (50.7 mmol, 4.0 equiv) was added in one portion and the reaction was allowed to stir at 0° C. for 30 minutes. Zinc powder (50.7 mmol, 4.0 equiv) was then added in one portion at 0° C. and the reaction was allowed to warm to room temperature and maintained under stirring overnight. After stirring for 14 hours, TLC analysis showed complete conversion of starting material in a more polar product (Rf=0.43 in AcOEt / hexane 1:9). The solids were removed by filtration and the filtrate was concentrated under reduced pressure. After purification by flash column chromatography (hexane / AcOEt 100:0 to 90:10), tert-butyl 4-(bromomethylene)piperidine-1-carboxylate was obtained as a colorless oil (3.28 g, 94%). [ka]

[0288] (R)-2-Methylpropane-2-sulfinamide (32.5 mmol, 1.0 equiv.) was added to a solution of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (32.5 mmol, 1.0 equiv.) and copper sulfate (48.7 mmol, 1.5 equiv.) in toluene (55 mL). The reaction mixture was allowed to stir at 40-45° C. overnight. After 14 h, TLC showed complete conversion of starting material in the sulfonimide product (Rf=0.36 (hexanes / AcOEt 8:2). The crude mixture was allowed to cool at room temperature and then filtered through a celite pad and washed with DCM (2×10 mL). The filtrate was concentrated under vacuum and after purification by flash column chromatography (hexanes / EtOAc 100:0 to 80:20), tert-butyl 4-(bromomethylene)piperidine-1-carboxylate was obtained as a white solid (6.76 g, 75%). [ka]

[0289] A solution of tert-butyllithium (16.22 mmol, 3.0 equiv.) was dissolved in tert-butyl 4-(bromomethylene)piperidine-1-carboxylate (8.11 mmol, 1.5 equiv.) in dry Et 2 The reaction mixture was stirred at -78°C for 30 minutes. In parallel, a second solution was prepared by adding a trimethylaluminum solution (5.95 mmol, 1.1 equiv.) dropwise to a stirred solution of (R,Z)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide in dry THF (20 mL) under an argon atmosphere at -78°C. This second reaction mixture was allowed to stir for 5 minutes and then added dropwise to the first reaction mixture at -78°C. The reaction medium was allowed to stir for 3 hours at -78°C. At this point, the reaction showed the formation of two products (two diastereomers, one major, the other minor) (Rf1=0.29, Rf2=0.16 (hexane / AcOEt 7:3 ratio). The reaction medium was washed with saturated NH 4 Quench with aqueous Cl (30 mL) and remove the aqueous layer with Et 2 The organic layer was then collected, washed with brine (15 mL) and extracted with anhydrous MgSO. 4 After drying over rt and concentrating under vacuum, the desired products were isolated by flash column chromatography (Hexanes / EtOAc 100:0 to 50:50) as colorless oils in a 2:1 ratio, 1.38 g and 0.66 g, respectively, for an overall yield of 80%. [ka]

[0290] A solution of HCl (4M in dioxane) (4.36 mmol, 1.5 equiv.) was added dropwise to a stirred solution of tert-butyl 4-((S)-3-((tert-butyldimethylsilyl)oxy)-2-(((R)-tert-butylsulfinyl)amino)propylidene)piperidine-1-carboxylate (2.91 mmol, 1.0 equiv.) in MeOH (15 mL) at 0° C. The reaction mixture was kept stirring until complete deprotection of the starting material (1 h by TLC monitoring). The reaction mixture was then concentrated under reduced pressure. A white amalgam was obtained, which was triturated in cold diethyl ether. The mixture was filtered through a Buchner funnel. The resulting solid was washed several times with diethyl ether, then dissolved in MeOH and purified on flash column chromatography (eluent DCM / MeOH 100:0 to 80:20) to give tert-butyl (R)-4-(2-amino-3-hydroxypropylidene)piperidine-1-carboxylate (I10) as a white solid (0.53 g, 71%). [ka]

[0291] A round-bottom flask was charged with tert-butyl (R)-4-(2-amino-3-hydroxypropylidene)piperidine-1-carboxylate (1.64 mmol, 1.0 equiv.) and palladium activated on charcoal (10 w%, 0.33 mmol, 0.2 equiv.). Methanol (6 mL) was added and the solution was flushed with nitrogen before being diluted with H 2 The reaction was flashed back with H 2 The mixture was kept at room temperature under 1 atm pressure overnight. After stirring for 12 h, LCMS analysis showed complete reduction of the double bond. The reaction mixture was flushed with nitrogen and filtered through a celite pad. The celite cake was washed several times with methanol and the filtrate was concentrated under reduced pressure. Flash column chromatography (DCM / MeOH 100:0 to 80:20 + 1% NEt 3 After purification by HPLC, tert-butyl (R)-4-(2-amino-3-hydroxypropyl)piperidine-1-carboxylate (I11) was obtained as a colorless oil (0.41 g, 97%).

[0292] Intermediate scheme 5. [ka] To a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1 eq.) in dry THF (10 mL) was added imidazole (1.2 eq.), TPP (1.2 eq.), and iodine (1.2 eq.) at room temperature under argon atmosphere. The reaction mixture was kept under stirring at room temperature until complete consumption of the starting material (2 h by TLC monitoring). The solvent was removed under reduced pressure and the crude mixture was purified by column chromatography (hexane / EtOAc 100:0 to 90:10) to give tert-butyl 4-(iodomethyl)piperidine-1-carboxylate as a colorless oil, which gradually solidified. [ka]

[0293] A dry 100 mL round bottom flask (oven heated / argon cooled) was charged with ethyl 2-((diphenylmethylene)amino)acetate (1 eq, 7.48 mmol). The flask was purged with argon and 30 mL of dry THF was injected into the air-free system. The resulting solution was cooled to -78°C with stirring and NaHMDS (1.2 eq, 898 mmol) was added dropwise to the solution. The reaction was stirred at -78°C for 30 min and a solution of tert-butyl 4-(iodomethyl)piperidine-1-carboxylate (1.0 eq, 7.48 mmol) in dry THF (20 mL) was injected into the system via cannula. The solution was stirred at -78°C for 1 h, 0°C for 1 h, and at room temperature overnight. TLC indicated complete consumption of starting material. The reaction mixture was diluted with AcOEt (50 mL) and then washed with a solution of 0.5 g of citric acid (10 eq.) in water (20 mL). The organic layer was extracted, dried over magnesium sulfate, and then concentrated. The crude product was purified by column chromatography to give tert-butyl 4-(2-amino-3-ethoxy-3-oxopropyl)piperidine-1-carboxylate. [ka]

[0294] LAH (1 equiv., 2.203 equiv.) was added in portions to a solution of tert-butyl 4-(2-amino-3-ethoxy-3-oxopropyl)piperidine-1-carboxylate (1 equiv., 2.203 equiv.) in dry THF (10 mL) at -20°C. The reaction mixture was stirred at this temperature for 4 h. After complete consumption of the starting material (TLC monitoring), the reaction mixture was diluted with ether and cooled to 0°C. Water was slowly added followed by 15% aqueous NaOH (0.3 mL) and the mixture was stirred for 15 min. After drying over anhydrous magnesium sulfate and filtration to remove salts, the organic layer was concentrated under vacuum to give tert-butyl 4-(2-amino-3-hydroxypropyl)piperidine-1-carboxylate (I12), which was purified by column chromatography. [ka]

[0295] tert-Butyl 3-(2-amino-3-hydroxypropyl)azetidine-1-carboxylate (I13) was prepared using the same synthetic sequence used to prepare tert-butyl 4-(2-amino-3-hydroxypropyl)piperidine-1-carboxylate tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate, but by replacing tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate with tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate.

[0296] Intermediate scheme 6. [ka] Methylmagnesium bromide solution (3.0 M, 3.34 mmol, 2.5 equiv.) was added dropwise to a solution of tert-butyl 4-(2-((diphenylmethylene)amino)-3-ethoxy-3-oxopropyl)piperidine-1-carboxylate in dry THF (15 mL) at 0° C. The reaction mixture was maintained under stirring at 0° C. for 3 h. HRMS analysis showed complete conversion of the ester group to the corresponding tertiary alcohol. The reaction was warmed to room temperature and 1N aqueous citric acid solution (13.34 mmol, 10.0 equiv.) was added to the reaction medium. After 2 h of stirring, TLC analysis showed complete deprotection of the Schiff base. AcOEt (20 mL) was added to the reaction mixture and benzophenone was removed by extraction with AcOEt (2×20 mL). Solid Na was then added to the reaction mixture and the benzophenone was removed by extraction with AcOEt (2×20 mL). 2 CO 3 The aqueous phase was basified to pH=9-10 by careful addition of DCM (4×15 mL). The aqueous phase was then extracted with DCM (4×15 mL). The organic layers were combined and washed with anhydrous Na 2 SO 4 Drying over and concentration in vacuo afforded tert-butyl 4-(2-amino-3-hydroxy-3-methylbutyl)piperidine-1-carboxylate as a white solid (I14) (0.32 g, 84%).

[0297] Intermediate scheme 7. [ka] A first solution A was prepared: to a stirred solution of (S)-N-((R,E)-2-((tert-butyldimethylsilyl)oxy)propylidene)-2-methylpropane-2-sulfinamide (1 eq., 11.07 mmol) in dry diethyl ether (60 mL) was added t-BuLi (2.2 eq., 27.1 mmol) under an argon atmosphere at −78° C. The reaction mixture was stirred for 30 min at −78° C. In parallel, a second solution B was prepared: trimethylaluminum (1.1 eq., 13.53 mmol) was added dropwise to a stirred solution of iodine (1 eq., 12.30 mmol) in dry THF (40 mL) under an argon atmosphere at −78° C. This reaction mixture B was stirred for 5 min and then added dropwise to reaction mixture A. The reaction medium was left stirring at −78° C. for 16 h. The reaction mixture was diluted with NH 4 The mixture was quenched with Cl (10 mL) and the organic layer was extracted with Et 2 Extraction with HO (3×10 mL) gave tert-butyl 4-((R)-3-((tert-butyldimethylsilyl)oxy)-2-(((S)-tert-butylsulfinyl)amino)propyl)piperidine-1-carboxylate as a yellow oil after FCC (hexane / EtOAc 100:0 to 80:20).

[0298] [ka] To a stirred solution of tert-butyl 4-((R)-3-((tert-butyldimethylsilyl)oxy)-2-(((S)-tert-butylsulfinyl)amino)propyl)piperidine-1-carboxylate (1 equiv., 0.835) in methanol at 0° C. was added HCl in 1,4 dioxane (1.05 equiv., 0.877 mmol). The reaction mixture was kept under stirring at room temperature until complete consumption of starting material. (2.5 h by TLC monitoring). The reaction mixture was concentrated under reduced pressure and tert-butyl 4-((2R,3R)-2-amino-3-((tert-butyldimethylsilyl)oxy)butyl)piperidine-1-carboxylate was obtained as a yellow oil after column chromatography purification (DCM / MeOH: 100:0 to 80:20:0 to 80:20). [ka]

[0299] To a stirred THF solution of tert-butyl 4-((2R,3R)-2-amino-3-((tert-butyldimethylsilyl)oxy)butyl)piperidine-1-carboxylate (1 eq, 0.58 mmol) was added TBAF (2.5 eq). The reaction mixture was kept under stirring at room temperature until complete consumption of the starting material (2 h by TLC monitoring). The reaction mixture was quenched with water and the organic layer was extracted with DCM (3×10 mL) and concentrated under reduced pressure to give tert-butyl 4-((2R,3R)-2-amino-3-hydroxybutyl)piperidine-1-carboxylate (I15) after FCC purification.

[0300] Intermediate scheme 8. [ka] A dry 100 mL round bottom flask (oven heated / argon cooled) was charged with ethyl 2-((diphenylmethylene)amino)acetate. The flask was purged with argon and 30 mL of dry THF was injected into the air-free system. The resulting solution was cooled to -78°C with stirring and NaHMDS was added dropwise to the solution. The reaction was stirred at -78°C for 30 min and a solution of tert-butyl 4-(3-amino-4-ethoxy-4-oxobutyl)piperidine-1-carboxylate in dry THF (20 mL) was injected into the system via cannula. The solution was stirred at -78°C for 1 h, 0°C for 1 h, and at room temperature overnight. TLC showed complete consumption of starting material. The reaction mixture was diluted with AcOEt (50 mL) and then washed with a solution of 0.5 g of citric acid in water (20 mL). The organic layer was extracted, dried over magnesium sulfate, and then concentrated. The crude product was purified by FCC to give tert-butyl 4-(3-amino-4-ethoxy-4-oxobutyl)piperidine-1-carboxylate. [ka]

[0301] LAH was added in portions to a solution of tert-butyl 4-(3-amino-4-ethoxy-4-oxopropyl)piperidine-1-carboxylate in dry THF at -20°C. The reaction mixture was stirred at this temperature for 4 hours. After complete consumption of the starting material (TLC monitoring), the reaction mixture was diluted with ether, cooled to 0°C, and water was slowly added followed by 0.3 mL of 15% aqueous NaOH and stirred for 15 minutes. Some anhydrous magnesium sulfate was added, stirred for 15 minutes, and filtered to remove salts. The organic layer was concentrated under vacuum to give tert-butyl 4-(3-amino-4-hydroxybutyl)piperidine-1-carboxylate (I16), which was purified by column chromatography.

[0302] Intermediate scheme 9. [ka] C. 2.2 mL of methylpiperidine-4-carboxylate (15 g, 95 mmol) in a 500 mL round-bottom flask at 23.degree. C. 2 Cl 2 (100 mL) of stirred solution, di-tert-butyl dicarbonate (22.91 g, 105 mmol) was slowly added to the reaction mixture and stirred for 4 min. The reaction was neutralized with cold water (50 mL) at the same temperature and dissolved in CH 2 Cl 2 (50 mL) was added. The organic layer was separated and the aqueous layer was 2 Cl 2 (50 mL x 3). The combined organic layer was washed with brine and anhydrous Na 2 SO 4 It was dried over ice, concentrated in vacuo and purified by flash column chromatography to give 1-(tert-butyl) 4-methylpiperidine-1,4-dicarboxylate (18.34 g, 74%) as a colorless oil. [ka]

[0303] 1-(tert-butyl) 4-methylpiperidine-1,4-dicarboxylate CH 2 Cl 2 (200 mL) of DIBAL-H (43.2 mL, 43.3 mmol) was added slowly to the reaction mixture at -78 °C and stirred for 30 min. The reaction was neutralized with a saturated solution of sodium potassium tartrate (50 mL) at the same temperature and stirred in CH 2 Cl 2 (100 mL) was added and the reaction was allowed to stir until the layers separated at 23° C. The organic layer was separated and the aqueous layer was washed with CH 2 Cl 2 (50 mL x 3). The combined organic layer was washed with brine and anhydrous Na 2 SO 4 Dry it on a lid, concentrate it in vacuum, and purify it by flash column chromatography. Purification by chromatography afforded tert-butyl 4-formylpiperidine-1-carboxylate (8.78 g, 95%) as a colorless oil. [ka]

[0304] A 100 mL round bottom flask equipped with a stir bar was charged with anhydrous lithium chloride (1.55 g, 110 mmol, 7.8 equiv). The vessel was heated with a gentle flame under vacuum (0.1 mmHg) for 5 min. After cooling to 23 °C under vacuum, the flask was backfilled with argon and (R,R)-pseudoephenamine glycinamide (1.733 g, 18.29 mmol, 1.3 equiv) was added. Tetrahydrofuran (25 mL) was added via syringe and the reaction mixture was stirred at 23 °C until the pseudoephenamine glycinamide had dissolved (approximately 5 min); the lithium chloride was not allowed to completely dissolve. The resulting suspension was cooled to -78 °C in a dry ice-acetone cooling bath and a freshly prepared solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 2.5 mL, 2.5 mmol, 2.5 equiv) was added dropwise. After 5 min, the reaction vessel was transferred to an ice-water bath and stirring was continued for 25 min. The vessel was recooled to -78°C and a solution of tert-butyl 4-formylpiperidine-1-carboxylate (1.0 g, 1.0 equiv.) in tetrahydrofuran (3 mL) was added dropwise. Once the aldehyde was completely consumed as indicated by TLC (usually within 1 h), half-saturated aqueous ammonium chloride solution (10 mL) was added and the vessel was warmed to 23°C. The mixture was partitioned between half-saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The diastereomeric ratio of the crude product was: 1 The residue was purified by flash column chromatography on silica gel to give tert-butyl 4-((1R,2S)-2-amino-1-hydroxy-3-(((1R,2R)-2-hydroxy-1,2-diphenylethyl)(methyl)amino)-3-oxopropyl)piperidine-1-carboxylate (1.98 g, 85%). [ka]

[0305] Sodium borohydride (753 mg, 19.89 mmol, 5 equiv.) was added in one portion to an ethanolic solution (40 mL, 200 proof) of the aldol adduct tert-butyl 4-((1R,2S)-2-amino-1-hydroxy-3-(((1R,2R)-2-hydroxy-1,2-diphenylethyl)(methyl)amino)-3-oxopropyl)piperidine-1-carboxylate (1.98 mg, 3.98 mmol, 1 equiv.) in a 100 mL round bottom flask. The reaction vessel was immersed in an oil bath heated to 40° C. Reaction progress was monitored by TLC (10% methanol in dichloromethane+0.5% saturated aqueous ammonium hydroxide) for consumption of starting material. After 8 hours, the reaction mixture was allowed to cool to 23° C. and saturated aqueous ammonium chloride (approximately 1.5 mL) was carefully added until gas evolution ceased. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (10→30% methanol-dichloromethane+1% saturated aqueous ammonium hydroxide) to give tert-butyl 4-((1R,2R)-2-amino-1,3-dihydroxypropyl)piperidine-1-carboxylate (I17) (857 mg, 79%).

[0306] Intermediate scheme 10. [ka] A 100 mL round bottom flask equipped with a stir bar was charged with anhydrous lithium chloride (1.55 g, 110 mmol, 7.8 equiv). The vessel was heated with a gentle flame under vacuum (0.1 mmHg) for 5 min. After cooling to 23° C. under vacuum, the flask was backfilled with argon and (S,S)-pseudoephenamine glycinamide (1.733 g, 18.29 mmol, 1.3 equiv) was added. Tetrahydrofuran (25 mL) was added via syringe and the reaction mixture was stirred at 23° C. until the pseudoephenamine glycinamide had dissolved (approximately 5 min); the lithium chloride was not allowed to completely dissolve. The resulting suspension was cooled to −78° C. in a dry ice-acetone cooling bath and a freshly prepared solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 2.5 mL, 2.5 mmol, 2.5 equiv) was added dropwise. After 5 min, the reaction vessel was transferred to an ice-water bath and stirring was continued for 25 min. The vessel was recooled to -78°C and a solution of tert-butyl 4-formylpiperidine-1-carboxylate (1.0 g, 1.0 equiv.) in tetrahydrofuran (3 mL) was added dropwise. Once the aldehyde was completely consumed as indicated by TLC (usually within 1 h), half-saturated aqueous ammonium chloride solution (10 mL) was added and the vessel was allowed to warm to 23°C. The mixture was partitioned between half-saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The diastereomeric ratio of the crude product was determined by 1H NMR or HPLC analysis (see below). The residue was purified by flash column chromatography on silica gel to give tert-butyl 4-((1S,2R)-2-amino-1-hydroxy-3-(((1S,2S)-2-hydroxy-1,2-diphenylethyl)(methyl)amino)-3-oxopropyl)piperidine-1-carboxylate (2.03 g, 87%). [ka]

[0307] Sodium borohydride (753 mg, 19.89 mmol, 5 equiv.) was added in one portion to an ethanolic solution (40 mL, 200 proof) of the aldol adduct tert-butyl 4-((1S,2R)-2-amino-1-hydroxy-3-(((1S,2S)-2-hydroxy-1,2-diphenylethyl)(methyl)amino)-3-oxopropyl)piperidine-1-carboxylate (1.98 mg, 3.98 mmol, 1 equiv.) in a 100 mL round bottom flask. The reaction vessel was immersed in an oil bath heated to 40° C. Reaction progress was monitored by TLC (10% methanol in dichloromethane+0.5% saturated aqueous ammonium hydroxide) for consumption of starting material. After 8 hours, the reaction mixture was allowed to cool to 23° C. and saturated aqueous ammonium chloride (approximately 1.5 mL) was carefully added until gas evolution ceased. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (10→30% methanol-dichloromethane+1% saturated aqueous ammonium hydroxide) to give tert-butyl 4-((1S,2S)-2-amino-1,3-dihydroxypropyl)piperidine-1-carboxylate (I18) (857 mg, 79%).

[0308] Intermediate Scheme11. [ka] Triethylamine (7.02 mL, 50.4 mmol, 1.5 equiv.) was added to a solution of 1-benzyl-4-(ethoxycarbonyl)-3-oxopiperidin-1-imide chloride (10.0 g, 33.6 mmol, 1.0 equiv.) and palladium on carbon 10 wt.% (1.79 g, 1.77 mmol, 5 mol%) in 110 mL of ethanol at room temperature. Once the starting material was completely dissolved, the reaction medium was purged with nitrogen and then with H. 2 The reaction mixture was then flushed with 1 atm H at room temperature until the starting material was completely consumed. 2The mixture was maintained under stirring under reduced pressure. After 48 h reaction time, LCMS analysis showed complete deprotection of the benzyl group as well as complete reduction of the ketone. Nitrogen was flushed through the reaction medium. The crude mixture was filtered through a pad of Celite and washed several times with ethanol. The solvent was removed under vacuum to give 3-hydroxypiperidine-4-carboxylate as a white solid (5.75 g, 99%), which was used as such in the next step. [ka]

[0309] To a stirred solution of ethyl 3-hydroxypiperidine-4-carboxylate (5.65 g, 32.6 mmol, 1.0 eq.) and triethylamine (6.81 mL, 48.9 mmol, 1.5 eq.) in 150 mL of DCM, Boc-anhydride (7.83 g, 35.9 mmol, 1.1 eq.) was added in portions at 0° C. The reaction medium was allowed to warm to room temperature and was maintained under stirring overnight. TLC analysis revealed complete conversion of the starting material after 16 h of stirring. NaHCO 3 A saturated aqueous solution (100 mL) was added to the reaction medium and the organic phase was extracted with DCM (3×50 mL). 2 SO 4 After drying on a kettle and finally concentrating under vacuum, 1-(tert-butyl) 4-ethyl 3-hydroxypiperidine-1,4-dicarboxylate was obtained as a white solid (7.11 g, 80%) after purification with FCC (hexane / AcOEt: 100:0 to 70:30). [ka]

[0310] (E)-Diazene-1,2-diylbis(piperidin-1-ylmethanone) (6.92 g, 27.4 mmol, 1.5 equiv.) and 1H-pyrrole (1.84 g, 27.4 mmol, 1.5 equiv.) were added to a solution of 1-(tert-butyl) 4-ethyl 3-hydroxypiperidine-1,4-dicarboxylate (5.0 g, 18.29 mmol, 1.0 equiv.) in 280 mL of DCM at room temperature. Trimethylphosphane (36.6 mL, 36.6 mmol, 2.0 equiv.) (1 M solution in toluene) was then added dropwise and the reaction mixture was allowed to stir for 48 h. At this point, TLC indicated complete conversion of the starting material and the less polar major product (Rf=0.52 hexane / EtOAc 9:1). Hexane (200 mL) was added to the reaction mixture and the precipitate that formed was filtered. The filtrate was rinsed once with hexane. 1-(tert-Butyl) 4-ethyl 3,6-dihydropyridine-1,4(2H)-dicarboxylate was obtained as a yellow oil by purification on an FCC (Hexane / AcOEt 100:0 to 70:30) (3.81 g, 82%). [ka]

[0311] Diisobutylaluminum hydride (47.6 mL, 47.6 mmol, 3.2 equiv) was added dropwise to a stirred solution of 1-(tert-butyl) 4-ethyl 3,6-dihydropyridine-1,4(2H)-dicarboxylate (3.8 g, 14.88 mmol, 1.0 equiv) in THF (150 mL) under an argon atmosphere at -78°C. The reaction mixture was allowed to stir at -78°C for 30 min, then warmed to room temperature and maintained under stirring for an additional 20 min. At this point, TLC analysis indicated complete reduction of the ester to the corresponding alcohol (more polar spot, Rf=0.22 in hexane / AcOEt 7:3). 50 mL of NH 4 Cl was slowly added to the reaction mixture at 0° C. and stirring was maintained for 3 h. Then the reaction mixture was filtered through a Celite pad. The Celite cake was washed several times with EtOAc. The aqueous layer was extracted with AcOEt (3×30 mL). The organic layers were combined, washed once with brine (50 mL) and concentrated with Na2 SO 4 The solvent was removed under reduced pressure to give tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2 H)-carboxylate as a yellow oil (2.77 g, 87%). [ka]

[0312] A solution of iodine (3.91 g, 15.42 mmol, 1.2 equiv.) in dry THF (10 mL) was transferred via cannula to a stirred solution of tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2 H)-carboxylate (2.74 g, 12.85 mmol, 1.0 equiv.), triphenylphosphane (4.04 g, 15.42 mmol, 1.2 equiv.) and 1H-imidazole (1.05 g, 15.42 mmol, 1.2 equiv.) in dry THF (30 mL) at room temperature under argon atmosphere and stirring was maintained for 3 h (TLC monitoring). TLC showed complete conversion to the major product (Rf=0.64 in hexane / AcOEt 7:3 as eluent). The solvent was removed under reduced pressure and the crude mixture was purified by FCC (hexane / EtOAc 100:0 to 70:30) to give tert-butyl 4-(iodomethyl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale green oil (2.39 g, 58%). [ka]

[0313] A dry 100 mL round bottom flask (oven heated / argon cooled) was charged with ethyl 2-((diphenylmethylene)amino)acetate (2.34 g, 7.24 mmol, 1.0 equiv). The flask was purged with argon and 30 mL of dry THF was injected into the air-free system. The resulting solution was cooled to -78°C with stirring and NaHMDS (8.69 mL, 8.69 mmol, 1.2 equiv) was added dropwise to the solution. The reaction was stirred at -78°C for 30 min and a solution of tert-butyl 4-(iodomethyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.13 g, 7.96 mmol, 1.1 equiv) in dry THF (20 mL) was injected into the system via cannula. The solution was stirred at -78°C for 1 h, 0°C for 1 h, and at room temperature overnight. TLC indicated complete consumption of starting material. The reaction mixture was diluted with AcOEt (50 mL) and then washed with a solution of 0.5 g of citric acid (10 equiv.) in water (20 mL). The organic layer was extracted, dried over magnesium sulfate, and then concentrated. The crude product was purified by column chromatography (Hexane / EtOAc 100:0 to 50:50) to give 4-(2-amino-3-ethoxy-3-oxopropyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.93 g, 89%). [ka]

[0314] Lithium aluminum hydride (3.23 mL, 6.46 mmol, 1.0 equiv.) was added in portions to a solution of tert-butyl 4-(2-amino-3-ethoxy-3-oxopropyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.93 g, 6.46 mmol, 1.0 equiv.) in dry THF (80 mL) at -20°C. The reaction mixture was allowed to stir at this temperature for 4 h. After complete consumption of the starting material (TLC monitoring), the reaction mixture was diluted with 40 mL of AcOEt and Na 2 SO 3 Saturated aqueous solution (30 mL) was carefully added. The solid that formed was removed by filtration and the organic layer was extracted twice with EtOAc (2×20 mL), then washed with brine and MgSO4 The mixture was dried over 1000 ml and concentrated in vacuo to give the desired amino alcohol, which was then purified by HPLC using FCC (1% NH 4 The residue was purified by elution with 0.5% hexane / DCM / methanol (100:0 to 80:20) containing 0.5% OH. tert-Butyl 4-(2-amino-3-hydroxypropyl)-3,6-dihydropyridine-1(2H)-carboxylate (I19) was obtained as a colorless oil (0.69 g, 42% yield).

[0315] Intermediate scheme12. [ka] tert-Butyl (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylate (commercially available; 2.0 g, 8.72 mmol, 1 equiv.) was reacted with (+)Ipc 2 A 1M solution of B(allyl)borane in pentane (8.72 mL, 1 equiv.) was added at -78°C. The reaction mixture was stirred at -78°C for 4 h and quenched by dropwise addition of 10 mL of methanol. Triethylamine (1 mL) and hydrogen peroxide (3 mL) were added successively and the reaction mixture was allowed to stir at room temperature overnight (12 h). A saturated aqueous solution of sodium thiosulfate (30 mL) was added to the mixture, which was then concentrated in vacuo to leave an opaque residue. The residue was diluted with water (20 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated in vacuo to leave a pale yellow oil. Purification by flash chromatography afforded tert-butyl (S)-4-((R)-1-(hydroxybut-3-en-1-yl)-2,2-dimethyloxazolidine-3-carboxylate (1.6 g, 71%) as a liquid. [ka]

[0316] tert-Butyl (S)-4-((R)-1-hydroxybut-3-en-1-yl)-2,2-dimethyloxazolidine-3-carboxylate (1.5 g, 5.53 mmol, 1 equiv.) was dissolved in dry DMF (20 mL) and the solution was cooled to 0° C. and N 2 The mixture was stirred under reduced pressure. Tetrabutylammonium iodide (3.06 g, 8.29 mmol, 1.5 equiv.) and benzyl bromide (0.986 mL, 8.29 mmol, 1.5 equiv.) were added. NaH (60%, 0.398 g, 16.58 mmol, 3 equiv.) was then added in two portions. The reaction mixture was stirred at 0° C. for 45 min and then at room temperature for 45 min. After complete conversion of the reaction on TLC, the reaction mixture was quenched with aqueous ammonium chloride and the reaction mixture was extracted with diethyl ether (4×40 mL). The combined organic extracts were diluted with Na 2 SO 4 It was dried under reduced pressure and concentrated in vacuo to leave a pale yellow oil. Purification by flash chromatography afforded tert-butyl (S)-4-((R)-1-(benzyloxy)but-3-en-1-yl)-2,2-dimethyloxazolidine-3-carboxylate (1.69 g, 85%) as a liquid. [ka]

[0317] tert-Butyl (S)-4-((R)-1-(benzyloxy)but-3-en-1-yl)-2,2-dimethyloxazolidine-3-carboxylate (1.0 g, 2.77 mmol, 1 equiv.) was dissolved in dichloromethane (20 mL). A mixture of TFA (138 mmol, 50 equiv.) and water (9:1, 12 mL) was added. The reaction mixture was stirred at room temperature for 3 h until TLC analysis showed consumption of starting material. Afterwards, all volatiles were removed on a rotary evaporator and the residue was dissolved in 3 M NaOH solution and the pH was adjusted to pH=13. The mixture was diluted with CHCl 3 : i The combined organic extracts were washed with MgSO 4The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo to give a pale yellow oil. 2 Cl 2 Solvent system (TLC 10% MeOH:CH 2 Cl 2 ) was added to give (2S,3R)-2-amino-3-(benzyloxy)hex-5-en-1-ol (I20) (0.490 g, 80%).

[0318] Intermediate Scheme13. [ka] tert-Butyl (S)-4-((R)-1-methoxybut-3-en-1-yl)-2,2-dimethyloxazolidine-3-carboxylate (1.5 g, 5.53 mmol, 1 equiv.) was dissolved in dry THF (20 mL) and the solution was cooled to 0° C. and diluted with N 2 The mixture was stirred under reduced pressure. Methyl iodide (1.17 g, 8.29 mmol, 1.5 equiv.) was added. Subsequently, NaH (60%, 0.398 g, 16.58 mmol, 3 equiv.) was added in two portions. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 90 min. After complete conversion of the reactants on TLC, the reaction mixture was quenched with aqueous ammonium chloride solution and the reaction mixture was extracted with diethyl ether (4×40 mL). The combined organic extracts were washed with Na 2 SO 4 It was dried over, filtered and concentrated in vacuo to leave a pale yellow oil. Purification by flash chromatography afforded 1.42 g, 90% of the alcohol as a liquid. [ka]

[0319] (2S,3R)-2-amino-3-methoxyhex-5-en-1-ol was prepared in a manner similar to the procedure used to prepare (2S,3R)-2-amino-3-(benzyloxy)hex-5-en-1-ol (I21).

[0320] Intermediate Scheme14. [ka] To a stirred solution of tert-butyl (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylate (1.5 g, 6.54 mmol) in dry benzene (150 mL) at 23 °C, ethyl acetate 2-(triphenyl-15-phosphanylidene)(C-2 Wittig ylide (2.74 g, 7.85 mmol) was added to the reaction mixture and stirred for 7 h. After completion of the reaction, the reaction was monitored by TLC and the reaction precipitate was filtered on vacuum. The organic layer was concentrated under vacuum and purified by flash column chromatography to give tert-butyl (R,E)-4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2,2-dimethyloxazolidine-3-carboxylate (1.84 g, 94%) as a colorless oil. [ka]

[0321] Dry CH4 at 23 °C. 2 Cl 2 To the solution (30 mL), 2,2,2 trifluoroacetic acid (24.6 mL, 314 mmol) and H 2 2.6 mL, 137 mmol) was added to the reaction mixture and stirred for 7 h. After completion of the reaction, it was dissolved in solid Na 2 CO 3 The reaction mixture was quenched with the successive addition of water (pH 11) and then 15 mL of water was added. The organic layer was separated and the aqueous layer was washed with CH 2 Cl 2 (3×50 mL). The combined organic layers were washed with brine and the organic layer was extracted with anhydrous Na 2 SO 4The extract was dried over ice, concentrated in vacuo, and purified by flash column chromatography to give ethyl (R,E)-4-amino-5-hydroxypent-2-enoate (I22) (870 mg, 89%) as a colorless liquid.

[0322] Intermediate scheme15. [ka] To a solution of tert-butyl (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylate (1.8 g, 7.85 mmol) in dry THF under argon at -78°C, vinylmagnesium bromide (1 M solution in THF, 11.78 mL, 11.78 mmol) was added dropwise over 30 min. The reaction mixture was stirred at the same temperature for 2 h and then warmed to room temperature. After completion of the reaction, the reaction mixture was diluted with NH 4 The mixture was quenched with aqueous Cl and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried on a rotary evaporator. The solvent was removed on a rotary evaporator and the residue was purified by silica gel chromatography using ethyl acetate / hexane as eluent to give a mixture of both isomers as a colorless oil. Purification by flash chromatography on silica gel gave the desired tert-butyl (S)-4-((R)-1-hydroxyallyl)-2,2-dimethyloxazolidine-3-carboxylate (1.57 mg, 78%). [ka]

[0323] To a stirred solution of sodium hydride (0.439 g, 18.30 mmol) and tetrabutylammonium iodide (3.38 g, 9.15 mmol) in dry DMF (35 mL), tert-butyl (S)-4-((R)-1-hydroxyallyl)-2,2-dimethyloxazolidine-3-carboxylate (1.57 g, 6.10 mmol) was added to the reaction mixture diluted with dry DMF under an argon atmosphere. After 10 min, benzyl bromide (1.089 mL, 9.15 mmol) was added dropwise via syringe. The reaction mixture was stirred for 2 h. After completion of the reaction, it was eluted with NH 4 The mixture was quenched with aqueous Cl and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried on a rotary evaporator. The solvent was removed on a rotary evaporator and the residue was purified by silica gel chromatography using ethyl acetate / hexane as eluent to give a mixture of both isomers as a colorless oil. Purification by flash chromatography on silica gel gave tert-butyl (S)-4-((R)-1-(benzyloxy)allyl)-2,2-dimethyloxazolidine-3-carboxylate as a colorless liquid (1.728 mg, 82%). [ka]

[0324] To a stirred suspension of AD-mix-beta (7.5 g, 4.89 mmol) (1.4 g / mmol) in t-BuOH:HO (1:1, 40 mL) at 0 °C, MeSO 2 NH 2 (0.465 g, 4.89 mmol) was added in one portion. After stirring at 0° C. for 2 h, tert-butyl (S)-4-((R)-1-(benzyloxy)allyl)-2,2-dimethyloxazolidine-3-carboxylate (1.7 g, 4.89 mmol) was added in order to properly cool the reaction mixture. Stirring was continued at 0° C. for 48 h and the reaction was washed with saturated Na 2 SO 3(50 mL) and the resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with EtOAc (100 mL). The organic layer was separated and the aqueous phase was further extracted with EtOAc (300 mL). The combined organic layers were washed with brine (300 mL) and diluted with Na 2 SO 4 After drying over 100° C., filtration and concentration in vacuo, the crude residue was then purified by flash chromatography on silica gel (hexane:EtOAc=4:1) to give tert-butyl (S)-4-((1S,2S)-1-(benzyloxy)-2,3-dihydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.476 g, 79%). [ka]

[0325] Dry CH4 at 23 °C. 2 Cl 2 To the solution (30 mL), 2,2,2 trifluoroacetic acid (24.6 mL, 314 mmol) and H 2 2.6 mL, 137 mmol) was added to the reaction mixture and stirred for 7 h. After completion of the reaction, it was dissolved in solid Na 2 CO 3 The reaction mixture was quenched with the successive addition of water (pH 11) and then 15 mL of water was added. The organic layer was separated and the aqueous layer was washed with CH 2 Cl 2 (3×50 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The extract was dried over ice, concentrated in vacuo and purified by flash column chromatography to give ethyl (R,E)-4-amino-5-hydroxypent-2-enoate (I23) (870 mg, 89%) as a colorless liquid.

[0326] Intermediate Scheme16. [ka] To a stirred solution of (S)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (2.5 g, 9.01 mmol) in 20 ml of THF, allylmagnesium bromide (18.02 ml as a 1 molar solution, 18.02 mmol) was added dropwise to the reaction mixture at -78°C and then stirred for an additional 5 hours. After completion of the reaction, it was eluted with NH 4 The mixture was neutralized with a saturated solution of Cl (10 mL) and 10 mL of cold water, followed by 30 mL of EtOAc. The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL×3). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 It was dried over water, concentrated and purified by flash column chromatography to give (S)-N-((R)-1-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)-2-methylpropane-2-sulfinamide as a concentrated liquid (1.8 g, 61%). [ka]

[0327] To a stirred solution of (S)-N-((R)-1-((tert-butyldimethylsilyl)oxy)pent-4-en-2-yl)-2-methylpropane-2-sulfinamide (1.8 g, 5.63 mmol) in methanol at 0° C. was added a solution of HCl in dioxane (7.4 ml, 4 M. 28.4 mmol) and the reaction mixture was stirred at 23° C. for 15 h. The methanol was removed under vacuum and the reaction mixture was diluted with CH 2 Cl 2 (15 ml) and then diluted with NaHCO 3 The organic layer was separated and the aqueous layer was washed with CH 2 Cl 2 (20 ml x 3). The combined organic layer was washed with brine and anhydrous Na 2 SO 4The mixture was dried over water, concentrated, and purified by flash column chromatography to give (R)-2-aminopent-4-en-1-ol as a concentrate liquid (0.75 g, 82%).

[0328] Scheme 1. [ka] [ka] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3R,4R,6R)-7-(((S)-1-hydroxypent-4-en-2-yl)amino)-4-methoxy-4,6-dimethyl-2-(2,2,5-trimethyl-4-oxo-4H-1,3-dioxin-6-yl)heptan-3-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S1-2-I1).

[0329] (S)-2-aminopent-4-en-1-ol (343 mg, 3.40 mmol) and S1-1 (1.34 g, 2.27 mmol) were dissolved in EtOH (11.3 mL) and Ti(OEt) 4 (0.946 mL, 4.54 mmol) was added. After 30 min, a small aliquot was removed from the reaction mixture and diluted with a small amount of NaBH 4 A suspension of (S)-2-aminopent-4-en-1-ol (200 mg, 1.97 mmol) was added. After 30 min, a small aliquot was removed from the reaction mixture and washed with a small amount of NaBH in MeOH. 4 LC / MS analysis showed complete conversion. 4 (171 mg, 4.54 mmol) was added. When gas evolution ceased, 30% NH 4 Aqueous OH (6 mL) was added and the mixture was filtered through a pad of Celite®, washing with EtOAc. The filtrate was washed with brine and sodium 2 SO 4The mixture was dried over ice, filtered and concentrated. This material was used without further purification. MS(ESI+)m / z:675.25[M+H] + . [ka]

[0330] (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3R,4R,6R)-7-(((S)-1-hydroxypent-4-en-2-yl)(methyl)amino)-4-methoxy-4,6-dimethyl-2-(2,2,5-trimethyl-4-oxo-4H-1,3-dioxin-6-yl)heptan-3-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S1-3-I1-1).

[0331] S1-2-I1 (1.53 g, 2.26 mmol) was dissolved in dichloromethane (10 mL) and added with Na(OAc) 3 BH (957 mg, 4.52 mmol) was added. Formaldehyde (37 wt% in water, 1.82 mL, 22.5 mmol) was added. After 15 min, additional Na(OAc) 3 BH (475 mg, 2.24 mmol) and formaldehyde (37 wt % in water, 0.30 mL, 3.7 mmol) were added. After 20 min, the reaction mixture was cooled to room temperature with NaHCO 3 The mixture was quenched by the addition of (saturated aqueous solution). The layers were separated and the aqueous layer was extracted with dichloromethane (3 times). The combined dichloromethane extracts were washed with Na 2 SO 4 The material was dissolved in 100 ml of silica gel (0.5% NH 4 Purification on ice (elution with a gradient of 2-10% MeOH-dichloromethane containing aqueous OH) afforded the title compound as a thick oil (1.20 g, 76%, 2 steps). MS (ESI+) m / z: 689.26 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 8.04 (dt, 2H), 7.61-7.51 (m, 1H), 7.44 (t, 2H), 5.82-5.66 (m, 1H), 5.16-4.95 (m, 3H), 4.70 (d, 1H), 3.87 (d, 1H), 3.55 (dq, 1H), 3.47 (dd, 1H), 3.33-3.18 (m, 2H), 3.06 (s, 3H), 2.88 (td, 1H), 2.81-2.66 (m, 1H). ,2.49(dd,1H),2.38-2.23(m,7H),2.16(s,3H),2.10(dd,1H),1.92-1.75(m,5H),1.73(s,3H),1.68(s, 3H),1.64-1.55(m,1H),1.55-1.42(m,1H),1.38(dd,1H),1.34-1.18(m,7H),0.95(d,3H),0.83(d,3H). [ka]

[0332] (2S,3R,4S,6R)-2-(((3S,6R,8R,9R,10R)-3-allyl-8-methoxy-4,6,8,10,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S1-5-I1-1).

[0333] S1-3-I1-1 (1.19 g, 1.72 mmol) was concentrated from toluene three times. The material was dissolved in chlorobenzene (357 mL) and a stream of nitrogen was bubbled through the solution for 10 min. The mixture was heated at a bath temperature of 145 °C (approximately 130-135 °C internal temperature) overnight. The reaction was cooled to room temperature and concentrated. The residue was purified by precipitation onto 40 g of silica gel (0.5% NH 4 Purification on ice (elution with a gradient of 2-10% MeOH-dichloromethane containing aqueous OH) afforded the title compound as an off-white solid (835 mg, 77%). Mixture of C2 epimers. MS (ESI+) m / z: 631.23 [M+H] + .

[0334] Scheme 2. [ka] [ka] (2S,3R,4S,6R)-2-(((3S,6R,8R,9R,10R)-3-allyl-8-methoxy-4,6,8,10,12,12-hexamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S2-1-I1-1).

[0335] S1-5-I1-1 (834 mg, 1.32 mmol) was dissolved in 1,2-dimethoxyethane (6.6 mL) and the reaction mixture was cooled to -42 °C in a dry ice / acetonitrile bath. Potassium bis(trimethylsilyl)amide (1.0 M solution in THF, 1.71 mL, 1.71 mmol) was added. After 15 min, dimethyl sulfate (0.249 mL, 2.64 mmol) was added and the bath was replaced with an ice / water batch. After 30 min, triethylamine (1.83 mL, 13.2 mmol) was added and the reaction mixture was stirred at room temperature. After 20 min, the reaction was cooled to -42 °C in a dry ice / acetonitrile bath. 4 The mixture was quenched by the addition of saturated aqueous Cl and extracted with dichloromethane (3 times). 2 SO 4 The mixture was dried over 1000 ml of silica gel (2-10% MeOH-dichloromethane-0.5% NH 4 Purification on HPLC (elution with OH gradient) afforded the title compound as a white solid (551 mg, 64%). MS (ESI+) m / z: 645.24 [M+H] + . 1H NMR(400 MHz,chloroform-d)δ 8.11-7.92(m,2H),7.61-7.48(m,1H),7.43(t,2H),5.78(dddd,1H),5.15-4.90(m,3H),4.57(d,1H),4.16(dd,1H),4.01(d,1H),3.96-3.80(m ,1H),3.58(dtd,1H),3.41(ddd,1H),3.08(td,1H),2.99-2.86(m,1H), 2.81(s,3H),2.36-2.22(m,7H),2.19(s,3H),2.01(t,2H),1.75(m,7.1 Hz,5H),1.46-1.33(m,4H),1.33-1.15(m,9H),1.06-0.95(d,3H),0.88(d,3H). [ka]

[0336] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-4,6,8,10,12,12-hexamethyl-3-vinyl-1-oxa-4-azacyclotridecane-11,13-dione (S2-2-I3-1) (compound 14).

[0337] S2-1-I3-1 (18 mg, 0.029 mmol, prepared according to the method for S2-1-I1-1) was dissolved in MeOH (2 mL) and the reaction mixture was heated to 65 °C (external temperature) for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The material was purified by HPLC (Atlantis T3 column, 5-30% MeCN-water-0.1% HCO 2 H) to give 6.35 mg of the title compound as the formate salt. MS (ESI+) m / z: 176.1 [M+3H] 3+ ,263.7[M+2H] 2+ ,526.4[M+H] + ; 1 H NMR (400 MHz, methanol-d 4)δ 8.54(s,2H),5.97(dt,1H),5.68(s,2H),4.46(d,1H),4.29-4.17(m,2H),3.72(dtt,1H),3.48-3.37(m,2H),3.3 1(tq,2H),3.06(s,3H),2.95(d,1H),2.82(s,1H),2.75(s,6H),2.00(ddd,1H),1.53-1.25(m,16H),1.05(d,3H). [ka]

[0338] tert-Butyl 4-(((2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)piperazine-1-carboxylate (S2-2-I5-1) (compound 106).

[0339] Prepared from I5 according to methods S2-1-I1-1 and S2-2-I3-1 to give the title compound as the formate salt. MS (ESI+) m / z: 713.6 [M+H] + ; 1 H NMR (400 MHz, methanol-d) δ 8.34 (s, 3H), 5.43 (dd, 1H), 4.49 (d, 1H), 4.10 (d, 1H), 3.87 (ddd, 1H), 3.73 (ddd, 1H), 3.55-3.37 (m, 7H), 3.17 (s, 3H), 3.11-3.03 (m, 1H), 3.02 (s, 3H), 2.96-2.85 (m, 2H), 2.82 (s, 6 H),2.62-2.52(m,3H),2.52-2.40(m,2H),2.26(d,1H),2.08-1.97(m,1H),1.82(d,1H),1 .57-1.48(m,4H),1.44(s,9H),1.38(d,4H),1.37-1.33(m,9H),1.31(d,3H),1.06(d,3H).

[0340] Scheme 3. [ka] [ka] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2S,3S,6R,8R,9R,10R)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-3-(piperazin-1-ylmethyl)-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S3-1-I5-1).

[0341] S2-2-I5-1 (430 mg, 0.526 mmol) was dissolved in dichloromethane (4.4 mL) and cooled in an ice / water bath. Trifluoroacetic acid (0.5 mL, 6.52 mmol) was added, the ice / water bath was removed, and the reaction mixture was stirred at room temperature for 5.5 h. The reaction mixture was concentrated to a yellowish gum and NaHCO 3 (sat. aq., 10 mL) slowly and extracted with EtOAc (9 mL×4). The combined extracts were washed with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude title compound as a white solid. MS(ESI+)m / z:717.13[M+H] + . [ka]

[0342] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2S,3R,6R,8R,9R,10R)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-3-(piperazine-1-carbonyl)-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S3-1-I4-1).

[0343] Prepared according to the method for S3-1-I5-1, substituting S2-2-I4-1. This afforded the title compound as a white solid, which was used without further purification. MS (ESI+) m / z: 731.04 [M+H] + . [ka]

[0344] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-(piperazine-1-carbonyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-1) (compound 136). S3-1-I4-1 (35 mg, 0.048 mmol) was dissolved in MeOH (1 mL) and the reaction mixture was heated to 40 °C (external temperature) overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The material was purified by HPLC (Atlantis T3 column, 5-30% MeCN-water-0.1% HCO 2 H) to give 1.83 mg of the title compound as the formate salt. MS(ESI+)m / z:627.42[M+H] + ; 1 H NMR(400 MHz, methanol-d)δ 8.29(s,4H),5.27(s,1H),4.46(d,1H),4.30(s,1H),4.14-3.87(m,4H),3.81-3.63(m,2H),3.62-3.50(m,2H),3.46-3.35(m,2H),3.31 -3.12(m,3H),2.92(s,3H),2.74(d,10H),2.35(d,1H),2.08-1.84(m,2H),1.62(dd,1H),1.55-1.23(m,18H),1.19(d,3H),0.89(d,3H). [ka]

[0345] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-(4-methylpiperazine-1-carbonyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-2) (compound 97).

[0346] S3-1-I4-1 (36.4 mg, 0.0497 mmol) was dissolved in dichloromethane (0.5 mL) and added with Na(OAc) 3 BH (20 mg, 0.094 mmol) was added, followed by formaldehyde (37 wt % in water, 20.1 mg, 0.248 mmol). After 14 h, the reaction mixture was cooled to room temperature with NaHCO 3 (sat. aq.) and extracted with EtOAc (3x). The combined extracts were washed with Na 2 SO 4 The crude material was dissolved in methanol (1 mL) and the reaction mixture was heated to an external temperature of 40° C. overnight. The reaction was cooled to room temperature and concentrated. The residue was purified by HPLC (Atlantis T3 column, 5-50% MeCN-water-0.1% HCO 2 H) to give 9.45 mg of the title compound as the formate salt. MS(ESI+)m / z:641.36[M+H] + ; 1H NMR(400 MHz, methanol-d)δ 8.33(s,3H),5.30(s,1H),4.48(d,1H),4.31(s,1H),4.03(d,1H),3.94-3.80(m,2H),3.80-3.6 8(m,2H),3.67-3.54(m,2H),3.49-3.36(m,2H),2.95(s,3H),2.82(s,6H),2.76-2.65(m,6H),2. 65-2.52(m,2H),2.44(s,3H),2.42-2.31(m,1H),2.06-1.98(m,1H),1.92(s,1H),1.71-1.62(m, 1H),1.52(q,1H),1.47(s,3H),1.42-1.35(m,4H),1.35-1.29(m,9H),1.20(d,3H),0.92(d,3H). [ka]

[0347] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-(4-isopropylpiperazine-1-carbonyl)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-3) (compound 91).

[0348] Prepared from S3-1-I4-1 and acetone according to the method of S3-2-I4-1-2 to give the title compound as the formate salt. MS (ESI+) m / z: 669.44 [M+H] + ; 1H NMR(400 MHz, methanol-d)δ 8.50(s,2H),5.08(s,1H),4.48(d,1H),4.09-3.89(m,2H),3.87-3.54(m ,6H),3.50-3.35(m,3H),2.91(s,3H),2.80(s,6H),2.79-2.72(m,1H),2 .71-2.44(m,8H),2.15-1.93(m,2H),1.75(d,2H),1.52(q,1H),1.42(s, 3H), 1.39 (s, 3H), 1.31 (dd, 9H), 1.17 (d, 3H), 1.10 (d, 6H), 0.85 (d, 3H). [ka]

[0349] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I5-1-1) (compound 124).

[0350] S3-1-I5-1 (36.8 mg, 0.051 mmol) was dissolved in dry THF (0.6 mL) under nitrogen. Phenylsilane (12.5 μL, 1.020 mmol) was added followed by trifluoroacetic acid (6.8 μL, 0.090 mmol). The reaction mixture was placed in a preheated dry block at 70 °C and stirred for 6 h. The reaction was cooled and washed with saturated NaHCO 3 (1.5 mL) and extracted with EtOAc (1 mL×3). The combined extracts were washed with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated. The resulting crude material was dissolved in MeOH (1 mL), heated at 40 °C overnight and concentrated. The residue was purified by HPLC (Atlantis T3 column, 5-50% MeCN-water-0.1% HCO 2H) to give 8.31 mg of the title compound as the formate salt. MS(ESI+)m / z:695.33[M+H] + ; 1 H NMR (400 MHz, methanol-d) δ 8.40 (s, 3H), 5.41 (dt, 1H), 4.50 (d, 1H), 4.11 (d, 1H), 3.91-3.80 (m, 1H), 3.73 (ddd, 1H), 3.57-3.47 (m, 1H), 3.47-3.36 (m, 2H), 3.18 (s, 3H), 3.07 (q, 3H), 3.02 (s, 3H), 2 .95-2.84(m,2H),2.82(s,6H),2.77-2.61(m,6H),2.61-2.51(m,2H),2.27(d,1H),2 .08-1.99(m,1H),1.83(d,1H),1.58-1.47(m,4H),1.42-1.30(m,17H),1.07(d,3H). [ka]

[0351] (2S,3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-(4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I4-1-4) (compound 130).

[0352] Prepared according to the method of S3-2-I5-1-1 from S3-1-I4-1 to give the title compound as the formate salt. MS (ESI+) m / z: 709.29 [M+H] + ; 1H NMR (400 MHz, methanol-d) δ 8.49 (s, 1H), 5.27 (s, 1H), 4.49 (d, 1H), 4.23 (s, 1H), 4.03 (d, 1H), 3.90-3.66 (m, 4H), 3.66-3.54 (m, 2H), 3.49-3.37 (m, 2H), 3.14 (q, 2H), 2.95 (s, 3H), 2.82 (s, 6H), 2.80-2.62(m,8H),2.33(s,1H),2.09-1.98(m,1H),1.95-1.81(m,1H),1.70(d,1H) ),1.54(q,1H),1.50-1.41(m,4H),1.41-1.23(m,13H),1.20(d,3H),0.91(d,3H). [ka]

[0353] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-1-1) (compound 80).

[0354] S3-1-I5-1 (37.4 mg, 0.0521 mmol) and 4-dimethylaminopyridine (1 mg, 0.008 mmol) were dissolved in dichloromethane (0.45 mL) and N,N-diisopropylethylamine (0.050 mL, 0.26 mmol). The solution was cooled to 0° C., methanesulfonyl chloride (0.012 mL, 0.156 mmol) was added, and the reaction mixture was allowed to warm to room temperature. After 3 h, the reaction was quenched with saturated NaHCO 3 (1 mL) and extracted with EtOAc (1 mL x 3). The combined extracts were washed with Na 2 SO 4The mixture was dried over ice, filtered and concentrated. The resulting crude material was dissolved in MeOH (1 mL), heated at 40 °C overnight and concentrated. The residue was purified by HPLC (Atlantis T3 column, 5-50% MeCN-water-0.1% HCO 2 H) to give 14.1 mg of the title compound as the formate salt. MS(ESI+)m / z:691.30[M+H] + ; 1 H NMR(400 MHz, methanol-d)δ 8.33(s,3H),5.44(dq,1H),4.49(d,1H),4.10(d,1H),3.90-3.80(m,1H),3.72(ddd,1H), 3.55-3.37(m,3H),3.27-3.19(m,4H),3.16(s,3H),3.10-3.02(m,1H),3.02(s,3H),2.95 -2.85(m,2H),2.84(s,3H),2.81(s,6H),2.74-2.59(m,5H),2.31-2.21(m,1H),2.07-1.9 9(m,1H),1.82(d,1H),1.57-1.43(m,4H),1.42-1.33(m,13H),1.31(d,3H),1.06(d,3H). [ka]

[0355] 4-(((2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)-N,N-dimethylpiperazine-1-sulfonamide (S3-3-I5-1-2) (compound 142).

[0356] Prepared from S3-1-I5-1 and dimethylsulfamoyl chloride according to the method of S3-3-I5-1-1 to give the title compound as the formate salt. MS (ESI+) m / z: 720.24 [M+H] + ; 1H NMR(400 MHz, methanol-d)δ 8.25(s,1H),5.45(dq,1H),4.51(d,1H),4.11(d,1H),3.93-3.85(m,1H),3.79-3.70(m,1H ),3.58-3.40(m,3H),3.29-3.23(m,3H),3.19(s,3H),3.12-2.99(m,4H),2.94(dd,1H),2. 89(s,3H),2.87-2.81(m,9H),2.68(q,1H),2.64(s,6H),2.63-2.56(m,2H),2.37-2.20(m, 1H), 2.10-2.02 (m, 1H), 1.84 (d, 1H), 1.61-1.47 (m, 4H), 1.44-1.26 (m, 15H), 1.08 (d, 3H). [ka]

[0357] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-tosylpiperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-1-3) (compound 139).

[0358] Prepared according to the method of S3-3-I5-1-1 from S3-1-I5-1 and p-toluenesulfonyl chloride to give the title compound as the formate salt. MS (ESI+) m / z: 767.38 [M+H] + ; 1H NMR(400 MHz, methanol-d)δ 8.36(s,3H),7.63(d,2H),7.41(d,2H),5.38(dt,1H),4.46(d,1H),4.06(d,1H),3.78(ddd ,1H),3.74-3.66(m,1H),3.51-3.35(m,3H),3.03(s,3H),2.99(d,5H),2.96(s,3H),2.88-2 .82(m,2H),2.80(s,6H),2.71-2.62(m,2H),2.62-2.52(m,3H),2.42(d,3H),2.25-2.14(m ,1H),2.04-1.97(m,1H),1.78(d,1H),1.55-1.41(m,5H),1.37-1.24(m,16H),1.00(d,3H). [ka]

[0359] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-3-I5-1-4) (compound 81).

[0360] Prepared according to the method of S3-3-I5-1-1 from S3-1-I5-1 and 1-methyl-1H-imidazole-4-sulfonyl chloride to give the title compound as the formate salt. MS (ESI+) m / z: 757.32 [M+H] + ; 1H NMR(400 MHz, methanol-d)δ 8.35(s,3H),7.76(d,1H),7.71(d,1H),5.39(dt,1H),4.47(d,1H),4.07(d,1H),3.85-3.78(m ,1H),3.77(s,3H),3.71(ddd,1H),3.52-3.45(m,1H),3.44-3.35(m,2H),3.19-3.10(m,4H),3 .08(s,3H),3.04-2.93(m,4H),2.92-2.82(m,2H),2.80(s,6H),2.70-2.53(m,5H),2.28-2.14 (m,1H),2.06-1.98(m,1H),1.79(d,1H),1.59-1.41(m,4H),1.39-1.25(m,17H),1.02(d,3H). [ka]

[0361] (2S,3S,6R,8R,9R,10R)-3-((4-acetylpiperazin-1-yl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-1) (compound 135).

[0362] S3-1-I5-1 (36.0 mg, 0.0502 mmol) and 4-dimethylaminopyridine (1 mg, 0.008 mmol) were dissolved in dichloromethane (0.45 mL) and N,N-diisopropylethylamine (0.050 mL, 0.26 mmol). The solution was cooled to 0° C., acetyl chloride (0.0106 mL, 0.150 mmol) was added, and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction was placed in the freezer overnight. After stirring at room temperature for an additional hour, the reaction was diluted with saturated NaHCO 3 (1 mL) and extracted with EtOAc (1 mL x 3). The combined extracts were washed with Na 2 SO 4The mixture was dried over ice, filtered and concentrated. The resulting crude material was dissolved in MeOH (1 mL), heated at 40 °C overnight and concentrated. The residue was purified by HPLC (Atlantis T3 column, 5-50% MeCN-water-0.1% HCO 2 H) to give 12.9 mg of the title compound as the formate salt. MS(ESI+)m / z:655.39[M+H] + ; 1 H NMR(400 MHz, methanol-d)δ 8.35(s,3H),5.43(dq,1H),4.49(d,1H),4.10(d,1H),3.88(ddt,1H),3.73(ddd,1H),3.65 -3.36(m,7H),3.18(d,3H),3.07(t,1H),3.02(d,3H),2.98-2.85(m,2H),2.82(d,6H),2.68 -2.53(m,4H),2.53-2.44(m,1H),2.26(d,1H),2.09(s,3H),2.07-2.01(m,1H),1.83(d,1H) ,1.59-1.43(m,4H),1.42-1.37(m,5H),1.37-1.33(m,9H),1.33-1.27(m,3H),1.07(d,3H). [ka]

[0363] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-propionylperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-2) (compound 133).

[0364] Prepared from S3-1-I5-1 and propionyl chloride according to the method of S3-4-I5-1-1 to give the title compound as the formate salt. MS (ESI+) m / z: 669.43 [M+H] + ; 1H NMR (400 MHz, methanol-d) δ 8.43 (s, 3H), 5.44 (dt, 1H), 4.49 (d, 1H), 4.10 (d, 1H), 3.88 (ddd, 1H), 3.73 (ddd, 1H), 3.65-3.37 (m, 7H), 3.18 (s, 3H), 3.10-2.98 (m, 4H), 2.98-2.84 (m, 2H), 2.82 (s, 6H), 2.59 (dt,3H),2.53-2.45(m,1H),2.40(q,2H),2.27(d,1H),2.03(ddd,1H),1.83(d,1H),1.6 1-1.52(m,1H),1.50(s,3H),1.43-1.33(m,14H),1.33-1.27(m,3H),1.14-1.03(m,6H). [ka]

[0365] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-pivaloylperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-3) (compound 114).

[0366] Prepared from S3-1-I5-1 and pivaloyl chloride according to the method of S3-4-I5-1-1 to give the title compound as the formate salt. MS (ESI+) m / z: 697.33 [M+H] + ; 1H NMR(400 MHz, methanol-d)δ 8.37(s,3H),5.42(dq,1H),4.49(d,1H),4.10(d,1H),3.93-3.81(m,1H),3.78-3.59(m,5H),3 .54-3.46(m,1H),3.46-3.36(m,2H),3.18(d,3H),3.07(t,1H),3.02(s,3H),2.97-2.83(m,2H ),2.81(d,6H),2.65-2.55(m,3H),2.55-2.47(m,2H),2.33-2.20(m,1H),2.02(ddd,1H),1.82 (d,1H),1.59-1.44(m,4H),1.42-1.33(m,13H),1.31(d,3H),1.26(d,9H),1.10-1.03(m,3H). [ka]

[0367] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-3-((4-(2-methoxybenzoyl)piperazin-1-yl)methyl)-2,4,6,8,10,12,12-heptamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-4) (compound 84).

[0368] Prepared from S3-1-I5-1 and 2-methoxybenzoyl chloride according to the method of S3-4-I5-1-1 to give the title compound as the formate salt. MS (ESI+) m / z: 747.35 [M+H] + ; 1H NMR (400 MHz, methanol-d) δ 8.36 (s, 3H), 7.36 (t, 1H), 7.03 (ddd, 1H), 6.97-6.89 (m, 2H), 5.43 (dd, 1H), 4.49 (d, 1H), 4.09 (d, 1H), 3.92-3.83 (m, 1H), 3.81 (s, 3H), 3.79-3.68 (m, 3H), 3.55-3.35 (m, 5H), 3.17 (s, 3H),3.10-2.98(m,4H),2.96-2.85(m,2H),2.81(s,7H),2.74-2.40(m,5H),2.26(d,1H),2 .06-2.00(m,1H),1.82(d,1H),1.49(d,4H),1.42-1.33(m,12H),1.30(d,3H),1.06(d,3H). [ka]

[0369] (2S,3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2,4,6,8,10,12,12-heptamethyl-3-((4-(2,2,2-trifluoroacetyl)piperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-4-I5-1-5) (compound 109).

[0370] Prepared from S3-1-I5-1 and trifluoroacetic anhydride according to the method of S3-4-I5-1-1 to give the title compound as the formate salt. MS (ESI+) m / z: 709.27 [M+H] + ; 1H NMR(400 MHz, methanol-d)δ 8.49(s,3H),5.46(s,1H),4.51(d,1H),4.12(d,1H),3.89(s,1H),3.80-3. 65(m,5H),3.53(dd,1H),3.49-3.34(m,2H),3.19(s,3H),3.04(s,4H),2.9 3(dd,2H),2.80(s,6H),2.74-2.58(m,5H),2.28(s,1H),2.06-1.99(m,1H) ,1.85(d,1H),1.52(s,4H),1.45-1.35(m,13H),1.33(d,3H),1.09(d,3H).

[0371] The following examples were prepared according to the method in Scheme 3, substituting the appropriate intermediates from Table 1. [ka]

[0372] 4-(((3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12,-pentamethyl-11,13-dioxo-4-propyl-1-oxa-4-azacyclotridecan-3-yl)methyl)piperidine-1-carboxylate (S3-1-I7-3).

[0373] The oven-dried flask was evacuated and backfilled with nitrogen (twice) and then cooled to room temperature. S2-1-I7-3 (196 mg, 0.226 mmol, prepared from I7 and propionaldehyde as described in Scheme 1) in ethanol (4 mL) was added to the flask, then the flask was evacuated and backfilled with nitrogen (twice). 10% Pd / C (50% wet, 40 mg, 0.0187 mmol) was added to the flask, the reaction mixture was evacuated and backfilled with nitrogen (twice), then evacuated and backfilled with hydrogen (four times). The reaction mixture was stirred under a hydrogen balloon for 1.5 hours. The reaction mixture was evacuated and backfilled with nitrogen (four times). Celite® was added, and the reaction mixture was stirred for about 10 minutes and filtered through Celite®. The wet pad was rinsed with EtOH (5 mL x 2) and the combined organic layers were concentrated to give the crude title compound (166.4 mg, 100%), which was used without further purification. MS (ESI+) m / z: 730.26 [M+H] + , formate, 1 H NMR(400 MHz, methanol-d)δ 8.48(s,3H),4.46(dd,1H),4.34-4.06(m,2H),3.80-3.67(m,1H),3.55-3.34(m,5H),3.25-3.05(m,2H),3.04-2.86(m,6) H),2.86-2.74(m,10H),2.18-1.90(m,4H),1.85-1.57(m,7H),1.57-1.46(m,6H),1.43-1.23(m,13H),1.09-0.90(m,6H). [ka]

[0374] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-methylpiperidin-4-yl)methyl)-4-propyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-3-1) (compound 95).

[0375] Prepared from S3-1-I7-3 and formaldehyde according to the method of S3-2-I4-1-2 to give the title compound as a formate salt. MS (ESI+) m / z: 640.33 [M+H] + ; 1 H NMR(400 MHz, methanol-d)δ 8.48(s,3H),4.46(dd,1H),4.34-4.06(m,2H),3.80-3.67(m,1H),3.55-3.34(m,5H),3.25-3.05(m,2H),3.04-2.86(m,6) H),2.86-2.74(m,10H),2.18-1.90(m,4H),1.85-1.57(m,7H),1.57-1.46(m,6H),1.43-1.23(m,13H),1.09-0.90(m,6H). [ka]

[0376] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-4-propyl-3-((1-propylpiperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-3-2) (compound 96).

[0377] Prepared from S3-1-I7-3 and propionaldehyde according to the method of S3-2-I4-1-2 to give the title compound as a formate salt. MS (ESI+) m / z: 668.38 [M+H] + ; 1H NMR(400 MHz, methanol-d)δ 8.51(s,3H),4.46(d,1H),4.26-3.96(m,2H),3.79-3.66(m,1H),3.62-3.49(m,3H),3.49-3.34(m,3H),3.05-2.96(m,3H),2.96-2 .83(m,5H),2.83-2.73(m,7H),2.15-1.91(m,4H),1.82-1.70(m,3H),1.70-1.43(m,11H),1.41-1.22(m,13H),1.07-0.83(m,9H). [ka]

[0378] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-methylpiperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-1) (compound 98).

[0379] Prepared from S3-1-I7-2 and formaldehyde according to the method of S3-2-I4-1-2 to give the title compound as a formate salt. MS (ESI+) m / z: 209.5 [M+3H] 3+ ,313.8[M+2H] 2+ ,626.5[M+H] + ; 1 H NMR (400 MHz, methanol-d 4 )δ 8.50(s,2H),4.41(d,1H),4.14(s,1H),3.68(m,1H),3.46-3.25(m,5H),2.95-2.80(m,5H),2.75(d,6H), 2.07-1.94(m,3H),1.89(d,1H),1.52(s,1H),1.44(d,3H),1.30(m,12H),1.21(s,2H),1.00-0.93(m,2H). [ka]

[0380] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-3-((1-ethylpiperidin-4-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-2) (compound 118). Prepared from S3-1-I7-2 and acetaldehyde according to the method of S3-2-I4-1-2 to give the title compound as the formate salt. MS (ESI+) m / z: 640.35 [M+H] + ; 1 H NMR(400 MHz, methanol-d)δ 8.54(s,3H),4.46(d,1H),4.37-3.97(m,2H),3.79-3.65(m,1H),3.64-3.40(m,5H),3.40-3.33(m,1H),3.16-3.03(m,3 H),3.03-2.81(m,6H),2.81-2.70(m,8H),2.16-1.84(m,5H),1.57-1.41(m,8H),1.41-1.08(m,20H),1.08-0.81(m,4H). [ka]

[0381] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-3-((1-propylpiperidin-4-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-3) (compound 102).

[0382] Prepared from S3-1-I7-2 and propionaldehyde according to the method of S3-2-I4-1-2 to give the title compound as a formate salt. MS (ESI+) m / z: 654.30 [M+H]+ ; 1 H NMR(400 MHz, methanol-d)δ 8.51(s,2H),4.46(d,1H),4.36-3.90(m,2H),3.78-3.65(m,1H),3.62-3.39(m,5H),3.39-3.33(m,1H),3.07-2.82(m,8H),2.82- 2.67(m,8H),2.14-1.87(m,4H),1.82-1.60(m,5H),1.60-1.41(m,8H),1.41-1.24(m,14H),1.24-1.07(m,3H),1.07-0.81(m,6H). [ka]

[0383] (2S,3R,4S,6R)-2-(((3R,6R,8R,9R,10R)-3-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)methyl)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate.

[0384] S3-1-I7-2 (90 mg, 0.13 mmol) was dissolved in dry methylene chloride (2 mL). Acetic acid (0.021 mL, 0.38 mmol) and 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (0.036 mL, 0.19 mmol) were added. Then NaBH(OAc) 3 (53 mg, 0.25 mmol) was added in one portion to the reaction mixture. The reaction was allowed to stir at room temperature for 2 h, at which time LC / MS showed complete conversion. The reaction was cooled to 30° C. with saturated NaHCO 3 The reaction was quenched by the addition of aqueous solution (5 mL) and the aqueous layer was extracted with methylene chloride (3×10 mL). The combined extracts were washed with MgSO 4 The mixture was dried over 1000 ml of silica gel (0-10% MeOH-dichloromethane + 0.5% 30% NH 4The mixture was purified on a 500 rpm column (eluted with aqueous OH) to give the title compound as a white solid (60 mg, 55%). MS (ESI+) m / z: 292.2 [M+3H] 3+ ,437.8[M+2H] 2+ ,874.6[M+H] + . [ka]

[0385] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((3R,6R,8R,9R,10R)-4-ethyl-3-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate.

[0386] (2S,3R,4S,6R)-2-(((3R,6R,8R,9R,10R)-3-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)methyl)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (60 mg, 0.067 mmol) was dissolved in dry THF (2 mL) and TBAF (1 M in THF, 0.20 mL, 0.020 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 h and concentrated. The residue was purified by elution with 4 g of silica gel (0-20% MeOH-dichloromethane + 0.5% 30% NH 4 The mixture was purified on a 500 rpm column (eluted with aqueous OH) to give the title compound as a white solid (46 mg, 88%). MS (ESI+) m / z: 254.2 [M+3H] 3+ ,380.8[M+2H] 2+ ,760.5[M+H] + . [ka]

[0387] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-3-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-4) (compound 169).

[0388] Prepared by methanation of (2S,3R,4S,6R)-4-(dimethylamino)-2-(((3R,6R,8R,9R,10R)-4-ethyl-3-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate according to the method of S3-2-I4-1-2. MS(ESI+)m / z:219.5[M+3H] 3+ , 328.8[M+2H] 2+ ,656.5[M+H] + ; 1 H NMR (400 MHz, methanol-d 4 )δ 8.53(s,2H),4.45(d,1H),3.84(t,2H),3.71(ddd,1H),3.53-3.40(m,4H),3.40-3.27(m,6H),3.13(d,1H),3.08(s,2H),2.99-2.9 0(m,3H),2.84(s,1H),2.77(s,7H),2.08-1.96(m,3H),1.92(d,1H),1.59(s,1H),1.47(dd,5H),1.39-1.27(m,12H),0.97(s,2H). [ka]

[0389] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((3R,6R,8R,9R,10R)-4-ethyl-8-methoxy-3-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate.

[0390] In an 8 mL vial, a solution of (2S,3R,4S,6R)-4-(dimethylamino)-2-(((3R,6R,8R,9R,10R)-4-ethyl-3-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (26 mg, 0.035 mmol) in 1,2-dimethoxyethane (2 mL) was precooled at -60°C. KHMDS (0.10 mL, 0.10 mmol) was added dropwise. The reaction mixture was stirred at -60°C for 20 min. Me 2 SO 4 (16 μL, 0.17 mmol) was added. The reaction mixture was warmed to −15° C. LC / MS shows complete conversion. The reaction was quenched by adding triethylamine (1 mL) and the resulting mixture was diluted with dichloromethane and saturated NaHCO 3 The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with MgSO 4 The mixture was dried over 1000 ml of silica gel (0-10% MeOH-dichloromethane + 0.5% 30% NH 4 The mixture was purified on a 500 rpm column (eluted with aqueous OH) to give the title compound as a white solid (22 mg, 82%). MS (ESI+) m / z: 258.8 [M+3H] 3+ ,387.8[M+2H] 2+ ,774.5[M+H] + . [ka]

[0391] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-3-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I7-2-5).

[0392] Prepared by methanation of (2S,3R,4S,6R)-4-(dimethylamino)-2-(((3R,6R,8R,9R,10R)-4-ethyl-8-methoxy-3-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-6,8,10,12,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate according to the method of S3-2-I4-1-2. MS(ESI+)m / z:224.2[M+3H] 3+ , 335.8[M+2H] 2+ , 670.5[M+H] + ; 1 H NMR(400 MHz, Methanol-d 4 )δ 8.53(s,2H),4.45(d,1H),4.14(s,1H),3.69(dt,3H),3.54-3.44(m,2H),3.44-3.27(m,10H),3.19(d,1H),3.13(s,2H),2.94(s,2H) ,2.78(d,8H),2.06-1.96(m,2H),1.89(d,1H),1.54(s,4H),1.51-1.40(m,3H),1.39-1.27(m,12H),1.25-1.18(m,2H),0.98(s,2H). [ka]

[0393] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-4,6,8,10,12,12-hexamethyl-3-((4-methylpiperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-1-1) (compound 154).

[0394] Prepared from S3-2-I8-1 and formaldehyde according to the method of S3-2-I4-1-2 to give 7.33 mg of the title compound as a formate salt. (ESI+) m / z: 205.04 [M+3H] 3+ , 307.01[M+2H] 2+ , 613.01[M+H] + ; 1 H NMR (400 MHz, methanol-d 4 )δ 8.53(s,2H),4.58(d,1H),4.45(d,1H),4.34(t,1H),4.26(d,1H),3.90(d,1H) ),3.77-3.67(m,1H),3.54-3.33(m,3H),3.19(s,1H),3.02(s,3H),2.82(s,3 H),2.76(s,9H),2.73-2.54(m,7H),2.45(s,3H),2.18(s,1H),2.04-1.95(m, 1H),1.57(s,3H),1.53-1.43(m,1H),1.39(d,6H),1.33(dd,6H),1.04(d,3H). [ka]

[0395] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((4-ethylpiperazin-1-yl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-1-2) (compound 155).

[0396] Prepared from S3-2-I8-1 and acetaldehyde according to the method of S3-2-I4-1-2 to give 6.82 mg of the title compound as a formate salt. (ESI+) m / z: 209.72 [M+3H] 3+ , 313.98[M+2H] 2+ , 627.02[M+H] + ; 1 H NMR (400 MHz, methanol-d 4 )δ 8.53(s,2H),4.58(d,1H),4.46(d,1H),4.34(t,1H),4.25(d,1H),3.83(s,1H),3.77- 3.68(m,1H),3.54-3.36(m,2H),3.14(s,1H),3.02(s,3H),2.92-2.78(m,6H),2.76(s ,8H),2.74-2.64(m,5H),2.60(dd,2H),2.17(s,1H),2.06-1.97(m,1H),1.70(s,2H), 1.55(s,3H),1.54-1.44(m,1H),1.39(d,6H),1.33(dd,6H),1.20(t,3H),1.03(d,3H). [ka]

[0397] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((4-isopropylpiperazin-1-yl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-1-3) (compound 156).

[0398] Prepared from S3-2-I8-1 and acetone according to the method of S3-2-I4-1-2 to give 11.7 mg of the title compound as a formate salt. (ESI+) m / z: 214.41 [M+3H] 3+ , 321.01[M+2H] 2+ , 641.09[M+H] + ;1 H NMR (400 MHz, methanol-d 4 )δ 8.59(s,2H),4.64(d,1H),4.51(d,1H),4.39(t,1H),4.29(d,1H),3.85(s,1H) ),3.82-3.73(m,1H),3.58-3.43(m,2H),3.27-3.12(m,2H),3.05(s,7H),2.82 (s,14H),2.66(dd,2H),2.20(s,1H),2.11-2.00(m,1H),1.75(s,2H),1.59(s, 3H),1.58-1.48(m,1H),1.44(s,6H),1.38(dd,6H),1.30(d,6H),1.08(d,3H). [ka]

[0399] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-8-methoxy-6,8,10,12,12-pentamethyl-3-((4-methylpiperazin-1-yl)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-2-1) (compound 157).

[0400] Prepared from S3-2-I8-2 and formaldehyde according to the method of S3-2-I4-1-2 to give 7.63 mg of the title compound as a formate salt. (ESI+) m / z: 209.74 [M+3H] 3+ , 314.01[M+2H] 2+ , 627.11[M+H] + ; 1 H NMR (400 MHz, methanol-d 4)δ 8.49(s,2H),4.69(s,1H),4.46(d,1H),4.29(s,1H),4.15(d,1H),3.79-3.66(m,1H),3.54(s,2H),3.49-3.33(m,2H),3.25-3.00(m,3H), 2.95(s,6H),2.81(s,8H),2.61(s,7H),2.10-1.97(m,2H),1.88(s,1H),1.61-1.47(s,4H),1.41-1.29(m,12H),1.24(t,3H),0.99(d,3H). [ka]

[0401] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-3-((4-ethylpiperazin-1-yl)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-2-2) (compound 158).

[0402] Prepared from S3-2-I8-2 and acetaldehyde according to the method of S3-2-I4-1-2 to give 6.83 mg of the title compound as a formate salt. (ESI+) m / z: 214.41 [M+3H] 3+ , 321.03[M+2H] 2+ , 641.14[M+H] + ; 1 H NMR (400 MHz, methanol-d 4)δ 8.52(s,2H),4.54(s,1H),4.46(d,1H),4.19(s,1H),4.09(d,1H),3.78-3.65 (m,1H),3.59(s,1H),3.44(dd,2H),3.35(dd,1H),2.90(s,8H),2.83(d,3H), 2.78(s,9H),2.60(s,4H),2.00(ddd,2H),1.91(s,1H),1.53(d,3H),1.48(dd ,1H),1.36(s,4H),1.32(d,9H),1.23(t,4H),1.19-1.13(m,2H),0.94(d,3H). [ka]

[0403] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((4-isopropylpiperazin-1-yl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S3-2-I8-2-3) (compound 159).

[0404] Prepared according to the method of S3-2-I4-1-2 from S3-2-I8-2 and acetone to give 6.11 mg of the title compound as the formate salt. (ESI+) m / z: 219.05 [M+3H] 3+ , 328.02[M+2H] 2+ , 655.08[M+H] + ; 1 H NMR (400 MHz, methanol-d 4)δ 8.52(s,2H),4.53(s,1H),4.46(d,1H),4.18(s,1H),4.08(d,1H),3.76-3.66(m ,1H),3.61(s,1H),3.44(dd,1H),3.35(dd,1H),3.25(d,1H),3.07(s,4H),2.89( s,6H),2.78(s,7H),2.71-2.52(m,4H),2.01(dd,2H),1.88(s,1H),1.52(s,3H) ,1.51-1.44(m,1H),1.36(s,3H),1.34-1.22(m,15H),1.18(d,3H),0.93(d,3H).

[0405] Scheme 4. [ka] [ka] (2S,3R,4S,6R)-2-(((3R,6R,8R,9R,10R)-3-(((1r,3S)-3-((tert-butoxycarbonyl)amino)cyclobutyl)methyl)-8-methoxy-4,6,8,10,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S1-5-I8-1).

[0406] Prepared according to the method of S1-5-I1-1 substituting I8 to give 218 mg of the title compound. MS(ESI+)m / z:387.72[M+2H] 2+ , 774.25[M+H] + ; 1H NMR (400 MHz, chloroform-d) δ 8.10-7.90(m,2H), 7.56(t,1H), 7.44(t,2H), 5.04(dd,1H), 4.76-4.61(m,1H), 4.55(d,1H), 4.35(s,1H), 4.23-4.09(m,1H), 4.06(d,1H), 3.72(t,1H), 3.62-3.44(m,2H), 3.44-3.19(m,1H), 2.91(d,1H), 2.87-2.78(m,1H), 2.77(s ,2H),2.70-2.58(m,1H),2.46(d,1H),2.37-2.29(m,1H),2.26(s,4H),2.16(s,2H),2.09(s,1H),2.07-1.86(m,5H) ,1.80(t,2H),1.43(s,9H),1.34-1.30(m,1H),1.27(d,3H),1.22(s,3H),1.18(d,3H),0.99(dd,4H),0.83(dd,3H). [ka]

[0407] (2S,3R,4S,6R)-2-(((3R,6R,8R,9R,10R)-3-(((1r,3S)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutyl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S4-1-I8-1).

[0408] S1-5-I8-1 (212 mg, 0.273 mmol) was dissolved in 1,2-dimethoxyethane (2.72 mL) and the reaction mixture was cooled to -78 °C in a dry ice / acetone bath. Potassium bis(trimethylsilyl)amide (1.0 M solution in THF, 0.818 mL, 0.818 mmol) was added. After 5 min, dimethyl sulfate (0.128 mL, 1.36 mmol) was added. The dry ice was removed from the acetone bath and the reaction mixture was allowed to warm slowly to -10 °C over 50 min. Triethylamine (0.378 mL, 2.27 mmol) was added and the reaction was allowed to warm to room temperature over 30 min. The reaction was diluted with NH 4 The mixture was quenched by adding Cl (sat. aq.) and diluted with EtOAc. The EtOAc layer was washed with water (2x) and brine (1x) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered, and concentrated. The residue was purified by precipitation onto 12 g of silica gel (0-12% MeOH-dichloromethane-0.5% NH 4 Purification on HPLC (elution with OH gradient) gave 120 mg of the title compound. MS (ESI+) m / z: 401.77 [M+2H] 2+ , 802.19[M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ 8.08-7.97 (m, 2H), 7.59-7.49 (m, 1H), 7.43 (t, 2H), 5.03 (dd, 1H), 4.60 (d, 2H), 4.04-3.86 (m, 3H), 3.58 (dd, 1H), 3.51-3.36 (m, 1H), 2.82 (d, 7H), 2.50-2.39 (m, 1H), 2.25 (s, 7H), 2.21(s,3H),2.05-1.96(s,1H),1.95-1.79(m,4H),1.80-1.57(m,3H),1.43(s,9H),1.38 (s,4H),1.31(s,3H),1.27(d,4H),1.22(s,3H),1.04(d,3H),0.94(dd,1H),0.83(d,4H). [ka]

[0409] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-(((1r,3S)-3-(dimethylamino)cyclobutyl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S4-2-I8-1-1) (compound 111).

[0410] A solution of S4-1-I8-1 (120 mg, 0.149 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.25 mL) was stirred at room temperature for 2 hours and concentrated. The residue was suspended in ethyl acetate and saturated NaHCO 3 The resulting secondary amine (25 mg, 0.0356 mmol) was dissolved in dichloromethane (1 mL) and added with Na(OAc) 3 BH (15 mg, 0.0712 mmol) was added, followed by formaldehyde (37 wt% in water, 0.0238 mL, 0.356 mmol). After 15 min, the reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with aqueous hexanes and extracted with dichloromethane (3 times). The combined extracts were concentrated in vacuo. The residue was dissolved in methanol (1.5 mL) and the reaction mixture was heated to an external temperature of 45 °C for 16 h. The solvent was removed in vacuo and the residue was purified by HPLC (Atlantis T3 column, 2-40% MeCN-water-0.1% HCO 2 H) to give the title compound as the formate salt (15.8 mg, 0.0236 mmol, 61%). MS (ESI+) m / z: 204.79 [M+3H] 3+ , 306.59[M+2H] 2+ , 612.21[M+H] + ; 1 H NMR (400 MHz, methanol-d 4)δ 8.55(s,2H),4.69(s,1H),4.42(d,1H),4.36-4.01(m,2H),3.68(ddd,2H),3.36(dd,1H),3.24-2.69(m,9H),2. 60(s,7H),2.40-2.14(m,10H),1.94(dd,4H),1.88-1.69(m,1H),1.52(s,3H),1.47-1.25(m,13H),1.03(s,3H). [ka]

[0411] (3R,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-(((1r,3S)-3-(isobutyl(methyl)amino)cyclobutyl)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S4-2-I8-1-2) (compound 134).

[0412] Prepared according to the method of S4-2-I8-1-1, substituting isobutyraldehyde, to give 11.09 mg of the title compound as the formate salt. MS(ESI+)m / z:218.78[M+3H] 3+ , 327.61[M+2H] 2+ , 654.31[M+H] + ;1H NMR (400 MHz, methanol-d 4)δ 8.54(s,2.5H),4.66(s,1H),4.44(d,1H),4.33-4.12(m,2H),3.72(ddd,1H),3 .66(s,0.5H),3.53(s,1H),3.47-3.34(m,2H),3.34-3.26(m,1H),3.04(s,5H), 2.84(s,3H),2.76(s,6H),2.58-2.30(m,8H),2.29-1.94(m,6H),1.87-1.57(m ,3H),1.56-1.44(m,4H),1.40(d,6H),1.33(dd,6H),1.05(d,3H),1.01(d,6H). [ka]

[0413] (3R,6R,8R,9R,10R)-3-(((1r,3S)-3-((cyclopropylmethyl)(methyl)amino)cyclobutyl)methyl)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S4-2-I8-1-3) (compound 138).

[0414] Prepared according to the method of S4-2-I8-1-1, substituting cyclopropanecarboxaldehyde to give 16.73 mg of the title compound as the formate salt. MS(ESI+)m / z:218.12[M+3H] 3+ , 326.61[M+2H] 2+ , 652.27[M+H] + ; 1 H NMR (400 MHz, methanol-d 4)δ 8.55(s,2.6H),4.65(s,1H),4.44(d,1H),4.32-4.13(m,2H),3.78-3.67(m,2H),3.60(s, 0.4H),3.48-3.34(m,2H),3.35-3.25(m,1H),3.04(s,4H),2.90-2.77(m,4H),2.76(s,7H) ),2.69(s,3H),2.59-2.34(m,3H),2.27-1.95(m,5H),1.87-1.58(m,3H),1.56-1.44(m,4 H),1.39(d,6H),1.33(dd,6H),1.15-0.96(m,4H),0.76-0.68(m,2H),0.42-0.28(m,2H).

[0415] Scheme 5. [ka] [ka] (2S,3R,4S,6R)-2-(((2R,3R,4R,6R)-7-(((S)-1-(((benzyloxy)carbonyl)amino)-3-hydroxypropan-2-yl)(methyl)amino)-4-methoxy-4,6-dimethyl-2-(2,2,5-trimethyl-4-oxo-4H-1,3-dioxin-6-yl)heptan-3-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S5-1-I9-1).

[0416] S1-2-I9 (380 mg, 0.48 mmol) was dissolved in dry methylene chloride (5 mL) and formaldehyde (0.38 mL, 4.8 mmol) was added. Then, NaBH(OAc) 3 (201 mg, 0.96 mmol) was added in one portion to the reaction mixture. The reaction was allowed to stir at room temperature for 10 min, at which time LC / MS showed complete conversion. The reaction was washed with saturated NaHCO 3 (5 mL) and the aqueous layer was extracted three times with methylene chloride (10 mL). The combined organic layers were washed with MgSO 4The mixture was dried over ice, filtered, and concentrated. The residue was purified by elution with 24 g of silica gel (0-10% MeOH-dichloromethane + 0.5% 30% NH 4 The mixture was purified on a 500 rpm column (eluted with aqueous OH) to give the title compound as a white solid (310 mg, 80%). MS (ESI+) m / z: 406.8 [M+2H] 2+ ,812.5[M+H] + . [ka]

[0417] (2S,3R,4S,6R)-2-(((2R,3R,4R,6R)-7-(((S)-1-(((benzyloxy)carbonyl)amino)-3-hydroxypropan-2-yl)(tert-butoxycarbonyl)amino)-4-methoxy-4,6-dimethyl-2-(2,2,5-trimethyl-4-oxo-4H-1,3-dioxin-6-yl)heptan-3-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S5-1-I9-2).

[0418] In a 40 mL vial, S1-2-I9 (410 mg, 0.51 mmol) was dissolved in dichloromethane (5 mL) and stirred at room temperature to give a yellow solution. 2 O (0.12 mL, 0.51 mmol) was added in one portion and stirred at room temperature for 2 h. The reaction was diluted with dichloromethane and saturated NaHCO 3 The aqueous phase was extracted with dichloromethane and the combined organic phase was washed with MgSO 4 The mixture was dried over 1000 ml, filtered and concentrated. The residue was purified on 24 g of silica gel (eluted with 0-6% MeOH-dichloromethane) to give the title compound as a white solid (360 mg, 78%). MS (ESI+) m / z: 898.5 [M+H] + . [ka]

[0419] (2S,3R,4S,6R)-2-(((3S,6R,8R,9R,10R)-3-(((benzyloxy)carbonyl)amino)methyl)-8-methoxy-4,6,8,10,12-pentamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S5-2-I9-1). In a 250 mL flask, S5-1-I9-1 (310 mg, 0.38 mmol) was concentrated twice from toluene.

[0420] The flask was fitted with a reflux condenser, which was flame dried under vacuum, allowed to cool, and backfilled with nitrogen. Chlorobenzene (95 mL) was added via cannula, the flask was placed under slight vacuum, sonicated for 2 minutes, and then backfilled with nitrogen. The degassing procedure was repeated, then the mixture was heated at a bath temperature of 155 °C for 16 h, then at a bath temperature of 165 °C for 4 h. The reaction was cooled to room temperature and concentrated. The residue was purified by centrifugation using 24 g of silica gel (0-10% MeOH-dichloromethane + 0.5% 30% NH 4 The mixture was purified on a 500 rpm column (eluted with aqueous OH) to give the title compound as a white solid (242 mg, 82%). MS (ESI+) m / z: 377.7 [M+2H] 2+ ,754.4[M+H] + . [ka]

[0421] (2S,3R,4S,6R)-2-(((3S,6R,8R,9R,10R)-3-(((benzyloxy)carbonyl)(methyl)amino)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S5-3-I9-1).

[0422] In a 20 mL vial, a solution of S5-2-I9-1 (242 mg, 0.32 mmol) in 1,2-dimethoxyethane (5 mL) was precooled at -60°C. KHMDS (0.96 mL, 0.96 mmol) was added dropwise. The reaction mixture was stirred at -60°C for 20 min. Then, Me 2 SO 4 (150 μL, 1.59 mmol) was added. The reaction mixture was warmed to −15° C. LC / MS shows complete conversion. The reaction was quenched by adding triethylamine (1 mL) and the resulting mixture was diluted with dichloromethane and saturated NaHCO 3 The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with MgSO 4 The mixture was dried over 1000 ml of silica gel (0-10% MeOH-dichloromethane + 0.5% 30% NH 4 The mixture was purified on a 500 rpm column (eluted with aqueous OH) to give the title compound as a white solid (220 mg, 88%). MS (ESI+) m / z: 391.8 [M+2H] 2+ , 782.5[M+H] + . [ka]

[0423] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((3S,6R,8R,9R,10R)-8-methoxy-4,6,8,10,12,12-hexamethyl-3-((methylamino)methyl)-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S5-4-I9-1).

[0424] S5-3-I9-1 (220 mg, 0.28 mmol) was dissolved in EtOAc (5 mL) and AcOH (32 μL, 0.56 mmol) was added. The reaction mixture was sonicated briefly under mild vacuum and then backfilled with nitrogen. Pd / C (60 mg, 0.028 mmol) was added and the mixture was stirred under a stream of hydrogen for 10 min and then under static hydrogen until LC / MS showed complete consumption of starting material. The reaction mixture was filtered through a syringe filter with the aid of EtOAc and saturated NaHCO 3 (5 mL) was added. The aqueous layer was extracted three times with methylene chloride (10 mL). The combined organic layers were diluted with MgSO 4 It was dried over, filtered and concentrated. The crude title compound (154 mg, 85%) was used in the next step without further purification. MS (ESI+) m / z: 216.8 [M+3H] 3+ , 324.7[M+2H] 2+ , 648.4[M+H] + . [ka]

[0425] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-4,6,8,10,12,12-hexamethyl-3-((methylamino)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S5-7-I9-1-1) (compound 9).

[0426] S5-4-I9-1 (39 mg, 0.06 mmol) was dissolved in MeOH (0.5 mL) and heated at 60° C. until LC / MS showed complete consumption of the starting material (16 h). The reaction mixture was filtered through a syringe filter with the aid of methanol and concentrated. The residue was purified by HPLC (MeCN-water-0.1% HCO 2 H) to give 9.07 mg of the title compound as the formate salt. MS(ESI+) m / z: 182.1[M+3H] 3+ , 272.7[M+2H]2+ , 544.4[M+H] + ; 1 H NMR(400 MHz, Methanol-d 4 )δ 8.50(s,3H),4.45(dd,1H),4.23(dd,1H),4.10(d,1H),3.77-3.65(m,1H),3.55-3.27(m,4H),3.17-3.03(m,1H),2.90(d,3H),2.81( d,7H),2.69(d,1H),2.65(s,2H),2.33(s,1H),2.06-1.97(m,1H),1.53(s,3H),1.51-1.43(m,1H),1.37-1.19(m,12H),0.97(dd,3H). [ka]

[0427] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-6,8,10,12,12-pentamethyl-3-((methylamino)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S5-7-I9-2) (compound 15).

[0428] S5-4-I9-2 (39 mg, 0.06 mmol) was dissolved in MeOH (0.5 mL) and heated at 60° C. until LC / MS showed complete consumption of starting material (16 h). The reaction mixture was cooled and aqueous HCl (4 M, 52 μL, 4 equiv.) was added. The reaction mixture was stirred at room temperature until LC / MS showed complete consumption of starting material. The reaction mixture was filtered through a syringe filter with the aid of methanol and concentrated. The residue was purified by HPLC (MeCN-water-0.1% HCO 2 H) to give 2.35 mg of the title compound as the formate salt. MS (ESI+) m / z: 177.5 [M+3H] 3+ , 265.7[M+2H] 2+ , 530.4[M+H] + ; 1H NMR (400 MHz, methanol-d 4 )δ 8.50(s,3H),4.57(dd,1H),4.47(d,1H),4.07-3.95(m,2H),3.82-3.67(m,2H),3.50-3.37(m,2H),3.32(h,3H),3.21(d,1H),3.10-2.86( m,3H),2.86-2.78(m,8H),2.73-2.52(m,5H),2.02(dt,1H),1.92(s,1H),1.63(dd,1H),1.49(ddd,4H),1.37-1.18(m,12H),1.01(dd,3H). [ka]

[0429] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((3S,6R,8R,9R,10R)-3-((dimethylamino)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S5-5-I9-1-1) (compound 5).

[0430] S5-4-I9-1 (37 mg, 0.057 mmol) was dissolved in dry methylene chloride (1 mL) and formaldehyde (0.046 mL, 0.57 mmol) was added. Then, NaBH(OAc) 3 (24 mg, 0.12 mmol) was added in one portion to the reaction mixture. The reaction was allowed to stir at room temperature for 10 min, at which time LC / MS showed complete conversion. The reaction was washed with saturated NaHCO 3 (5 mL) and the aqueous layer was extracted three times with methylene chloride (10 mL). The combined organic layers were washed with MgSO 4 The mixture was dried over 1000 ml of silica gel (0-10% MeOH-dichloromethane + 0.5% 30% NH 4 The mixture was purified on a 500 rpm column (eluted with aqueous OH) to give 37 mg of the title compound. MS (ESI+) m / z: 221.5 [M+3H] 3+, 331.7[M+2H] 2+ , 662.4[M+H] + . [ka]

[0431] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((dimethylamino)methyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S5-6-I9-1-1). S5-5-I9-1-1 (37 mg, 0.06 mmol) was dissolved in MeOH (0.5 mL) and heated at 60° C. until LC / MS showed complete consumption of starting material (16 h). The reaction mixture was filtered through a syringe filter with the aid of methanol and concentrated. The residue was purified by HPLC (MeCN-water-0.1% HCO 2 H) to give 9.07 mg of the title compound as the formate salt. MS (ESI+) m / z: 186.8 [M+3H] 3+ , 279.7[M+2H] 2+ , 558.4[M+H] + ; 1 H NMR (400 MHz, methanol-d 4 )δ 8.55(s,3H),4.42(d,2H),4.14(d,3H),3.68(dtt,2H),3.49(t,1H),3.44-3.28(m,4H),3.13(s,2H),3.02(s,1H),2.80(s,1H),2.67(d, 11H),2.44(dd,3H),2.33(d,11H),1.94(ddd,2H),1.44(t,5H),1.38(s,6H),1.36-1.27(m,12H),1.23(d,2H),1.03(s,2H),0.95(d,1H). [ka]

[0432] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-4,6,8,10,12,12-hexamethyl-3-((methyl((1-methyl-1H-imidazol-2-yl)methyl)amino)methyl)-1-oxa-4-azacyclotridecane-11,13-dione (S5-6-I9-1-2) (compound 104).

[0433] Prepared according to the method of S5-6-I9-1-1, substituting 1-methyl-1H-imidazole-2-carbaldehyde to give 14.35 mg of the title compound as the formate salt. MS(ESI+)m / z:240.5[M+3H] 3+ , 360.3[M+2H] 2+ , 719.5[M+H] + ; 1 H NMR (400 MHz, methanol-d 4 )δ 8.45(s,3H),7.12(d,1H),6.93(d,1H),4.43(d,1H),4.20(d,1H),4.11(d,1H),3.78-3.66(m,5H),3.66-3.56(m,1H),3.49-3.34(m,3H),3 .30(q,1H),3.04(d,4H),2.80(d,7H),2.50(dt,1H),2.39(s,3H),2.07-1.97(m,1H),1.58-1.41(m,5H),1.41-1.21(m,13H),0.98(d,3H). [ka]

[0434] (3S,6R,8R,9R,10R)-9-(((2S,3R,4S6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-((dimethylamino)methyl)-8-methoxy-6,8,10,12,12-pentamethyl-1-oxa-4-azacyclotridecane-11,13-dione (S5-6-I9-2-1) (compound 17).

[0435] S5-5-I9-2-1 (39 mg, 0.06 mmol), prepared by method S5-5-I9-2-1 to S5-5-I9-1-1, was dissolved in MeOH (0.5 mL) and heated at 60° C. until LC / MS indicated complete consumption of starting material (16 h). The reaction mixture was cooled and aqueous HCl (4 M, 52 μL, 4 equiv.) was added. The reaction mixture was stirred at room temperature until LC / MS indicated complete consumption of starting material. The reaction mixture was filtered through a syringe filter with the aid of methanol and concentrated. The residue was purified by HPLC (MeCN-water-0.1% HCO 2 H) to give 2.33 mg of the title compound as the formate salt. MS(ESI+) m / z: 182.1[M+3H] 3+ , 272.7[M+2H] 2+ , 544.4[M+H] + ; 1 H NMR (400 MHz, methanol-d 4 )δ 8.52(s,3H),4.47(d,1H),4.11(d,1H),3.97(dd,1H),3.77-3.61(m,3H), 3.44(dd,1H),3.31(dt,4H),2.94(s,3H),2.83(d,2H),2.77(s,6H),2.70- 2.58(m,2H),2.58-2.46(m,1H),2.46-2.38(m,2H),2.37(s,4H),2.03(d,2 H),1.72(dd,1H),1.63(dd,1H),1.50(d,3H),1.34(dd,13H),1.06(d,3H). [ka]

[0436] 2-(Dimethylamino)-N-(((3S,6R,8R,9R,10R)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-4,6,8,10,12,12-hexamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-3-yl)methyl)-N-methylacetamide (S5-8-I9-1-1) (compound 13).

[0437] S5-4-I9-1 (43 mg, 0.066 mmol) was dissolved in DMF (0.5 mL). DIEA (34 μL, 0.20 mmol), dimethylglycine (10.2 mg, 0.10 mmol) and HATU (33 mg, 0.086 mmol) were added at room temperature. The reaction mixture was allowed to stir at room temperature for 2 hours. LC / MS showed complete consumption of starting material. The reaction was diluted with dichloromethane and saturated NaHCO 3 (10 mL) was added to quench the reaction. The aqueous layer was extracted with dichloromethane and the combined organic layers were extracted with MgSO 4 The mixture was dried over 1000 ml of silica gel (0-10% MeOH-dichloromethane + 0.5% 30% NH 4 The mixture was purified on a 500 rpm column (eluted with aqueous OH) to give the title compound as a white solid (39 mg, 80%). MS (ESI+) m / z: 245.2 [M+3H] 3+ , 367.3[M+2H] 2+ , 733.5[M+H] + This material (39 mg, 0.06 mmol) was dissolved in MeOH (0.5 mL) and heated at 60° C. until LC / MS showed complete consumption of the starting material (16 h). The reaction mixture was filtered through a syringe filter with the aid of methanol and concentrated. The residue was purified by HPLC (MeCN-water-0.1% HCO 2 H) to give 5.49 mg of the title compound as the formate salt. MS(ESI+) m / z: 210.3[M+3H] 3+ , 314.7[M+2H] 2+ , 628.4[M+H] + ; 1 H NMR (400 MHz, methanol-d 4)δ 8.27(s,3H),4.57(dd,1H),4.36(d,1H),4.23-4.01(m,4H),3.96-3.83(m,3H),3.60 (q,2H),3.49(dd,2H),3.32(p,2H),3.17(dd,2H),3.01(d,3H),2.94(s,4H),2.85(d ,8H),2.75(d,1H),2.71(s,2H),2.62(ddd,1H),2.11(d,1H),1.79(d,1H),1.69(s,3 H),1.59(s,1H),1.41-1.16(m,12H),0.99(qd,7H),0.84-0.74(m,2H),0.69(dd,2H).

[0438] Scheme 6. [ka] [ka] (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((3S,6R,8R,9R,10R)-3-(3-hydroxypropyl)-8-methoxy-4,6,8,10,12,12-hexamethyl-11,13-dioxo-1-oxa-4-azacyclotridecan-9-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylbenzoate (S6-1-I1-1).

[0439] To S2-1-I1-1 (240 mg, 0.372 mmol) in dry THF (3.71 mL) was added 9-BBN (0.5 M solution in THF, 2.22 mL, 1.11 mol). After 30 min at room temperature, the mixture was cooled to 0° C. and diluted with NaOH (6 N aq., 371 μL, 2.23 mmol) and H 2 O 2 (30% in water, 252 μL, 2.23 mmol) was added. After 15 min, the mixture was extracted three times with t-butyl methyl ether / EtOAc (2:1). The organic layer was washed once with water and once with brine, and then washed with Na 2 SO 4 After removing the solvent, the residue was concentrated on 4 g of silica gel (0-20% MeOH-dichloromethane / 0.5% NH4 The mixture was purified on a 500 rpm column (eluted with a gradient of...

Claims

1. Formula IIA, IIB, IIC or IID 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein R ９ａ is H, optionally substituted C １～１０ Alkyl, hydroxyalkyl, optionally substituted C １ - １０ Alkylene -NR Ｔ R Ｔ’ , optionally substituted C １ - １０ Alkylene-cycloalkyl-NR Ｔ R Ｔ’ and optionally substituted alkoxyalkyl; Ｔ and R Ｔ’ each independently represents H, optionally substituted alkyl, and optionally substituted C １ - １０ alkylene-heterocycloalkyl selected from the group consisting of: R １０ｂ is H; and (a) R １０ａ is an optionally substituted C ３ Alkylene-R １０１ or optionally substituted C ２ Alkylene-R １０１ａ１ wherein R １０１ is -H, -OH, -O-alkyl, -NR ｘ R ｘ’ , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R １０１ａ１ (C １～６ alkyl)-S-, (C １～６ alkyl)-SO-, (C １～６ Alkyl)-SO ２ -, -OH, -O-alkyl, -NR ｘ R ｘ’ , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, R ｘ and R ｘ’ are each independently -H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl and -C(=O)-alkylene-N(R ｙ’ )(R ｙ’’ ) wherein R ｙ’ and R ｙ’’ are each independently selected from the group consisting of H and optionally substituted alkyl; or R ｘ and R ｘ’ together with the atom to which they are attached, optionally O, S, SO, SO ２ Or N.R. ｙ forming an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of: Each R ｙ are independently —H and optionally substituted C １～１０ alkyl; or (b) R １０ａ is R １０１ａ２ -CH ２ - and R １０１ａ２ is NR ｘ R ｘ’ Wherein R ｘ and R ｘ’ are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl or optionally substituted alkylene-heteroaryl groups, and -C(=O)-alkylene-N(R ｙ’ )(R ｙ’’ ) wherein R ｙ’ and R ｙ’’ are each independently selected from the group consisting of H and optionally substituted alkyl; or R １０１ａ２ is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; The compound or a pharma- ceutically acceptable salt thereof.

2. R １０ａ is optionally substituted R １０１ -CH ２ CH ２ CH ２ -, optionally substituted R １０１ -CH ２ CH ２ CH—OH— or optionally substituted R １０１ -CH ２ CH ２ CH-OMe-; R １０１ -H, -OH, -O-alkyl, -N(Me)(Et), -N(Me) ２ , -N(Me)(t-Bu), -N(Me)(iPr), -NH(Me), -NH(iPr), -N(Et) ２ , -N(Me)(cyclopropyl), -NH(cyclopropyl), -N(Me)(cyclobutyl), -NH(cyclobutyl), -N(Me)(cyclopentyl), -NH(cyclopentyl), -N(Me)(cyclohexyl), -NH(cyclohexyl), optionally substituted aziridinyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted piperazinyl-2-one, optionally substituted tetrahydroisoquinolinyl, optionally substituted indolinyl or optionally substituted isoindolinyl, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

3. R １０ａ but 【Chemistry 2】 is selected from the group consisting of: N.R. ｘ R ｘ’ -N(Me)(Et), -N(Me) ２ , -N(Me)(t-Bu), -N(Me)(iPr), -NH(Me), -NH(iPr), -N(Et) ２ , -N(Me)(cyclopropyl), -NH(cyclopropyl), -N(Me)(cyclobutyl), -NH(cyclobutyl), -N(Me)(cyclopentyl), -NH(cyclopentyl), -N(Me)(cyclohexyl) and -NH(cyclohexyl); 【Chemistry 3】 " indicates the attachment point, 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof.

4. R １０ａ がMeSCH ２ CH ２ -、MeSOC ２ CH ２ -MeSO ２ CH ２ CH ２ -、 【Chemistry 4】 wherein the formula is selected from the group consisting of 【Chemistry 5】 " indicates the attachment point, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

5. R １０１ａ２ Ga-NHR ｚ and -NMeR ｚ wherein the compound is selected from the group consisting of: R ｚ is an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted —CH ２ -cycloalkyl, optionally substituted -CH ２ -heterocycloalkyl, optionally substituted -CH ２ -aryl, optionally substituted -CH ２ -heteroaryl, -(C=O)-cycloalkyl or -(C=O)-alkylene-NR Ｚ’ R Ｚ’’ wherein R ｚ’ and R ｚ’’ are each independently H or alkyl; or R ｚ is -optionally substituted alkylene-R １０１ａ２’ Wherein R １０１ａ２’ is optionally substituted heteroaryl; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

6. R １０１ａ２ -CH ２ - is -CH ２ NHMe, -CH ２ N(Me) ２ , -CH ２ N(Me)(cyclopropyl), -CH ２ NH(oxetanyl), -CH ２ N.H.C.H. ２ (cyclopropyl) and 【Chemistry 6】 wherein the formula is selected from the group consisting of: 【Chemistry 7】 " indicates the attachment point, 6. The compound of claim 5 or a pharma- ceutically acceptable salt thereof.

7. Compound of Formula III 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof, R １０１ｂ is -H, methyl or methoxy; R １０ｂ is -H; R １１ａ and R １１ｂ is independently selected from the group consisting of -H and methyl; R ｘ and R ｘ’ are each independently -H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl and -C(=O)-alkylene-N(R ｙ ) ２ or R ｘ and R ｘ’ together with the atoms to which they are attached, optionally O, S, SO, SO ２ and N.R. ｙ forming an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of: Each R ｙ are independently —H and optionally substituted C １～１０ selected from the group consisting of alkyl, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

8. N.R. ｘ R ｘ’ -N(Me)(Et), -N(Me) ２ , -N(Me)(t-Bu), -N(Me)(iPr), -NH(Me), -NH(iPr), -N(Et) ２ 8. The compound of claim 7, wherein the aryl group is selected from the group consisting of -N(Me)(cyclopropyl), -NH(cyclopropyl), -N(Me)(cyclobutyl), -NH(cyclobutyl), -N(Me)(cyclopentyl), -NH(cyclopentyl), -N(Me)(cyclohexyl) and NH(cyclohexyl), or a pharma- ceutically acceptable salt thereof.

9. Compound of Formula IV 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof, R １０１ｂ is selected from the group consisting of -H, methyl and methoxy; R １０ｂ is -H; R １１ａ and R １１ｂ is independently selected from the group consisting of -H and methyl; and 【Chemistry 10】 is selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

10.

11. is selected from the group consisting of optionally substituted aziridinyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted piperazinyl-2-one, optionally substituted tetrahydroisoquinolinyl, optionally substituted indolinyl, or optionally substituted isoindolinyl, or a pharma- ceutically acceptable salt thereof.

11. A compound of formula V: 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof, R １０１ｂ is -H, methyl or methoxy; R １０ｂ is -H; R １１ａ and R １１ｂ is independently selected from the group consisting of -H and methyl; and 【Chemistry 13】 is optionally substituted heterocycloalkyl; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

12.

14. 12. The compound of claim 11, or a pharma- ceutically acceptable salt thereof, wherein is optionally substituted piperidinyl.

13. Compound of Formula VI 【Chemistry 15】 or a pharma- ceutically acceptable salt thereof, R １０１ｂ is -H; R １０ｂ is -H; R １１ａ and R １１ｂ is independently selected from the group consisting of -H and methyl; and R ｘ and R ｘ’ are each independently -H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocycloalkyl, optionally substituted alkylene-aryl, optionally substituted alkylene-heteroaryl, -C(=O)-alkyl and -C(=O)-alkylene-N(R ｙ’ )(R ｙ’’ ) wherein R ｙ’ and R ｙ’’ are each independently H or optionally substituted alkyl; or R ｘ and R ｘ’ together with the atoms to which they are attached, optionally O, S, SO, SO ２ and N.R. ｙ forming an optionally substituted 3-, 4-, 5-, 6-, or 7-membered ring containing an additional heteroatom selected from the group consisting of: Each R ｙ are independently —H and optionally substituted C １～１０ alkyl; or R ｘ and R ｘ’ is —H or alkyl, and the other is R ｚ where R ｚ is -(C=O)-cycloalkyl or -(C=O)-alkylene-NR ｚ’’ R Ｚ’’’ wherein R ｚ’’ and R ｚ’’’ are each independently —H or alkyl; or R ｚ -Alkylene-R １０１ａ Wherein R １０１ａ is optionally substituted heteroaryl; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

14. R ９ａ is -H or C １～４ alkyl; R １０ｂ is H; and R １１ａ and R １１ｂ The compound according to any one of claims 6 to 13, or a pharma- ceutically acceptable salt thereof, wherein each is independently H or methyl.

15. 2. The compound of claim 1, wherein the compound is: or a pharma- ceutically acceptable salt thereof. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 【Table 14】 【Table 15】 【Table 16】 【Table 17】 【Table 18】 【Table 19】 【Table 20】 【Table 21】 【Table 22】 【Table 23】 【Table 24】 【Table 25】 【Table 26】 【Table 27】 【Table 28】 【Table 29】

16. The compound is Compound 84: 【Chemistry 16】 2. The compound of claim 1, wherein:

17. The compound is Compound 112: 【Chemistry 17】 2. The compound of claim 1, wherein:

18. The compound is Compound 113: 【Chemistry 18】 2. The compound of claim 1, wherein:

19. The compound is Compound 156: 【Chemistry 19】 2. The compound of claim 1, wherein:

20. The compound is Compound 182: 【Chemistry 20】 2. The compound of claim 1, wherein:

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

22. 22. The pharmaceutical composition of claim 21, for use in a subject in need thereof to treat an infectious disease, wherein the infectious disease is an infection with gram-positive or gram-negative bacteria or the infectious disease is a parasitic infection.

23. 23. The pharmaceutical composition of claim 22, wherein the bacterial infection is a Staphylococcus infection, an Acinetobacter infection, a Klebsiella infection, an Escherichia infection or a Pseudomonas infection.

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