Antibacterial compounds

Abstract

Provided herein are inhibitors of LpxH, pharmaceutical compositions comprising said inhibitory compounds, and methods for using said LpxH inhibitory compounds for the treatment of infectious disease.

Description

WSGR Ref: 60134-707.601 ANTIBACTERIAL COMPOUNDS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 641,827, filed May 2, 2024, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Inhibitors of LpxH are thought to be useful for the treatment of infectious disease, particularly infection by Gram-negative bacteria. BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are inhibitors of LpxH, pharmaceutical compositions comprising said inhibitory compounds, and methods for using said inhibitory compounds for the treatment of disease.

[0004] One embodiment provides a compound of Formula (I-a-0),or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; wherein B is substituted with one or more substituent selected from the group consisting ofWSGR Ref: 60134-707.6013-aminopiperidin-1-yl, optionally substituted 4-aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of B are substituted by the divalent group consisting of ; L is -N(Rj)-, -C(Rn)2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3- C6carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; each Rmis independently optionally substituted C1-C3alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6- membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3- C6carbocyclyl;WSGR Ref: 60134-707.601 or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; W is N or C-R; X is N or C-R; Y is N or C-R; Z is N or C-R; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1- C10alkyl), optionally substituted -(C1-C3alkylene)-N(C1-C3alkyl)(heteroaryl), optionally substituted -(C1-C3 alkylene)-NH(C1-C6 alkyl), optionally substituted C4- C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl; provided the compound is notWSGR Ref: 60134-707.601compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0006] One embodiment provides a method of treating a bacterial infection in a patient in need thereof comprising administering to the patient a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the bacterial infection arises from at least one Gram-negative pathogen. INCORPORATION BY REFERENCE

[0007] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION

[0008] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intendedWSGR Ref: 60134-707.601 to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of" or "consist essentially of" the described features. Definitions

[0009] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0010] "Amino" refers to the –NH2 radical.

[0011] "Cyano" refers to the -CN radical.

[0012] "Nitro" refers to the -NO2 radical.

[0013] "Oxa" refers to the -O- radical.

[0014] "Oxo" refers to the =O radical.

[0015] "Thioxo" refers to the =S radical.

[0016] "Imino" refers to the =N-H radical.

[0017] "Oximo" refers to the =N-OH radical.

[0018] "Hydrazino" refers to the =N-NH2 radical.

[0019] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises two to fifteen carbon atoms (e.g., C2-C15 alkyl). In certain embodiments, an alkyl comprises three to fifteen carbon atoms (e.g., C3-C15 alkyl). In certain embodiments, an alkyl comprises four to fifteen carbon atoms (e.g., C4-C15 alkyl). In certain embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In certain embodiments, an alkyl comprises six to fifteen carbon atoms (e.g., C6-C15 alkyl). In certain embodiments, an alkyl comprises seven to fifteen carbon atoms (e.g., C7-C15 alkyl). In certain embodiments, an alkyl comprises eight to fifteen carbon atoms (e.g., C8-C15 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl),WSGR Ref: 60134-707.601 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -C(=NRa)N(Ra)2, -N(Ra)C(=NRa)Ra, -N(Ra)C(=NRa)N(Ra)2, - N(Ra)S(O)tRa(where t is 1 or 2), -N=S(=O)t(Ra)2 (where t is 0 or 1), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -O-S(O)tRa(where t is 1 or 2), -O-S(O)tORa(where t is 1 or 2), - S(O)tN(Ra)2(where t is 1 or 2), and -P(O)(Ra)2, where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, - CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, - NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or -CN), aralkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or -CO2H), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or -CN), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.

[0020] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.

[0021] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, andWSGR Ref: 60134-707.601 having from two to fifteen carbon atoms. In certain embodiments, an alkenyl comprises two to twelve carbon atoms. In other embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to six carbon atoms. In other embodiments, an alkenyl comprises three to fifteen carbon atoms. In other embodiments, an alkenyl comprises four to fifteen carbon atoms. In other embodiments, an alkenyl comprises five to fifteen carbon atoms. In other embodiments, an alkenyl comprises six to fifteen carbon atoms. In other embodiments, an alkenyl comprises eight to fifteen carbon atoms. In other embodiments, an alkenyl comprises three to twelve carbon atoms. In other embodiments, an alkenyl comprises four to twelve carbon atoms. In other embodiments, an alkenyl comprises five to twelve carbon atoms. In other embodiments, an alkenyl comprises six to twelve carbon atoms. In other embodiments, an alkenyl comprises eight to twelve carbon atoms. In other embodiments, an alkenyl comprises ten to twelve carbon atoms. In other embodiments, an alkenyl comprises five to ten carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -C(=NRa)N(Ra)2, - N(Ra)C(=NRa)Ra, -N(Ra)C(=NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), -N=S(=O)t(Ra)2(where t is 0 or 1), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -O-S(O)tRa(where t is 1 or 2), -O-S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), and -P(O)(Ra)2, where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy,WSGR Ref: 60134-707.601 amino, -NHMe, -NMe2, morpholino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl).

[0022] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to fifteen carbon atoms. In certain embodiments, an alkynyl comprises two to twelve carbon atoms. In other embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises three to fifteen carbon atoms. In other embodiments, an alkynyl comprises four to fifteen carbon atoms. In other embodiments, an alkynyl comprises five to fifteen carbon atoms. In other embodiments, an alkynyl comprises six to fifteen carbon atoms. In other embodiments, an alkynyl comprises eight to fifteen carbon atoms. In other embodiments, an alkynyl comprises three to twelve carbon atoms. In other embodiments, an alkynyl comprises four to twelve carbon atoms. In other embodiments, an alkynyl comprises five to twelve carbon atoms. In other embodiments, an alkynyl comprises six to twelve carbon atoms. In other embodiments, an alkynyl comprises eight to twelve carbon atoms. In other embodiments, an alkynyl comprises ten to twelve carbon atoms. In other embodiments, an alkynyl comprises five to ten carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -C(=NRa)N(Ra)2, -N(Ra)C(=NRa)Ra, - N(Ra)C(=NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), -N=S(=O)t(Ra)2(where t is 0 or 1), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -O-S(O)tRa(where t is 1 or 2), -O- S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), and -P(O)(Ra)2, where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2,WSGR Ref: 60134-707.601 morpholino, -CN, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or -CO2H), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, - NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, - CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl).

[0023] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -WSGR Ref: 60134-707.601 N(Ra)C(O)Ra, -C(=NRa)N(Ra)2, -N(Ra)C(=NRa)Ra, -N(Ra)C(=NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), -N=S(=O)t(Ra)2(where t is 0 or 1), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2),-O-S(O)tRa(where t is 1 or 2), -O-S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), and -P(O)(Ra)2, where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, - NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, - CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or -CO2H), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl).

[0024] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene). InWSGR Ref: 60134-707.601 other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -C(=NRa)N(Ra)2, -N(Ra)C(=NRa)Ra, - N(Ra)C(=NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), -N=S(=O)t(Ra)2(where t is 0 or 1), - S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -O-S(O)tRa(where t is 1 or 2), -O- S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), and -P(O)(Ra)2, where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or -CO2H), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, - NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, - CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl).

[0025] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments,WSGR Ref: 60134-707.601 an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -C(=NRa)N(Ra)2, - N(Ra)C(=NRa)Ra, -N(Ra)C(=NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), -N=S(=O)t(Ra)2(where t is 0 or 1), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -O-S(O)tRa(where t is 1 or 2), -O-S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), and -P(O)(Ra)2, where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or -CO2H), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, - NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, - CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl).

[0026] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon fromWSGR Ref: 60134-707.601 five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, cyano, nitro, -Ra, -O-Rb-Ra, -N(Ra)-Rb-Ra, -Rb- ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- C(=NRa)N(Ra)2, -Rb-N(Ra)C(=NRa)Ra, -Rb-N(Ra)C(=NRa)N(Ra)2, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-N=S(=O)t(Ra)2 (where t is 0 or 1), -Rb-S(O)tRa(where t is 1 or 2), -Rb-O-S(O)tRa(where t is 1 or 2), -Rb-O-S(O)tORa(where t is 1 or 2), -Rb-O-S(O)tN(Ra)2(where t is 1 or 2), - Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tN(Ra)2 (where t is 1 or 2), -Rb-S(O)tNH(CO-alkyl) (where t is 1 or 2), -Rb-P(O)(Ra)2, -Rb-N(Ra)-P(O)(Ra)2, -Rb-O-P(O)(Ra)2, -Rb-P(O)(ORa)2, -Rb- N(Ra)-P(O)(ORa)2, -Rb-O-P(O)(ORa)2, -Rb-P(O)(ORa)Ra, -Rb-N(Ra)-P(O)(ORa)Ra, -Rb-O- P(O)(ORa)Ra, -Rb-P(O)R2(where two R groups are joined to form an optionally substituted heterocyclyl), -Rb-N(Ra)-P(O)R2 (where two R groups are joined to form an optionally substituted heterocyclyl), and -Rb-O-P(O)R2 (where two R groups are joined to form an optionally substituted heterocyclyl), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or -CO2H), heterocyclylalkyl (optionally substituted with halogen, hydroxy,WSGR Ref: 60134-707.601 methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, -CH2NH2, -CH2NHCH3, or -CH2N(CH3)2), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain or alkynylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated. In some embodiments, “Aryl” is optionally substituted with asubstituent selected from the group consisting of ,optionally substituted 3-or two adjacent atoms of the aryl are substituted by the divalent group consisting of(Rn)2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl;WSGR Ref: 60134-707.601 each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted C3-C6carbocyclyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0027] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0028] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0029] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0030] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0031] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In certain embodiments, a carbocyclyl comprises three atoms. In certain embodiments, a carbocyclyl comprises four atoms. In certain embodiments, a carbocyclyl comprises five atoms. In certain embodiments, a carbocyclyl comprises six atoms. In certain embodiments, a carbocyclyl comprises seven atoms. In certain embodiments, a carbocyclyl comprises eight atoms. In certain embodiments, a carbocyclyl comprises nine atoms. In certain embodiments, a carbocyclyl comprises ten atoms. In other embodiments, aWSGR Ref: 60134-707.601 carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Ra, -Rb-ORa, -Rb-OC(O)-Ra, -Rb- OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb- O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-C(=NRa)N(Ra)2, -Rb- N(Ra)C(=NRa)Ra, -Rb-N(Ra)C(=NRa)N(Ra)2, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb- N=S(=O)t(Ra)2 (where t is 0 or 1), -Rb-S(O)tRa(where t is 1 or 2), -Rb-O-S(O)tRa(where t is 1 or 2), -Rb-O-S(O)tORa(where t is 1 or 2), -Rb-O-S(O)tN(Ra)2 (where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tN(Ra)2(where t is 1 or 2), -Rb-P(O)(Ra)2, -Rb-N(Ra)-P(O)(Ra)2, -Rb- O-P(O)(Ra)2, -Rb-P(O)(ORa)2, -Rb-N(Ra)-P(O)(ORa)2, -Rb-O-P(O)(ORa)2, -Rb-P(O)(ORa)Ra, -Rb- N(Ra)-P(O)(ORa)Ra, -Rb-O-P(O)(ORa)Ra, -Rb-P(O)R2 (where two R groups are joined to form an optionally substituted heterocyclyl), -Rb-N(Ra)-P(O)R2(where two R groups are joined to form an optionally substituted heterocyclyl), and -Rb-O-P(O)R2(where two R groups are joined to form an optionally substituted heterocyclyl), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, - CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl,WSGR Ref: 60134-707.601 difluoromethyl, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or -CO2H), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, -CH2NH2, -CH2NHCH3, or -CH2N(CH3)2), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated. In some embodiments, “Carbocyclyl” is optionally substituted with a substituentselected from the group consisting of , , ,,optionally substituted 3-aminopyrrolidin-or two adjacent atoms of the carbocyclyl are substituted by the divalent group consisting of ; L is -N(Rj)-, -C(Rn)2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH;WSGR Ref: 60134-707.601 or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted C3-C6carbocyclyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl. each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. "Carbocyclylalkyl" refers to a radical of the formula –Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain part of the carbocyclylalkyl radical is optionally substituted as described above for an alkylene chain. The carbocyclyl part of the carbocyclylalkyl radical is optionally substituted as described above for a carbocyclyl group.

[0032] "Carbocyclylalkynyl" refers to a radical of the formula –Rc-carbocyclyl where Rcis an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0033] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula – O-Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0034] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0035] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0036] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. TheWSGR Ref: 60134-707.601 heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, phospholane, phospholane oxide, phosphinane, phosphinane oxide, 1,3,2-dioxaphosphinane, and 1,3,2-dioxaphosphinane oxide. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -Ra, -Rb-ORa, -Rb-OC(O)-Ra, - Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb- C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- C(=NRa)N(Ra)2, -Rb-N(Ra)C(=NRa)Ra, -Rb-N(Ra)C(=NRa)N(Ra)2, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-N=S(=O)t(Ra)2 (where t is 0 or 1), -Rb-S(O)tRa (where t is 1 or 2), - Rb-O-S(O)tRa (where t is 1 or 2), -Rb-O-S(O)tORa (where t is 1 or 2), -Rb-O-S(O)tN(Ra)2 (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), - Rb-P(O)(Ra)2, -Rb-N(Ra)-P(O)(Ra)2, -Rb-O-P(O)(Ra)2, -Rb-P(O)(ORa)2, -Rb-N(Ra)- P(O)(ORa)2, -Rb-O-P(O)(ORa)2, -Rb-P(O)(ORa)Ra, -Rb-N(Ra)P(O)(ORa)Ra, -Rb-O- P(O)(ORa)Ra, -Rb-P(O)R2 (where two R groups are joined to form an optionally substituted heterocyclyl), -Rb-N(Ra)-P(O)R2 (where two R groups are joined to form an optionally substituted heterocyclyl), and -Rb-O-P(O)R2 (where two R groups are joined to form an optionally substituted heterocyclyl), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, - NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, - CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally substitutedWSGR Ref: 60134-707.601 with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or -CO2H), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, -CH2NH2, -CH2NHCH3, or -CH2N(CH3)2), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, - CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rc substituents is unsubstituted unless otherwise indicated. In some embodiments, “Heterocyclyl” is optionally substituted with asubstituent selected from the group consisting of ,,optionally substituted 3-or two adjacent atoms of the heterocyclyl are substituted by the divalent group consisting of(Rn)2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH;WSGR Ref: 60134-707.601 or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted C3-C6carbocyclyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0037] "N-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0038] "C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0039] "Heterocyclylalkyl" refers to a radical of the formula –Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0040] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substitutedWSGR Ref: 60134-707.601 as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0041] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, oxazolonyl, 2-oxoazepinyl, oxazolyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, pyrazolyl, pyrazolo[1,5-a]pyrimidine, pyrazolo[3,4-d]pyrimidinyl, pyrazolonyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, imidazolonyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, triazolonyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in theWSGR Ref: 60134-707.601 specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -Ra, -O-Rb-Ra, -N(Ra)-Rb-Ra, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb- OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, - Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-C(=NRa)N(Ra)2, -Rb-N(Ra)C(=NRa)Ra, -Rb- N(Ra)C(=NRa)N(Ra)2, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-N=S(=O)t(Ra)2 (where t is 0 or 1), -Rb-S(O)tRa(where t is 1 or 2), -Rb-O-S(O)tRa(where t is 1 or 2), -Rb-O-S(O)tORa(where t is 1 or 2), -Rb-O-S(O)tN(Ra)2(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb- S(O)tN(Ra)2 (where t is 1 or 2), -Rb-S(O)tNH(CO-alkyl) (where t is 1 or 2), -Rb-P(O)(Ra)2, -Rb- N(Ra)-P(O)(Ra)2, -Rb-O-P(O)(Ra)2, -Rb-P(O)(ORa)2, -Rb-N(Ra)-P(O)(ORa)2, -Rb-O-P(O)(ORa)2, - Rb-P(O)(ORa)Ra, -Rb-N(Ra)-P(O)(ORa)Ra, -Rb-O-P(O)(ORa)Ra, -Rb-P(O)R2(where two R groups are joined to form an optionally substituted heterocyclyl), -Rb-N(Ra)-P(O)R2 (where two R groups are joined to form an optionally substituted heterocyclyl), and -Rb-O-P(O)R2 (where two R groups are joined to form an optionally substituted heterocyclyl), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or -CO2H), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, - NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, -CH2NH2, - CH2NHCH3, or -CH2N(CH3)2), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,WSGR Ref: 60134-707.601 amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), each Rbis independently a direct bond, or a straight or branched alkylene or alkenylene chain or alkynylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated. In some embodiments, “Heteroaryl” is optionally substituted with a substituentselected from the group consisting of , , , ,optionally substituted 3-aminopyrrolidin-or two adjacent atoms of the heteroaryl are substituted by the divalent group consisting of(Rn)2-, or -O-; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rmis independently optionally substituted C1-C3alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted C3-C6 carbocyclyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl;WSGR Ref: 60134-707.601 each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0042] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0043] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0044] "Heteroarylalkyl" refers to a radical of the formula –Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0045] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula – O-Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0046] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene doubleWSGR Ref: 60134-707.601 bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0047] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include: OH O O OH

[0048] Theenriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0049] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0050] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,3H,11C,13C,14C,15C,12N,WSGR Ref: 60134-707.60113N,15N,16N,17O,18O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0051] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0052] Deuterium substituted compounds are synthesized using various methods such as described in: Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, edited by Dennis C. Dean, Curr., Pharm. Des., 2000; 6(10), 110; George W. Kabalka and Rajender S. Varma, The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Anthony Evans, Synthesis of Radiolabeled Compounds, J. Radioanal. Chem., 1981, 64(1-2), 9- 32.

[0053] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0054] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below. OH CD3I O D

[0055] Deuterium-transfer(LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below. R LiAlD CN4 R NH2COH LiAlD4D D O LiAlD4D R' DDR2R OH RR'R OHWSGR Ref: 60134-707.601

[0056] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below. Br D H D2H D 'In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0058] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the LpxH inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0059] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates,WSGR Ref: 60134-707.601 phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1- 19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0060] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0061] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0062] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep,WSGR Ref: 60134-707.601 goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0063] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. LpxH

[0064] Multi-drug resistant (MDR) and even pan-drug resistant bacterial infections pose a public health risk with potentially dire consequences. As early as 2013, the Centers for Disease Control and Prevention (CDC) declared it the “post-antibiotic era,” given the rapid appearance of antibiotic-resistant infections. Antibiotic resistant strains have emerged rapidly due to the widespread prescription of antibiotics in the clinic and the extensive application of preventative antibiotics in agriculture. Despite this growing threat, poor economic incentives and regulatory complexities have discouraged the development of new antibiotics, and no new classes of antibiotics for treating gram-negative pathogens have reached the market since the 1980s. Therefore, new treatments with novel mechanisms of action are urgently needed.

[0065] The World Health Organization (WHO) has identified those MDR pathogens that are of “critical priority,” most important of which are MDR gram-negative pathogens. Gram-negative bacteria are uniquely characterized by an outer cell membrane. This outer cell membrane poses both a challenge and opportunity: Although the outer membrane prevents some antibiotics from passively diffusing to their intracellular bacterial targets, the outer membrane is constructed by a biosynthetic pathway that can be a novel target for drug development.

[0066] The outer cell membrane of gram-negative bacteria is an asymmetric bilayer composed of an inner monolayer of phospholipids and an outer monolayer of lipopolysaccharides (LPS) and lipooligosaccharises (LOS). This outer monolayer contains “Lipid A,” a glucosamine-based phospholipid. Lipid A is essential for bacterial growth and viability in a human host, and it must be prepared by the bacteria by constitutive lipid synthesis, known as the Raetz pathway. Therefore, the enzymes of the Raetz pathway are promising novel targets for gram-negative antibiotic development.WSGR Ref: 60134-707.601

[0067] The Raetz biosynthesis of Lipid A is mediated by nine intracellular enzymes (LpxA– LpxD, LpxH, LpxK–LpxM, and KdtA) that are conserved in the majority of Gram-negative bacteria. Antibiotics targeting LpxC have been successful against MDR gram-negative bacteria in vitro and in animal models, demonstrating the Raetz pathway is a suitable target for treating MDR infections.

[0068] Despite success in targeting LpxC, the uridine diphosphate (UDP) 2,3-diacylglucosamine pyrophosphatase hydrolase LpxH is of particular interest because it is widespread and functions in the majority of the WHO priority Gram-negative pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, Haemophilus influenzae, and Neisseria gonorrhoeae. Furthermore, LpxH is the fourth of nine enzymes in the Raetz pathway, and inhibiting LpxH leads to not only the expected inhibition of Lipid A production but also the toxic buildup of intermediate lipid metabolites. This added effect provides a secondary killing mechanism for any LpxH-targeting antibiotic.

[0069] In 2015, AstraZeneca reported the first known LpxH inhibitor, AZ1, a sulfonyl piperazine (J. Bacteriol.2015, 197(10), 1726–1734). Notably, as early as 2009, Karale et al. reported one antibacterial sulfonyl piperidine with a similar structure to that reported by AstraZeneca. However, the activity of this compound against LpxH was not specifically identified (Karale et al., J. Serb. Chem. Soc.2009, 74(12) 1377–1387). Recently, Zhou and coworkers reported the crystal structure of LpxH-bound AZ1, revealing AZ1 binds outside of the active site but potentially within striking distance of a nearby di-manganese cluster (Proc. Natl. Acad. Sci. USA 2020117(8): 4109–4116). Armed with this knowledge, Hong and coworkers demonstrated that a tethered hydroxamate chelating moiety renders sulfonyl piperazines more active antibiotics by chelating the proximal dimanganese cluster (ChemMedChem, 2023, 18(11) e202300023).

[0070] Researchers at Duke University reported sulfonyl piperazines in a PCT publication (WO2021072369) and a journal article (Bioorganic Chem.2020, 102, 104055). Researchers at Hoffmann-La Roche reported sulfonyl piperazines bearing pendant cyclic amides and cyclic carbamates (WO2023072794 and WO2023061617). Parallel to these studies, Zamaratski et al. disclosed related sulfonyl piperazines bearing an acyclic benzamide group with potent activity against LpxH (WO2022220725A1). Despite these developments, no LpxH inhibitors have been demonstrated in a clinical setting, and the ever-increasing need for novel antibiotics remains. LpxH Inhibitory Compounds

[0071] In one aspect, provided herein is a LpxH inhibitory compound.

[0072] One embodiment provides a compound of Formula (I-a-0),WSGR Ref: 60134-707.601or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; wherein B is substituted with one or more substituent selected from the group consisting of3-aminopiperidin-1-yl, optionally substituted 4-aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of B are substituted by the divalent group consisting of ; L is -N(Rj)-, -C(Rn)2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2;WSGR Ref: 60134-707.601 or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3- C6carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; each Rmis independently optionally substituted C1-C3alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6- membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3- C6 carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; W is N or C-R; X is N or C-R; Y is N or C-R; Z is N or C-R; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1- C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted -(C1-C3 alkylene)-NH(C1-C6 alkyl), optionally substituted C4-WSGR Ref: 60134-707.601 C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl;

[0073] WSGR Ref: 60134-707.601or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; wherein B is substituted with one or more substituent selected from the group consisting ofor two adjacent atoms of B are substituted by the divalent group consisting of L is2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl;WSGR Ref: 60134-707.601 or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rmis independently optionally substituted C1-C3alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; W is N or C-R; X is N or C-R; Y is N or C-R; Z is N or C-R; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl; provided the compound of Formula (I) is notWSGR Ref: 60134-707.601or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted 4- to 6-membered heterocyclyl; wherein B is substituted with one or more substituent selected from the group consistingWSGR Ref: 60134-707.6013-aminopiperidin-1-yl, optionally substituted 4-aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of B are substituted by the divalent group consisting of L is -Nor -O-; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rmis independently optionally substituted C1-C3alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6carbocyclyl;WSGR Ref: 60134-707.601 or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; W is N or C-R; X is N or C-R; Y is N or C-R; Z is N or C-R; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3alkylene)-N(C1-C3alkyl)(heteroaryl), optionally substituted -(C1-C3 alkylene)-NH(C1-C6 alkyl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted 4-membered carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl;provided the compound of Formula (I-b-0) is not .

[0075] of a compound of Formula (I-b),or a pharmaceutically acceptable salt or solvate thereof, wherein,WSGR Ref: 60134-707.601 B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted 4- to 6-membered heterocyclyl; wherein B is substituted with one or more substituent selected from the group consisting of, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted1-yl; or two adjacent atoms of B are substituted by the divalent group consisting of L is2-, or -O-; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rmis independently optionally substituted C1-C3alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl;WSGR Ref: 60134-707.601 or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; W is N or C-R; X is N or C-R; Y is N or C-R; Z is N or C-R; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3alkylene)-N(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted 4-membered carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl.

[0076] One embodiment provides a compound of Formula (II-a),or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; X is N or C-R; W is N or C-R; Y is N or C-R; Z is N or C-R;WSGR Ref: 60134-707.601 wherein at least one of W, X, Y, and Z is N; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5alkyl; each R9is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0077] One embodiment provides a compound of Formula (II-b),or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted 4- to 6-membered heterocyclyl; X is N or C-R; W is N or C-R; Y is N or C-R; Z is N or C-R; wherein at least one of W, X, Y, and Z is N; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2;WSGR Ref: 60134-707.601 R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C5-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3alkylene)-N-(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0078] In some embodiments, B is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted 4 to 6-membered heterocyclyl.

[0079] In some embodiments, B is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted 4 to 6-membered C-heterocyclyl.

[0080] In some embodiments, RLis optionally substituted C5-C12 alkyl, optionally substituted - (C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3alkylene)-N(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0081] In some embodiments, RLis optionally substituted C5-C12 alkyl, optionally substituted - (C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3alkylene)-N(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0082] In some embodiments, RLis optionally substituted C5-C12alkyl, optionally substituted - (C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4 to 6- membered C-heterocyclyl.

[0083] One embodiment provides a compound of Formula (II-c),WSGR Ref: 60134-707.601or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3alkylene)-N-(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0084] One embodiment provides a compound of Formula (II-d),or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted 4- to 6-membered heterocyclyl;WSGR Ref: 60134-707.601 each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3alkylene)-N-(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0085] One embodiment provides a compound of Formula (II-e),or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3alkyl; E is O or N-R1; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5alkyl; each R9is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl), optionallyWSGR Ref: 60134-707.601 substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0086] One embodiment provides a compound of Formula (III), or a pharmaceutically acceptableB is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; W is N or C-R; X is N or C-R; Y is N or C-R; Z is N or C-R; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5alkyl; each R9is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0087] In some embodiments, RLis optionally substituted C4-C12alkyl, optionally substituted - (C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl,WSGR Ref: 60134-707.601 optionally substituted C4-C10 carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0088] In some embodiments, RLis optionally substituted C4-C12 alkyl, optionally substituted - (C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted C5-C10 carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0089] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.

[0090] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted C-heterocyclyl.

[0091] In some embodiments, B is an optionally substituted aryl, optionally substituted C- heteroaryl, optionally substituted carbocyclyl, or optionally substituted C-heterocyclyl.

[0092] In some embodiments, B is an optionally substituted aryl, optionally substituted 5- to 10- membered C-heteroaryl, optionally substituted 4- to 6-membered carbocyclyl, or optionally substituted 4- to 6-membered C-heterocyclyl.

[0093] In some embodiments, B is an optionally substituted aryl, optionally substituted 5- to 6- membered C-heteroaryl, optionally substituted 4- to 6-membered carbocyclyl, or optionally substituted 4- to 6-membered C-heterocyclyl.

[0094] In some embodiments, B is an optionally substituted aryl, optionally substituted 5- to 6- membered heteroaryl, optionally substituted 4- to 6-membered carbocyclyl, or optionally substituted 4- to 6-membered heterocyclyl.

[0095] In some embodiments, B is an optionally substituted aryl, optionally substituted 5- to 6- membered heteroaryl, optionally substituted 4- to 5-membered carbocyclyl, or optionally substituted 4- to 5-membered heterocyclyl.

[0096] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 4 to 8-membered carbocyclyl, or optionally substituted 4 to 8- membered heterocyclyl.

[0097] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 4 to 8-membered carbocyclyl, or optionally substituted 4 to 8- membered heterocyclyl; wherein, if B is a 4-membered carbocyclyl, it is not an unsubstituted cyclobutyl.WSGR Ref: 60134-707.601

[0098] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 4 to 8- membered heterocyclyl.

[0099] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 4 to 8- membered C-heterocyclyl.

[0100] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 5 to 8- membered heterocyclyl.

[0101] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 5 to 8- membered C-heterocyclyl.

[0102] In some embodiments, B is optionally substituted pyrrolidinyl. In some embodiments,

[0103] B is optionally substituted pyrazolidinyl. In some embodiments,

[0104] In some embodiments, B is an optionally substituted aryl or optionally substituted 5- to 6-membered heteroaryl.

[0105] In some embodiments, B is an optionally substituted aryl or optionally substituted 5-membered heteroaryl.

[0106] In some embodiments, B is an optionally substituted pyrazolyl or optionally substituted triazolyl.

[0107] In some embodiments, B is an optionally substituted aryl or optionally substituted heteroaryl.

[0108] In some embodiments, B is an optionally substituted carbocyclyl.

[0109] In some embodiments, B is an optionally substituted 3- to 6-membered carbocyclyl.

[0110] In some embodiments, B is an optionally substituted 3-membered carbocyclyl.

[0111] In some embodiments, B is an optionally substituted 4-membered carbocyclyl.

[0112] In some embodiments, B is an optionally substituted 5-membered carbocyclyl.

[0113] In some embodiments, B is an optionally substituted 6-membered carbocyclyl.WSGR Ref: 60134-707.601

[0114] In some embodiments, B is an optionally substituted 4- to 8-membered heterocyclyl.

[0115] In some embodiments, B is an optionally substituted 4- to 8-membered C- heterocyclyl.

[0116] In some embodiments, B is an optionally substituted 4 to 6-membered heterocyclyl.

[0117] In some embodiments, B is an optionally substituted 4 to 6-membered C- heterocyclyl.

[0118] In some embodiments, B is an optionally substituted 5-membered heterocyclyl.

[0119] In some embodiments, B is an optionally substituted 5-membered C-heterocyclyl.

[0120] In some embodiments, B is an optionally substituted 6-membered heterocyclyl.

[0121] In some embodiments, B is an optionally substituted 6-membered C-heterocyclyl.

[0122] In some embodiments, B is an optionally substituted heteroaryl.

[0123] In some embodiments, B is an optionally substituted 5- to 6-membered heteroaryl.

[0124] In some embodiments, B is an optionally substituted 5-membered heteroaryl.

[0125] In some embodiments, B is an optionally substituted pyrazolyl, optionally substituted thiazolyl, or optionally substituted triazolyl.

[0126] In some embodiments, B is an optionally substituted 6-membered heteroaryl.

[0127] In some embodiments, B is an optionally substituted pyridinyl.

[0128] In some embodiments, B is an optionally substituted 9-membered heteroaryl.

[0129] In some embodiments, B is an optionally substituted pyrazolopyrimidinyl.

[0130] In some embodiments, B is an optionally substituted 10-membered heteroaryl.

[0131] In some embodiments, B is an optionally substituted aryl.

[0132] In some embodiments, B is an optionally substituted phenyl.

[0133] In some embodiments, B is substituted with one or more substituent selectedWSGR Ref: 60134-707.6013- aminopiperidin-1-yl, optionally substituted 4-aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3- aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of B are substituted by the divalent group consisting of ; wherein: L is -N(Rj)-, -C(Rn)2-, or -O-;RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.WSGR Ref: 60134-707.601

[0134] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:substituted 3-aminopyrrolidin-1-yl, and optionallyor two adjacent atoms of B are substituted by the divalent group consisting of L is2-, or -O-; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rmis independently optionally substituted C1-C3alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6carbocyclyl;WSGR Ref: 60134-707.601 or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0135] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted1-yl; or two adjacent atoms of B are substituted by the divalent group consisting of L is2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl;WSGR Ref: 60134-707.601 or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0136] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:optionally substituted 4-aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of B are substituted by the divalent group consisting of ; wherein L is -N(Rj)-, -C(Rn)2-, or -O-;RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rmis independently optionally substituted C1-C3alkyl; andWSGR Ref: 60134-707.601 each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl.

[0137] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted1-yl; or two adjacent atoms of B are substituted by the divalent group consisting of L is2-, or -O-; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; each Rmis independently optionally substituted C1-C3alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl.

[0138] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:WSGR Ref: 60134-707.601aminopiperidin-1-yl, optionally substituted 4-aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3- aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of B are substituted by the divalent group consisting of L is2-, or -O-; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; each Rmis independently optionally substituted C1-C3 alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl.

[0139] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: ,yl; or two adjacent atoms of B are substituted by the divalent group consisting of L is2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; each Rmis independently optionally substituted C1-C3 alkyl; andWSGR Ref: 60134-707.601 each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl.

[0140] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rmis independently optionally substituted C1-C3 alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl.

[0141] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rmis independently optionally substituted C1-C3alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl.

[0142] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:WSGR Ref: 60134-707.601RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rmis independently optionally substituted C1-C3alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl.

[0143] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; each Rmis independently optionally substituted C1-C3 alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl.

[0144] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2;WSGR Ref: 60134-707.601 each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; each Rmis independently optionally substituted C1-C3alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl.

[0145] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl.

[0146] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:-, -C(Rn)2-, or -O-; RSis optionally substituted C1-C3 alkyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C2alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C2 alkyl.

[0147] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: L is -N(Rj)-, -C(Rn)2-, or -RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl;WSGR Ref: 60134-707.601 or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0148] In some embodiments, B is substituted with one or more substituents selected from: .

[0149] In some embodiments, B is substituted with one or more substituents selectedfrom:from:B is substituted with one or more substituents selected from: .

[0153] In some embodiments, B is substituted with one or more substituents selected from: .In some embodiments, B is substituted with one or more substituents selected from: ; L is -N(Rj)-, -C(Rn)2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rjis hydrogen or -CH3; and each Rnis independently hydrogen, -F, -Cl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3.WSGR Ref: 60134-707.601

[0155] In some embodiments, B is substituted with one or more substituents selected from: ; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, or optionally substituted C2-C5 alkynyl; and each Rjis independently hydrogen or -CH3.

[0156] In some embodiments, B is substituted with one or more substituents selected from: ; RSis optionally substituted C1-C3 alkyl; and each Rjis independently hydrogen or -CH3.

[0157] In some embodiments, B is substituted with one or more substituents selected from: RSis --CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2; and Rjis hydrogen or -CH3.

[0158] In some embodiments, B is substituted with one or more substituents selected from: RSis --CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2. In some embodiments RSis -CH3, -CH2F, -CHF2, or -CF3.

[0159] In some embodiments, B is substituted with one or more substituents selected from: .In some embodiments, B is substituted with one or more substituents selected from: ; RSis -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2. In some embodiments RSis -CH3, -CH2F, -CHF2, -CF3, or -CH2OCH3. In some embodiments, RSis -CH3, - CH2F, -CHF2, or -CF3. In some embodiments, RSis -CH3. In some embodiments, RSis - CF3. In some embodiments, RSis -CHF2. In some embodiments, RSis -CH2F.WSGR Ref: 60134-707.601

[0161] In some embodiments, B is substituted with one or more substituents selectedfrom:. In some embodiments, B is substituted with one or more substituents selectedsome embodiments,B is substituted with one or more substituents selected from:some embodiments, B is substituted with one or more substituents selectedfrom:some embodiments, B is substituted with one or more substituents selected from: ,

[0163] In some embodiments, B is substituted with one or more substituents selected from: RSissubstituted C1-C5alkyl, optionally substituted C2-C5alkenyl, or optionally substituted C2-C5 alkynyl. In some embodiments RSis -CH3, -CH2F, -CHF2, -CF3, - CH2OCH3, -CH2NH2, or -CH2CH2NH2.

[0164] In some embodiments, B is substituted with one or more substituents selected from: .WSGR Ref: 60134-707.601

[0165] In some embodiments, B is substituted with one or more substituents selected from: ; RSis -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl.

[0166] In some embodiments, B is substituted with one or more substituents selected from: RSis -(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3alkyl.

[0167] In some embodiments, B is substituted with one or more substituents selected from: ; RSis -ORj, or -N(Rj)2; each Rjis independently hydrogen or -CH3.

[0168] In some embodiments, B is substituted with one or more substituents selected from: .

[0169] In some embodiments, B is substituted with one or more substituents selected from: RSisC1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl. each Rnis independently hydrogen, -F, -Cl, or -CH3.

[0170] In some embodiments, B is substituted with one or more substituents selected from: ; RSis -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2. each Rnis independently hydrogen, -F, or -CH3.WSGR Ref: 60134-707.601

[0171] In some embodiments, B is substituted with one or more substituents selected from: RSis --CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2. In some embodiments, RSis -CH3, -CH2F, -CHF2, or -CF3.

[0172] In some embodiments, B is substituted with one or more substituents selected from: .In some embodiments, B is substituted with one or more substituents selected from: ; RSis -ORj, or -N(Rj)2; each Rnis independently hydrogen, -F, -Cl, or -CH3; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl.

[0174] In some embodiments, B is substituted with one or more substituents selected from: ; RSis -ORj, or -N(Rj)2; each Rnis independently hydrogen, -F, -Cl, or -CH3; each Rjis independently hydrogen or optionally substituted C1-C3alkyl.

[0175] In some embodiments, B is substituted with one or more substituents selected from: ; RSis -ORj, or -N(Rj)2; each Rnis independently hydrogen, -F, or -CH3; each Rjis independently hydrogen or -CH3.

[0176] In some embodiments, B is substituted with one or more substituents selected from: .WSGR Ref: 60134-707.601

[0177] In some embodiments, B is substituted with one or more substituents selected from: L is --, -CH2-, or -O-; wherein each RPindependently optionally substituted C1-C3 alkyl; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl.

[0178] In some embodiments, B is substituted with one or more substituents selected from: L is --, or -CH2-; wherein each RPindependently optionally substituted C1-C3 alkyl; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl.

[0179] In some embodiments, B is substituted with one or more substituents selected from: ; L is -NH-, -N(CH3)-, or -CH2-; wherein each RPindependently optionally substituted C1-C3alkyl.

[0180] In some embodiments, B is substituted with one or more substituents selected from: .

[0181] In some embodiments, B is substituted with one or more substituents selected from:is substituted with one or more substituents selected from:WSGR Ref: 60134-707.601optionally substituted azetidine-1-yl, optionally3-aminopiperidin-1-yl, optionally substituted 4- aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.

[0183] In some embodiments, B is substituted with one or more substituents selected from:In some embodiments, B is substituted with one or more substituents selected from: ,, optionally substituted azetidine-1-yl, optionally substituted C-3-aminopiperidin-1-yl, optionally substituted 4- aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.

[0184] In some embodiments, B is substituted with one or more substituents selected from:WSGR Ref: 60134-707.601

[0185] In some embodiments, B is substituted with one or more substituents selected from:, optionally substituted azetidine-1-yl, optionally substituted C-3-aminopiperidin-1-yl, optionally substituted 4- aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.

[0186] In some embodiments, B is substituted with one or more substituents selected from: ,optionally substituted 3-1-yl.

[0187] In some embodiments, B is substituted with one or more substituents selected, optionally substituted azetidine-1-yl, optionally substituted C-piperidinyl,3-aminopiperidin-1-yl, optionally substituted 4-aminopiperidin-1-yl,WSGR Ref: 60134-707.601 optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3- aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.In some embodiments, B is substituted with one or more substituents selected from: optionally substituted 3-aminopyrrolidin-1-yl, and

[0188] In some embodiments, B is substituted with one or more substituents selected from: optionally substituted 3-aminopyrrolidin-1-yl and optionally substituted piperazin-1-yl.

[0189] In some embodiments, B is substituted with one or more substituents selected from: optionally substituted 3-each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; and each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0190] In some embodiments, B is substituted with one or more substituents selected from:and each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH.

[0191] In some embodiments, B is substituted with one or more substituents selected from:WSGR Ref: 60134-707.601each Rkis independently hydrogen, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, or -OH.

[0192] In some embodiments, B is substituted with one or more substituents selected from:each Rkis independently hydrogen, -F, -CH3, or -OH.

[0193] In some embodiments, B is substituted with one or more substituents selected from: eachhydrogen or -CH3.

[0194] In some embodiments, B is substituted with one or more substituents selected from: .In some embodiments, B is substituted with one or more substituents selected from: .In some embodiments, B is substituted with one or more substituents selected from: eachhydrogen, -F, or -CH3. In some embodiments, each Rkis independently hydrogen or -CH3. In some embodiments, each Rkis independently hydrogen or -F. In some embodiments, each Rkis independently -F. In some embodiments, each Rkis independently -H.

[0197] In some embodiments, B is substituted with one or more substituents selected from: .WSGR Ref: 60134-707.601

[0198] In some embodiments, B is substituted with one or more substituents selected from: each

[0199] In some embodiments, B is substituted with one or more substituents selected from: ; each Rjis independently hydrogen or -CH3.embodiments, B is substituted with one or more substituents selected from: ; each Rjis independently hydrogen or -CH3.embodiments, B is substituted with one or more substituents selected from: each Rjis independently hydrogen or -CH3.embodiments, B is substituted with one or more substituents selected from: each Rjis independently hydrogen or -CH3; and each Rkis-F, -Cl, -CH3, or -OH.

[0203] In some embodiments, B is substituted with one or more substituents selected from: each Rjis independently hydrogen or -CH3; and each Rkis-F, or -CH3.WSGR Ref: 60134-707.601

[0204] In some embodiments, B is substituted with one or more substituents selectedfrom: optionally substituted optionally substituted azetidine-1-yl. In some embodiments, B issubstituted with one or more substituents selected from: someembodiments, B is substituted with one or more substituents selected from: . In some embodiments, B is substituted with one or more substituents selected from: someembodiments, B is substituted with one or more substituents selected from: . Insome embodiments, B is substituted with one or more substituents selected from: .WSGR Ref: 60134-707.601

[0207] In some embodiments, B is substituted with one or more substituents selected from: optionally substituted 3-aminopyrrolidin-1-yl.

[0208] In some embodiments, B is substituted with one or more substituents selected from: 3-aminopyrrolidin-1-yl optionally substituted with one or more groups selected from -F, - OH, and -CH3.

[0209] In some embodiments, B is substituted with one or more substituents selected from: .

[0210] In some embodiments, B is substituted with one or more substituents selected from: .some embodiments, B is substituted with one or more substituents selected from: some embodiments, B is substituted with one or moresubstituents selected from: . In some embodiments, B is substituted with one ormore substituents selected from: .

[0212] In somewith one or more substituents selected some embodiments, B is substituted with one or more substituents selectedWSGR Ref: 60134-707.601

[0213] In some embodiments, B is substituted with one or more substituents selected from: optionally substituted C-piperidinyl. In some embodiments, B is substituted with one or more substituents selected from: .

[0214] In some embodiments, B is substituted with one or more substituents selected from: 3-aminopiperidin-1-yl. In some embodiments, B is substituted with one or more substituents selected from: .

[0215] In some embodiments, B is substituted with one or more substituents selected from: 4-aminopiperidin-1-yl. In some embodiments, B is substituted with one or more substituents selected from:.

[0216] In some embodiments, B is substituted with one or more substituents selected some embodiments, B is substituted with one or moresubstituents selected from:

[0217] In somewith one or more substituents selected from: optionally substituted piperazin-1-yl.

[0218] In some embodiments, B is substituted with one or more substituents selected from: piperazin-1-yl optionally substituted with one or more groups selected from -CH3.

[0219] In some embodiments, B is substituted with one or more substituents selected from: .WSGR Ref: 60134-707.601

[0220] In some embodiments, B is substituted with one or more substituents selectedis substituted with one or more substituents selected from: some embodiments, B issubstituted with one or more substituents selected from: . In some embodiments, B issubstituted with one or more substituents selected from: . In some embodiments, B issubstituted with one or more substituents selected from: some embodiments,B is substituted with one or more substituents selected from: .

[0221] In some embodiments, B is substituted withselected from: optionally substituted optionally substituted azepan-1-yl. In some embodiments, B is substituted with one or more substituents selected from:.

[0222] In some embodiments, B is substituted with one or more substituents selected from: optionally substituted 4-diazepan-1-yl. In some embodiments, B is substituted with one or more substituents selected from:WSGR Ref: 60134-707.601

[0223] In some embodiments, B is substituted with one or more substituents selectedsubstituents selected from: some embodiments, B is substituted with one or moresubstituents selected from: .

[0224] In someB is substituted with one or more substituents selectedoptionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl.

[0225] In some embodiments, B is substituted with one or more substituents selectedoptionally substituted C1-C3 alkyl.

[0226] In some embodiments, B is substituted with one or more substituents selected from: eachunsubstituted C1-C3alkyl.WSGR Ref: 60134-707.601

[0227] In some embodiments, B is substituted with one or more substituents selected from: .In some embodiments, two adjacent atoms of B are substituted by the divalent group consisting each Rjisor optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl.

[0229] In some embodiments, two adjacent atoms of B are substituted by the divalent group consisting each Rjisor -CH3.

[0230] In some embodiments, two adjacent atoms of B are substituted by the divalent group consisting each Rjisor optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl.

[0231] In some embodiments, two adjacent atoms of B are substituted by the divalent group consisting

[0232] InB is substituted with one or more substituents selectedWSGR Ref: 60134-707.601WSGR Ref: 60134-707.601WSGR Ref: 60134-707.601

[0236] In some embodiments, B is substituted with one or more substituents selectedselectedsubstituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.

[0240] In some embodiments, RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3alkylene)-N(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.WSGR Ref: 60134-707.601

[0241] In some embodiments, RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3alkylene)-N(C1-C3alkyl)(heteroaryl), optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.

[0242] In some embodiments, RLis optionally substituted C4-C12 alkyl, optionally substituted C4-C12alkenyl, or optionally substituted C4-C12alkynyl.

[0243] In some embodiments, RLis optionally substituted C5-C12 alkyl, optionally substituted C5-C12 alkenyl, or optionally substituted C5-C12 alkynyl.

[0244] In some embodiments, RLis optionally substituted C6-C12alkyl, optionally substituted C6-C12alkenyl, or optionally substituted C6-C12alkynyl.

[0245] In some embodiments, RLis an optionally substituted C4-C12 alkyl.

[0246] In some embodiments, RLis an optionally substituted C5-C12alkyl.

[0247] In some embodiments, RLis an optionally substituted, linear C4-C10alkyl.

[0248] In some embodiments, RLis an optionally substituted, linear C5-C10 alkyl.

[0249] In some embodiments, RLis an optionally substituted C4-C12 alkenyl.

[0250] In some embodiments, RLis an optionally substituted C4-C10alkenyl.

[0251] In some embodiments, RLis an optionally substituted C4-C12 alkynyl.

[0252] In some embodiments, RLis an optionally substituted C4-C10 alkynyl.

[0253] In some embodiments, RLis an optionally substituted carbocyclyl.

[0254] In some embodiments, RLis an optionally substituted C3-C8carbocyclyl.

[0255] In some embodiments, RLis an optionally substituted C4-C8 carbocyclyl.

[0256] In some embodiments, RLis an optionally substituted 4-membered carbocyclyl.

[0257] In some embodiments, RLis an optionally substituted aralkyl.

[0258] In some embodiments, RLis an optionally substituted heteroarylalkyl.

[0259] In some embodiments, RLis an optionally substituted carbocyclylalkyl.

[0260] In some embodiments, RLis an optionally substituted heterocyclylalkyl.

[0261] In some embodiments, RLis an optionally substituted C-heterocyclyl.

[0262] In some embodiments, RLis an optionally substituted 4 to 8-membered C- heterocyclyl.

[0263] In some embodiments, RLis an optionally substituted 5 to 6-membered C- heterocyclyl.

[0264] In some embodiments, RLis an optionally substituted 4 to 5-membered C- heterocyclyl.

[0265] In some embodiments, RLis an optionally substituted 4 to 6-membered C- heterocyclyl.WSGR Ref: 60134-707.601

[0266] In some embodiments, RLis an optionally substituted 5 membered C- heterocyclyl.

[0267] In some embodiments, RLis an optionally substituted oxetanyl.

[0268] In some embodiments, RLis an optionally substituted C-azetidinyl.

[0269] In some embodiments, RLis optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl).

[0270] In some embodiments, RLis optionally substituted -(C1-C3 alkylene)-N- (CH3)(heteroaryl). In some embodiments, RLis optionally substituted –(CH2)3-N- (CH3)(heteroaryl). In some embodiments, RLis optionally substituted –(CH2)2-N- (CH3)(heteroaryl).

[0271] In some embodiments, RLis optionally substituted -(C1-C2 alkylene)-O-(C1-C10 alkyl).

[0272] In some embodiments, RLis optionally substituted -(C1alkylene)-O-(C1-C10alkyl).

[0273] In some embodiments, RLis optionally substituted -CH2O(C1-C10 alkyl).

[0274] In some embodiments, RLis selected from the group consisting of:, , , , ,WSGR Ref: 60134-707.601WSGR Ref: 60134-707.601WSGR Ref: 60134-707.601

[0280] In some embodiments, Y is C-R.

[0281] In some embodiments, Z is N.

[0282] In some embodiments, Z is C-R.

[0283] In some embodiments, X is N.WSGR Ref: 60134-707.601

[0284] In some embodiments, X is C-R.

[0285] In some embodiments, W is N.

[0286] In some embodiments, W is C-R.WSGR Ref: 60134-707.601

[0294] In some embodiments,

[0295] In some embodiments,

[0296] In some embodiments,

[0297] In some embodiments,

[0298] In some embodiments,deuterium, halogen, - CN, or optionally substituted C1-2alkyl.

[0299] In some embodiments, each R is independently hydrogen, deuterium, halogen, - CN, or optionally substituted C1 alkyl.

[0300] In some embodiments, each R is independently hydrogen, deuterium, halogen, - CN, or -CH3.

[0301] In some embodiments, each R is independently hydrogen, deuterium, or halogen.

[0302] In some embodiments, each R is independently hydrogen, deuterium, or -F.

[0303] In some embodiments, each R is independently hydrogen or deuterium.

[0304] In some embodiments, E is absent.

[0305] In some embodiments, E is O or N-R1.

[0306] In some embodiments, E is O.

[0307] In some embodiments, E is N-R1.

[0308] In some embodiments, E is O or absent.

[0309] In some embodiments, E is N-R1or absent.

[0310] In some embodiments, R1is hydrogen, optionally substituted C1-C5alkyl, -OH, - CN, -C(O)R8, or -C(O)N(R9)2.

[0311] In some embodiments, R1is hydrogen, optionally substituted C1-C5 alkyl, -OH, - CN, -C(O)CH3, -C(O)NH2, -C(O)NH(CH3), or -C(O)N(CH3)2.

[0312] In some embodiments, R1is hydrogen, optionally substituted C1-C5 alkyl, -OH, - CN, -C(O)CH3, or -C(O)N(CH3)2.

[0313] In some embodiments, R1is hydrogen, optionally substituted C1-C5alkyl, -OH, or -CN.WSGR Ref: 60134-707.601

[0314] In some embodiments, R1is hydrogen, or optionally substituted C1-C5 alkyl. In some embodiments, R1is hydrogen, or optionally substituted C1-C4alkyl. In some embodiments, R1is hydrogen, or optionally substituted C1-C3alkyl. In some embodiments, R1is hydrogen, or optionally substituted C1-C2 alkyl. In some embodiments, R1is hydrogen, or optionally substituted C1 alkyl. In some embodiments, R1is hydrogen or -CH3.

[0315] In some embodiments, R1is hydrogen.

[0316] In some embodiments, R1is optionally substituted alkyl. In some embodiments, R1is optionally substituted C1-C5 alkyl. In some embodiments, R1is optionally substituted C1- C4alkyl. In some embodiments, R1is optionally substituted C1-C3alkyl. In some embodiments, R1is optionally substituted C1-C2alkyl. In some embodiments, R1is optionally substituted C1alkyl. In some embodiments, R1is C1-C5 alkyl substituted with one or more group selected from -CO2H. In some embodiments, R1is -H, -CH2CO2H, or -CH(CH3)CO2H. In some embodiments, R1is -CH2CO2H or -CH(CH3)CO2H. In some embodiments, R1is -CH2CO2H. In some embodiments, R1is -CH(CH3)CO2H.

[0317] In some embodiments, R1is -OH.

[0318] In some embodiments, R1is -C(O)R8.

[0319] In some embodiments, R1is -C(O)CH3.

[0320] In some embodiments, R1is -C(O)N(R9)2.

[0321] In some embodiments, R1is -C(O)N(CH3)2.

[0322] In some embodiments,

[0323] In some embodiments,2-, or -O-. In some embodiments, L is - N(Rj)-. In some embodiments, L is -C(Rn)2-. In some embodiments, L is -O-. In some embodiments, L is -NH-, -N(CH3)-, -CH2-, -CHF-, -CF2-, -C(CH3)H-, -C(CH3)2-, or -O-. In some embodiments, L is -NH-, -N(CH3)-, -CH2-, -CHF-, -CF2-, -C(CH3)H-, or -C(CH3)2-. In some embodiments, L is -CH2-, -CHF-, -CF2-, -C(CH3)H-, -C(CH3)2-, or -O-. In some embodiments, L is -CH2-, -CHF-, -CF2-, -C(CH3)H-, or -C(CH3)2-. In some embodiments, L is - CH2-. In some embodiments, L is -NH-, -N(CH3)-, CH2, or -O-. In some embodiments, L is - NH- or -N(CH3)-.

[0324] In some embodiments, RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2. In some embodiments, RSis optionally substituted C1-C4 alkyl, optionallyC4 alkenyl, optionally substituted C2-C4 alkynyl, -ORj, or -N(Rj)2. In some embodiments, RSis optionally substituted C1-C4alkyl, -ORj, or -N(Rj)2. In some embodiments, RSis optionally substituted C1-WSGR Ref: 60134-707.601 C4 alkyl. In some embodiments, RSis optionally substituted C1-C3 alkyl. In some embodiments, RSis optionally substituted C1-C2alkyl. In some embodiments, RSis optionally substituted C1alkyl. In some embodiments, RSis unsubstituted C1-C3alkyl. In some embodiments, RSis C1-C3alkyl optionally substituted with -F. In some embodiments, RSis optionally substituted -ORj, or - N(Rj)2. In some embodiments, RSis optionally substituted -ORj. In some embodiments, RSis optionally substituted N(Rj)2. In some embodiments, RSis optionally substituted -OH, -OCH3, - OCH2CH3, --NH2, -NHCH3, or -N(CH3)2.

[0325] In some embodiments, each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2. In some embodiments, each RPindependently optionally substituted C1-C3alkyl, -ORj,(Rj)2. In some embodiments, each RPindependently optionally substituted C1-C3 alkyl. In someembodiments, each RPindependently C1-C3alkyl optionally substituted by -F. In some embodiments, each RPis independently -CH3, -CH2CH3, -OCH3, -OCH2CH3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each RPis independently -CH3, -CH2CH3, OCH3, or - OCH2CH3. In some embodiments, each RPis independently -CH3. In some embodiments, two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl. In some embodiments, two RPare taken together to form an optionally substituted 4 to 10-membered heterocyclyl. In some embodiments, two RPare taken together to form an optionally substituted 5 to 6-membered heterocyclyl.

[0326] In some embodiments, each RPindependently optionally substituted C1-C5alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 4 to 10-memberedIn some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl. In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 4 to 7- membered heterocyclyl. In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C6 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl. In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C5 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 5-membered heterocyclyl.WSGR Ref: 60134-707.601 In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C4carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 4-membered heterocyclyl. In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C4carbocyclyl. In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3 carbocyclyl.

[0327] In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3alkyl. In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C2 alkyl. In some embodiments, each Rjis independently hydrogen or optionally substituted C1alkyl. In some embodiments, each Rjis independently hydrogen or -CH3.

[0328] In some embodiments, each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl.

[0329] In some embodiments, each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C5carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 5-membered heterocyclyl.

[0330] In some embodiments, each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C4carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 4-membered heterocyclyl.

[0331] In some embodiments, each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3-C4carbocyclyl.

[0332] In some embodiments, each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3carbocyclyl.

[0333] In some embodiments, each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH. In some embodiments, each Rkis independently hydrogen, halogen, optionally substituted C1-C2alkyl, or -OH. In some embodiments, each Rkis independently hydrogen, halogen, optionally substituted C1 alkyl, or -OH.WSGR Ref: 60134-707.601

[0334] In some embodiments, each Rkis independently hydrogen, -F, -OH, or -CH3. In some embodiments, each Rkis independently hydrogen, -F, or -CH3. In some embodiments, each Rkis independently hydrogen or -CH3.In some embodiments, each Rkis independently hydrogen.

[0335] In some embodiments, each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6- membered heterocyclyl.

[0336] In some embodiments, each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 5 to 6- membered heterocyclyl.

[0337] In some embodiments, each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 4-membered heterocyclyl.

[0338] In some embodiments, each Rmis independently optionally substituted C1-C3 alkyl. In some embodiments, each Rmis independently optionally substituted C1-C2 alkyl. In some embodiments, each Rmis independently optionally substituted C1alkyl. In some embodiments, each Rmis independently -CH3.

[0339] In some embodiments, each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C6carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl.

[0340] In some embodiments, each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C4 carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 4-membered heterocyclyl.

[0341] In some embodiments, each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3-C4 carbocyclyl.

[0342] In some embodiments, each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl. In some embodiments, each Rnis independently hydrogen, halogen, or optionally substituted C1-C2 alkyl. In some embodiments, each Rnis independently hydrogen, halogen, or optionally substituted C1 alkyl. In some embodiments, each Rnis independently hydrogen, -F, or -CH3.

[0343] In some embodiments, R8is optionally substituted C1-C5 alkyl. In some embodiments, R8is optionally substituted C1-C4 alkyl. In some embodiments, R8is optionallyWSGR Ref: 60134-707.601 substituted C1-C3 alkyl. In some embodiments, R8is optionally substituted C1-C2 alkyl. In some embodiments, R8is optionally substituted C1-C1alkyl. In some embodiments, R8is -CH3.

[0344] In some embodiments, each R9is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl.

[0345] In some embodiments, each R9is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 4 to 6-membered heterocyclyl.

[0346] In some embodiments, each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 5 to 6-membered heterocyclyl.

[0347] In some embodiments, each R9is independently hydrogen or optionally substituted C1-C3alkyl. In some embodiments, each R9is independently hydrogen or optionally substituted C1-C2 alkyl.

[0348] In some embodiments, each R9is independently hydrogen or optionally substituted C1alkyl. In some embodiments, each R9is independently hydrogen or -CH3.

[0349] In some embodiments, the compound is notWSGR Ref: 60134-707.601WSGR Ref: 60134-707.601

[0352] One embodiment provides a LpxH inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1. Table 1 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticWSGR Ref: 60134-707.601 SyntheticSingle enantiomer of unknown absolute configuration.

[0353] Another embodiment provides a LpxH inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 2. Table 2WSGR Ref: 60134-707.601WSGR Ref: 60134-707.601WSGR Ref: 60134-707.601WSGR Ref: 60134-707.601made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including but not limited to Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0355] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin,WSGR Ref: 60134-707.601 Inc. Menlo Park, Calif.1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0356] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. Pharmaceutical Compositions

[0357] In certain embodiments, the LpxH inhibitory compound described herein is administered as a pure chemical. In other embodiments, the LpxH inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected onWSGR Ref: 60134-707.601 the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0358] Another embodiment provides a pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, of Formula (I-a-0), (I-a), (I-b- 0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III) and a pharmaceutically acceptable excipient.

[0359] Another embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III), and a pharmaceutically acceptable carrier.

[0360] Provided herein is a pharmaceutical composition comprising at least one LpxH inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0361] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III), or a pharmaceutically acceptable salt or solvate thereof.

[0362] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II- d), (II-e), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0363] In certain embodiments, the LpxH inhibitory compound as described by Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0364] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

[0365] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.WSGR Ref: 60134-707.601

[0366] In certain embodiments, the LpxH inhibitory compound as described by Table 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0367] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0368] In some embodiments, the LpxH inhibitory compound as described by Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III), or Table 1 or 2, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0369] The dose of the composition comprising at least one LpxH inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0370] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0371] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. Methods of TreatmentWSGR Ref: 60134-707.601

[0372] One embodiment provides a compound of Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0373] One embodiment provides a compound of Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of infection by at least one Gram-negative pathogen.

[0374] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of infection by at least one Gram-negative pathogen.

[0375] One embodiment provides a use of a compound of Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment infection by at least one Gram- negative pathogen.

[0376] In some embodiments is provided a method of treating infection by at least one Gram-negative pathogen, in a patient in need thereof, comprising administering to the patient a compound of Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating infection by at least one Gram-negative pathogen, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0377] One embodiment provides a compound of Table 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0378] One embodiment provides a compound of Table 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of infection by at least one Gram-negative pathogen.

[0379] One embodiment provides a pharmaceutical composition comprising a compound of Table 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of infection by at least one Gram-negative pathogen.

[0380] One embodiment provides a use of a compound of Table 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of infection by at least one Gram-negative pathogen.WSGR Ref: 60134-707.601

[0381] In some embodiments is provided a method of treating infection by at least one Gram-negative pathogen, in a patient in need thereof, comprising administering to the patient a compound of Table 1 or 2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating infection by at least one Gram-negative pathogen, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0382] In some embodiments, at least one Gram-negative pathogen is selected from the group consisting of Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, Haemophilus influenzae, Neisseria gonorrhoeae, Morganella morganii, Proteus mirabilis, Yersinia pestis, Citrobacter freundii, Citrobacter koseri, Enterobacter cloacae, Serratia marcescens, Achromobacter xylosoxidans, Salmonella typhi, Salmonella enterica, Moraxella catarrhalis, Helicobacter pylori, Stenotrophomonas maltophilia, Neisseria meningitis, Burkholderia cepacian, and Stenotrophomonas maltophilia. In some embodiments, at least one Gram-negative pathogen is selected from the group consisting of Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Citrobacter freundii or Proteus mirabilis.

[0383] In some embodiments the pathogen is a pandrug-resistant (PDR) pathogen. In some embodiments the pathogen is an extensively drug-resistant (XDR) pathogen. In some embodiments the pathogen is a multidrug-resistant (MDR) pathogen. In some embodiments the pathogen is an extended spectrum beta-lactamase positive pathogen. In some embodiments the pathogen is a carbapenemase positive pathogen. In some embodiments the pathogen is a Carbapenem-resistant pathogen. In some embodiments the pathogen is a Cephalosporin-resistant pathogen. In some embodiments the pathogen is a Penicillin-resistant pathogen. In some embodiments the pathogen is a Monobactam-resistant pathogen. In some embodiments the pathogen is a fluoroquinolone-resistant pathogen. In some embodiments the pathogen is a Tetracycline-resistant pathogen. In some embodiments the pathogen is an aminoglycoside- resistant pathogen. In some embodiments the pathogen is a Colistin-resistant pathogen. In some embodiments the pathogen is a Trimethoprim / Sulfamethoxazole-resistant (TMP / SMX-resistant) pathogen.

[0384] Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection. In some embodiments, the pharmaceutical composition is administered by intramuscular injection. In some embodiments, the pharmaceutical composition is administered by intravenous administration.WSGR Ref: 60134-707.601

[0385] One embodiment provides a method of inhibiting LpxH comprising contacting the LpxH enzyme with a compound of Formula (I-a-0), (I-a), (I-b-0), (I-b), (II-a), (II-b), (II-c), (II-d), (II-e), or (III) or Table 1 or 2. Another embodiment provides the method of inhibiting a LpxH enzyme, wherein the LpxH enzyme is contacted in an in vitro setting. Another embodiment provides the method of inhibiting a LpxH enzyme, wherein the LpxH enzyme is contacted in an in vivo setting.

[0386] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way. EXAMPLES I. Chemical Synthesis

[0387] In some embodiments, the LpxH inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:oC degrees Celsius δ chemical shift in parts per million downfield from tetramethylsilane ACN Acetonitrile AcOH Acetic acid Ar Argon Aq Aqueous CbzCl Benzyl chloroformate d doublet (spectral) dba dibenzylideneacetone DCM dichloromethane (CH2Cl2) DIPEA Diisoproylethylamine DMEA N,N'-Dimethylethylenediamine DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate ESI electrospray ionization Et ethyl EA or EtOAc Ethyl acetate FA Formic acidWSGR Ref: 60134-707.601 g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertz J coupling constant (in NMR spectrometry) LCMS liquid chromatography mass spectrometry μ micro m multiplet (spectral); meter(s); milli M molar M+parent molecular ion Me methyl MeOH Methanol MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliter Ms Mesylate MS mass spectrometry MsCl Methyl sulfonyl chloride M.W. Microwave NCS N-Chlorosuccinimide nm nanometer(s) NMI 1-methylimidazole NMR nuclear magnetic resonance p pentet (spectral) pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum ether q quartet (spectral) RT room temperature Rt retention time s singlet (spectral) t triplet (spectral) T temperature TBAF Tetrabutylammonium fluorideWSGR Ref: 60134-707.601 TCFH N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate TFA trifluoroacetic acid THF tetrahydrofuran TsCl p-toluenesulfonyl chloride Intermediate 1: 2-(N-methylmethylsulfonamido)benzoic acid

[0388] Step 1: methyl 2-(methylsulfonamido)benzoate To the solution of methyl 2-aminobenzoate (10 g, 66.2 mmol) in DCM (100 mL) was added pyridine (7.9 g, 69.5 mmol), then cooled to 0°C and MsCl (13.4 g, 132.3 mmol) was added dropwise into the mixture. The mixture was stirred at room temperature overnight. After starting material was consumed completely, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:1) to give product methyl 2-(methylsulfonamido)benzoate (12 g, Y:79%) as a white solid. TLC: PE / EA = 5:1, UV Rf = 0.3

[0389] Step 2: methyl 2-(N-methylmethylsulfonamido)benzoate To the solution of methyl 2-(methylsulfonamido)benzoate in DMF (200 mL) was added caesium carbonate (25.6 g, 78.7 mmol) then added MeI (8.9 g, 62.7 mmol) into the mixture and stirred at room temperature for 2 h. It was poured into water, extracted with ethyl acetate, the combined organic layer was washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:1) to give product ethyl 2-(N-methylmethylsulfonamido)benzoate (15.3 g) as a white solid. TLC: PE / EA = 5:1, UV Rf = 0.2

[0390] Step 3: 2-(N-methylmethylsulfonamido)benzoic acid To the solution of ethyl 2-(N-methylmethylsulfonamido)benzoate (15.3 g, 62.9 mmol) in MeOH (100 mL) was added the solution of NaOH (12.6 g, 314.4 mmol) in H2O (100 mL), then mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with DCM, then the aqueous phase was acidified with aqueous HCl till pH = 3 and extracted withWSGR Ref: 60134-707.601 DCM to give product 2-(N-methylmethylsulfonamido)benzoic acid (10.0 g, Y:69.3%) as a white solid. Intermediate 2: N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide2-(N-methylmethylsulfonamido)benzoic acid was dissolved in SOCl2(10 mL), then the mixture was stirred at 80°C for 2 h. The reaction mixture was concentrated for the subsequent step without further purification.

[0392] Step 2: tert-butyl N-(4-bromophenyl)-2-(N-methylmethylsulfonamido)benzamide To the solution of tert-butyl 4-bromoaniline (7.36 g, 42.81 mmol) in DCM (200 mL) was added TEA (4.32 g, 128.43 mmol), then the solution of 2-(N-methylmethylsulfonamido)benzoyl chloride (10.60 g, 42.81 mmol) in DCM (4 mL) was added dropwise at room temperature and the solution was stirred at room temperature overnight. It was poured into water, extracted with ethyl acetate, the combined organic layer was washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:1) to give product N-(4-bromophenyl)-2-(N- methylmethylsulfonamido)benzamide (13.2 g, Y:80.48%) as a white solid. LCMS: Rt = 1.599 min, [M+H]+=383.1.

[0393] Step 3: N-(4-(benzylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide To the solution of tert-butyl 5-bromoindoline-1-carboxylate (3 g, 10.06 mmol) in toluene (10 mL) were added phenylmethanethiol (10 g, 26.17 mmol), Pd2(dba)3(1.91 g, 2.09 mmol), Xant- phos (2.42 g, 4.18 mmol) and DIPEA (10.12 g, 78.51 mmol) at 25°C. The mixture was stirred at 110oC for 5 h. After cooling to room temperature, DCM and H2O were added to the mixture, and insoluble materials were removed by filtration. The filtrate was diluted with DCM. The organic phase was concentrated in vacuo and purified by flash chromatography eluted withWSGR Ref: 60134-707.601 PE / EA=10:1 to give product N-(4-(benzylthio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (9.34 g, 83.8 % yield) as a yellow solid. TLC: PE / EA = 10:1, UV Rf = 0.7

[0394] Step 4: N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide To the solution of N-(4-(benzylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide (9.34 g, 21.92 mmol) in toluene (50 mL) were added AlCl3 (11.66 g, 87.68 mmol) at 25°C and the solution was stirred at room temperature overnight., DCM and H2O were added to the mixture, and insoluble materials were removed by filtration. The filtrate was diluted with DCM. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE / EA=1:1 to give product N-(4-(benzylthio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (6.4 g, 86.9 % yield) as a yellow solid. TLC: PE / EA = 1:1, UV Rf = 0.7 Intermediate 3: 6-(heptylthio)pyridazin-3-amine

[0395] Step 1: 6-(heptylthio)pyridazin-3-amine To the solution of 6-bromopyridazin-3-amine (3 g, 17.2 mmol) in dioxane (15 mL) was added heptane-1-thiol (3.2 mL, 20.64 mmol), Pd2(dba)3 (1.8 g, 1.72 mmol), DPPF(1.9 g, 3.3 mmol) and DIEA (8.5 mL, 51.6 mmol) under argon atmosphere. The mixture was heated to 110°C and stirred for 12 h. The reaction was concentrated by vacuo. The reside was purified by flash column chromatography on silica gel (eluted with PE / EA = 0%) to give product Y: 64.3%) as a white solid. TLC: PE, UV Rf = 0.5 Intermediate 4: 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoic acid

[0396] Step 1: methyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoateWSGR Ref: 60134-707.601 To the solution of methyl 3-hydroxybenzoate (5 g, 32.9 mmol) in DMF (100 mL) were added K2CO3 (9.1 g, 65.8 mmol) and tert-butyl (2-bromoethyl)carbamate (22.12 g, 98.7 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was extracted with DCM and H2O. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with DCM / MeOH = 20:1 to give TM as a white solid (5 g, 99 % yield). TLC: DCM / MeOH = 20:1, UV Rf = 0.4

[0397] Step 2: 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoic acid To the methyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate (4.5 g, 15.24 mmol) in THF (90 mL) and H2O (30 mL) was added LiOH (3.65 g, 152.4 mmol) and the mixture was stirred at 0 °C to room temperature for 24 h. The reaction mixture was concentrated and washed with DCM, then the aqueous phase was acidified with aqueous HCl till pH = 5 and extracted with DCM to give product 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoic acid (5 g, crude) as a white solid. LCMS: Rt = 0.328 min, [M+1-56]+ = 226.0 Intermediate 5: (R)-3-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)benzoic acid- tert-butyl (R)-pyrrolidin-3-ylcarbamate (2.0 g, 1.07 mmol), methyl 3-bromobenzoate (2.3 g, 10.7 mmol), Pd2(dba)3 (910 mg, 1.00 mmol) and BINAP(1.31 g, 2.10 mmol) was dissolved in dry dioxane (30 mL) and Cs2CO3(6.67 g, 21.4 mmol) was added under Ar. atmosphere. The mixture was stirred at 100 °C for overnight. The reaction was detected by LCMS. The reaction mixture was extracted with EA (80 mL*3), the organic phase was separated, washed with brine (80 mL*3) and dried with Na2SO4 then concentrated and purified by flash chromatography eluted with PE:EA = 0-15% to give a yellow solid as desired product (3.16 g, 92.2%yield). LCMS: Rt = 1.568 min, [M+H]+= 321.1.

[0399] Step 2: (R)-3-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)benzoic acid methyl (R)-3-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)benzoate (3.1 g, 9.68 mmol) was dissolved in THF (15 mL) at room temperature, then the solution of NaOH (1.94 g, 48.38 mmol)WSGR Ref: 60134-707.601 in H2O (5 mL) was added slowly. The mixture was stirred at room temperature overnight. The reaction was detected by LCMS. The reaction mixture was poured into ice water (100 mL) and neutralized with 1 N HCl to pH=3, the mixture was extracted with EA (50 mL*3), the organic phase was separated, washed with brine (30 mL*3) and dried with Na2SO4 then concentrated to get the desired product (2.69 g, 91.0% yield) as a yellow solid. LCMS: Rt = 1.389 min, [M+H]+= 307.2 Intermediate 6: 6-(tert-butoxycarbonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-carboxylic acid

[0400] Step 1: tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate To the solution of 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1.0 g, 5.2 mmol),TEA (1.1 g, 10.8 mmol), DMAP (64 mg, 0.5 mmol) and DCM (40 mL).Then Boc2O (2.3 g, 10.5 mmol) was added and the reaction solution was stirred at room temperature for 2 hours. After completion, the solvent was removed under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel and eluted with EA: PE=10%~30% to afford product tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (1.2 g, Y:92%) as a white solid. LCMS: Rt = 1.676 min, [M+H]+= 255.1. TLC: PE / EA = 3:1, UV Rf = 0.6

[0401] Step 2: 6-(tert-butyl) 2-methyl 5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-2,6- dicarboxylate To the solution of tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (1.2 g, 4.7 mmol), Pd(dppf)Cl2 (0.7 g, 0.9 mmol), TEA (1.4 g, 14.1mmol) and Methanol(100 mL), the reaction solution was refilled with carbon monoxide for three times. Then the reaction solution was warmed up to 80°C and stirred for 36 hours under carbon monoxide atmosphere. After completion, the solvent was removed under reduced pressure and the resulting residue wasWSGR Ref: 60134-707.601 purified by flash column chromatography on silica gel and eluted with EA: PE=30%~50% to afford product 6-(tert-butyl) 2-methyl 5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-2,6-dicarboxylate (0.9 g, Y:70%) as a brown solid. LCMS: Rt = 1.452min, [M+H]+= 279.0. TLC: PE / EA = 2:1, UV Rf = 0.5

[0402] Step 3: 6-(tert-butoxycarbonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2- carboxylic acid To the solution of 6-(tert-butyl) 2-methyl 5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-2,6- dicarboxylate (0.9 g, 3.2 mmol) in THF (40 mL) and H2O (20 mL) was added Lithium hydroxide (0.5 g, 12.8 mmol). Then the reaction mixture was stirred at room temperature for 3 hours. Once the reaction was completion, the solvent was removed under reduced pressure and the resulting residue was treated pH to about 4 with 3M of hydrochloric acid aqueous solution. Then the mixture was extracted with DCM (30 mL) and washed with water (20 mL), the combined organic layer was washed with brine and dried over sodium sulfate. Then filtered, the filtrate was concentrated under reduced pressure to afford product 6-(tert-butoxycarbonyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridine-2-carboxylic acid (676.0 mg, Y:79%) as a white solid for the subsequent step without further purification. LCMS: Rt = 1.140min, [M+H]+= 265.1. TLC: PE / EA = 1:1, UV Rf = 0.1 Intermediate 7: 4-(Heptylthio)anilineTo a mixture of 4-nitrobenzenethiol (1 g, 6.445 mmol), 1-bromoheptane (1.21 g, 6.764 mmol) , KI (107 mg, 0.644 mmol) and K2CO3(2.67 g, 19.324 mmol) was added DMF (15 mL), then the mixture was heated to 85℃ and stirred for 2 h. The mixture was added water, extracted with EtOAc, combined the organic layer, and washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE = 0 ~ 3 / 97) to give the desired product (1.54g, 94.5% yield) as a yellow solid.WSGR Ref: 60134-707.601 LCMS: Rt = 2.221 min, [M+1]+= 254.1

[0404] Step 2: 4-(heptylthio)aniline To a solution of heptyl(4-nitrophenyl)sulfane (1.54 mg, 5.289 mmol) in EtOH (75 mL) and H2O (25 mL) were added Fe (2.95 g, 52.89 mmol) and NH4Cl (2.83 g, 52.89 mmol), the mixture was heated to 70℃ and stirred for 2h. The mixture was filtered and the filtrate was added water, extracted with EtOAc, combined the organic layer, washed with brine, the filtrate was concentrated under reduced pressure, the residue was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE = 0 ~ 15 / 85) to give the desired product (1.3 g, 100% yield) as a colorless liquid. LCMS: Rt =1.738 min, [M+1]+= 224.1. Intermediate 8: 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(N- methylmethylsulfonamido)benzoic acidTo the solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol) in pyridine (20 mL), then cooled to 0°C and MsCl (2.48 g, 21.73 mmol) was added dropwise into the mixture. The mixture was stirred at room temperature for 2 h. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:1) to give product methyl 5-bromo-2-(methylsulfonamido)benzoate (5.5 g, 83% yield) as a white solid. Step 2: tert-butyl 4-(3-(methoxycarbonyl)-4-(methylsulfonamido)phenyl)piperazine-1- carboxylate To a solution of methyl 5-bromo-2-(methylsulfonamido)benzoate (6.5 g, 21.1 mmol), RuphosPdG4 (935 mg, 1.1 mmol), Ruphos (1.97 g, 4.22 mmol), Cs2CO3(13.7 g, 42.2 mmol) in dioxane (100 mL) was added tert-butyl piperazine-1-carboxylate (407 mg, 25.3 mmol), the mixture was degassed under vacuum, purged with Argon several times, and then heated to 100 ℃ and stirred for 1 h. The mixture was filtered and the filter cake was washed with DCM, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=2 / 98) to give product (4.25 g, 49% yield) as a white solid. LCMS: Rt = 1.74 min, [M+1-56]+= 414WSGR Ref: 60134-707.601 Step 3: tert-butyl 4-(3-(methoxycarbonyl)-4-(N-methylmethylsulfonamido)phenyl)piperazine-1- carboxylate To a solution of tert-butyl 4-(3-(methoxycarbonyl)-4-(methylsulfonamido)phenyl)piperazine-1- carboxylate (4.25 g, 10.29 mmol) and Cs2CO3 (5 g, 15.44 mmol) in DMF (50 mL) was added MeI (1.75 g, 12.35 mmol). The mixture was allowed to room temperature for 2 h. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate, concentrated under reduced pressure, the residue was purified by silica gel chromatography (MeOH / DCM=3 / 97) to give product (4.2 g, 96% yield) as a white solid. Step 4: 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(N-methylmethylsulfonamido)benzoic acid To the solution of tert-butyl 4-(3-(methoxycarbonyl)-4-(N- methylmethylsulfonamido)phenyl)piperazine-1-carboxylate (4.2 g, 10 mmol) in MeOH (30 mL) was added the solution of LiOH (4.2 g, 100 mmol) in H2O (10 mL), then mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with DCM, then the aqueous phase was acidified with aqueous HCl till pH = 3 and extracted with DCM. Removal of the solvent to give product 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(N- methylmethylsulfonamido)benzoic acid (4.1 g, 100% yield) as a white solid. Intermediate 9: (R)-4-((5-methylheptyl)thio)anilineTo the solution of methyl acrylate (8.6 g, 10.0 mmol), Zn (2.16 g, 33.33 mmol) and NiCl2 (5.16 g, 4.0 mmol) in Py (66 mL),the reaction mixture were stirred at 50℃-RT for 30 min.Then added (R)-1-bromo-2-methylbutane (15.0 g, 10.0 mmol), the reaction mixture were stirred at room temperature for 3 h in Ar. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum to give product methyl (R)-5- methylheptanoate (10.0 g, crude) as a colorless oil Step 2: (R)-5-methylheptan-1-ol To the solution of (R)-5-methylheptanoate (4.0 g, 25.31 mmol), LiAlH4 (25 mL, 50.62 mmol ) in THF (50 mL), the reaction mixture were stirred at room temperature for 3 h. After startingWSGR Ref: 60134-707.601 material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE / EA=5 / 1 to give product (R)-5-methylheptan-1-ol (1.2 g, 37.5 % yield) as a colorless oil. Step 3: (R)-5-methylheptyl methanesulfonate To the solution of (R)-5-methylheptan-1-ol (1.0 g,7.69 mmol), Cs2CO3 (4.99 g, 15.38 mmol) in DCM (20 mL),the reaction mixture were stirred at 0℃-RT for 30 min.Then added MsCl (1.75 g, 15.38 mmol) , the reaction mixture were stirred at RT overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE / EA=5 / 1 to give product (R)-5-methylheptyl methanesulfonate as a colorless oil (1.3 g, 86.6% yield). Step 4: (R)-(5-methylheptyl)(4-nitrophenyl)sulfane To a solution of (R)-5-methylheptyl methanesulfonate (1.3 g, 6.25 mmol), 4-nitrobenzenethiol (968 mg, 6.25 mmol) and NaH (300 mg, 12.50 mmol ) in THF (20 mL), the reaction mixture were stirred at room temperature for 2 h in Ar. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE / EA=3 / 1 to give the product (R)-(5-methylheptyl)(4- nitrophenyl)sulfane (1.4 g, 84.3% yield) as yellow oil. MS(ESI) calculated for C14H21NO2S, 267.13; found, 268.1 Step 5: (R)-4-((5-methylheptyl)thio)aniline To a 100 mL bottom flask were added (R)-(5-methylheptyl)(4-nitrophenyl)sulfane (1.4 g,5.24 mmol), Fe (1.17 g, 20.97 mmol) in EtOH / H2O (15 mL / 15 mL), Then added NH4Cl (1.11 g, 20.97 mmol), the reaction mixture were stirred at 50℃for 1 h. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE / EA=4 / 1 to give crude product (R)-4-((5-methylheptyl)thio)aniline (1.1 g, 91.6% yield) as a yellow oil. MS(ESI) calculated for C14H23NS, 237.16; found, 238.1 Intermediate 10: N-(6-chloropyridazin-3-yl)-2-(N-methylmethylsulfonamido)benzamideWSGR Ref: 60134-707.6013-yl)-2-(N-methylmethylsulfonamido)benzamide of 6-chloropyridazin-3-amine (3.0 g, 23.16 mmol) in DCM (30 mL) was added pydrine (3.6 mL, 46.31 mmol) and 2-(N-methylmethylsulfonamido)benzoyl chloride (5.73 g, 23.16 mmol) at - 15°C. Then the reaction was stirred at room temperature overnight. The reaction was concentrated by vacuo to get the residue. The residue was purified by flash column chromatography (eluted with PE / EA = 1 / 4) to get the crude. The crude was triturated with MeOH to give product N-(6-chloropyridazin-3-yl)-2-(N-methylmethylsulfonamido)benzamide (6.0 g, 76.2% yield) as a white solid. LCMS: Rt = 1.326 min, [M+1]+= 385.0 Intermediate 11: 5-bromo-N-(4-(heptylthio)phenyl)-2-(N- methylmethylsulfonamido)benzamideThe solution of methyl 2-amino-5-bromobenzoate (15 g, 65.22 mmol) in DCM (50 mL) was cooled to 0°C and MsCl (18.59 g, 163.1 mmol) and pyridine (12.8 mL, 163.1) was added dropwise. The mixture was stirred at room temperature for 2 hours. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layer was washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:3) to give product methyl 2-(methylsulfonamido)benzoate (19.36 g, yield:97%) as a white solid. LCMS: Rt = 1.88 min, [M+1]+= 308 / 310 Step 2: methyl 5-bromo-2-(N-methylmethylsulfonamido)benzoate To a solution of methyl 5-bromo-2-(methylsulfonamido)benzoate (19.36 g, 63.06 mmol) and K2CO3 (17.4 g, 126.12 mmol) in DMF (50 mL) was added MeI (13.4 g, 94.59 mmol). The mixture was allowed to room temperature for 2 hours. The mixture was filtrated and added water, extracted with EtOAc, the combined organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure, the residue was purified by silica gelWSGR Ref: 60134-707.601 chromatography (eluted with ethyl acetate: petroleum ether =1:5) to give product (19.46 g, 96% yield) as a white solid. LCMS: Rt = 1.54 min, [M+1]+= 322 / 324 Step 3: 5-bromo-2-(N-methylmethylsulfonamido)benzoic acid To the solution of methyl 5-bromo-2-(N-methylmethylsulfonamido)benzoate (19.46 g, 60.6 mmol) in MeOH (40 mL) was added the solution of NaOH (24.24 g, 606 mmol) in H2O (10 mL), the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with DCM, then the aqueous phase was acidified with aqueous HCl till pH = 3 and extracted with DCM. After removal of the solvent, the residue (18.45 g, 99% yield) was used directly in the next step. LCMS: Rt = 1.32 min, [M+1]+=308 / 310 Step 4: 5-bromo-N-(4-(heptylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide To a solution of 5-bromo-2-(N-methylmethylsulfonamido)benzoic acid (11.3 g, 36.9 mmol) in ACN (40 mL) were added 4-(heptylthio)aniline (5.74 g, 24.62 mmol), TCFH (13.8 g, 49.22 mmol) and NMI (6.1 g, 73.86 mmol), the mixture was stirred for 1 hour at room temperature. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (elute with ethyl acetate: petroleum ether =1:2) to give product (13.83 g, 73% yield) as a white solid. LCMS: Rt =2.1 min, [M+1]+=513.2 Intermediate 12: 5-Bromo-N-(4-(heptylsulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamideThe solution of methyl 2-amino-5-bromobenzoate (15 g, 65.22 mmol) in DCM (50 mL) was cooled to 0°C and MsCl (18.59 g, 163.1 mmol) and pyridine (12.8 mL, 163.1) was added dropwise. The mixture was stirred at room temperature for 2 hours. After starting material wasWSGR Ref: 60134-707.601 consumed completely, water was added, extracted with ethyl acetate, the combined organic layer was washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:3) to give product methyl 2-(methylsulfonamido)benzoate (19.36 g, 97% yield) as a white solid. LCMS: Rt = 1.88 min, [M+1]+= 308 / 310 Step 2: methyl 5-bromo-2-(N-methylmethylsulfonamido)benzoate To a solution of methyl 5-bromo-2-(methylsulfonamido)benzoate (19.36 g, 63.06 mmol) and K2CO3(17.4 g, 126.12 mmol) in DMF (50 mL) was added MeI (13.4 g, 94.59 mmol). The mixture was allowed to room temperature for 2 hours. The mixture was filtrated and added water, extracted with EtOAc, the combined organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure, the residue was purified by silica gel chromatography (elute with ethyl acetate: petroleum ether =1:5) to give product (19.46 g, 96% yield) as a white solid. LCMS: Rt = 1.54 min, [M+1]+= 322 / 324 Step 3: 5-bromo-2-(N-methylmethylsulfonamido)benzoic acid To the solution of methyl 5-bromo-2-(N-methylmethylsulfonamido)benzoate (19.46 g, 60.6 mmol) in MeOH (40 mL) was added the solution of NaOH (24.24 g, 606 mmol) in H2O (10 mL), the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with DCM, then the aqueous phase was acidified with aqueous HCl till pH = 3 and extracted with DCM. After removal of the solvent, the residue (18.45 g, 99% yield) was used directly in the next step. LCMS: Rt = 1.32 min, [M+1]+=308 / 310 Step 4: 5-bromo-N-(4-(heptylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide To a solution of 5-bromo-2-(N-methylmethylsulfonamido)benzoic acid (11.3 g, 36.9 mmol) in ACN (40 mL) were added 4-(heptylthio)aniline (5.74 g, 24.62 mmol), TCFH (13.8 g, 49.22 mmol) and NMI (6.1 g, 73.86 mmol), the mixture was stirred for 1 hour at room temperature. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (elute with ethyl acetate: petroleum ether =1:2) to give product (13.83 g, 73% yield) as a white solid. LCMS: Rt =2.1 min, [M+1]+=513.2WSGR Ref: 60134-707.601 Step 5: 5-bromo-N-(4-(heptylsulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide To the solution of 5-bromo-N-(4-(heptylthio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (5.0 g, 9.76 mmol) in DCM (30 mL) was added m-CPBA (3.36 g, 19.53 mmol) at 0°C and the solution was stirred at room temperature overnight After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE / EA=1:1 to give the product 5-bromo-N-(4-(heptylsulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide (4.3 g, 81.1% yield) as a white solid. LCMS: Rt = 1.836 min, [M+H]+=545.1. Intermediate 13: N-(4-mercaptophenyl)-2-(methylsulfonamido)benzamideTo the solution of methyl 2-aminobenzoate (10 g, 66.2 mmol) in DCM (100 mL) was added pyridine (7.9 g, 69.5 mmol), then cooled to 0°C and MsCl (13.4 g, 132.3 mmol) was added dropwise into the mixture. The mixture was stirred at room temperature overnight. After starting material was consumed completely, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:1) to give product methyl 2-(methylsulfonamido)benzoate (12.0 g, 79% yield) as a white solid. TLC: PE / EA = 5:1, UV Rf = 0.3 Step 2: 2-(methylsulfonamido)benzoic acid To the solution of ethyl methyl 2-(methylsulfonamido)benzoate (12.0 g, 52.4 mmol) in MeOH (100 mL) was added the solution of NaOH (8.38 g, 209.6 mmol) in H2O (100 mL), then mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and washed withWSGR Ref: 60134-707.601 DCM, then the aqueous phase was acidified with aqueous HCl till pH = 3 and extracted with DCM to give product 2-(methylsulfonamido)benzoic acid (10.0 g, 89.2% yield) as a white solid. LCMS: Rt = 1.076 min, [M+H]+=216.1. Step 3: 2-(methylsulfonamido)benzoyl chloride 2-(methylsulfonamido)benzoic acid (10.0 g, 46.5 mmol) was dissolved in SOCl2(10 mL), then the mixture was stirred at 80°C for 2 h. The reaction mixture was concentrated for the subsequent step without further purification. Step 4: N-(4-bromophenyl)-2-(methylsulfonamido)benzamide To the solution of 2-(methylsulfonamido)benzoyl chloride (7.36 g, 42.81 mmol) in DCM (200 mL) was added TEA (4.32 g, 128.43 mmol), then the solution of 2-(N- methylmethylsulfonamido)benzoyl chloride (10.60 g, 42.81 mmol) in DCM (4 mL) was added dropwise at room temperature and the solution was stirred at room temperature overnight. It was poured into water, extracted with ethyl acetate, the combined organic layer was washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:1) to give product N-(4- bromophenyl)-2-(methylsulfonamido)benzamide (13.2 g, 80.48% yield) as a white solid. LCMS: Rt = 1.599 min, [M+H]+=369.1. Step 5: N-(4-(benzylthio)phenyl)-2-(methylsulfonamido)benzamide To the solution of N-(4-bromophenyl)-2-(methylsulfonamido)benzamide (3 g, 10.06 mmol) in toluene (10 mL) were added phenylmethanethiol (10 g, 26.17 mmol), Pd2(dba)3(1.91 g, 2.09 mmol), Xant-phos (2.42 g, 4.18 mmol) and DIPEA (10.12 g, 78.51 mmol) at 25°C. The mixture was stirred at 110oC for 5 h. After cooling to room temperature, DCM and H2O were added to the mixture, and insoluble materials were removed by filtration. The filtrate was diluted with DCM. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE / EA=10 / 1 to give product N-(4-(benzylthio)phenyl)-2- (methylsulfonamido)benzamide (9.34 g, 83.8 % yield) as a yellow solid. TLC: PE / EA = 10:1, UV Rf = 0.7 Step 6: N-(4-mercaptophenyl)-2-(methylsulfonamido)benzamide To the solution of N-(4-(benzylthio)phenyl)-2-(methylsulfonamido)benzamide (9.34 g, 21.92 mmol) in toluene (50 mL) were added AlCl3 (11.66 g, 87.68 mmol) at 25°C and the solution wasWSGR Ref: 60134-707.601 stirred at room temperature overnight., DCM and H2O were added to the mixture, and insoluble materials were removed by filtration. The filtrate was diluted with DCM. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE / EA=1 / 1 to give product N-(4-mercaptophenyl)-2-(methylsulfonamido)benzamide (6.4 g, 86.9 % yield) as a yellow solid. TLC: PE / EA = 1:1, UV Rf = 0.7 Intermediate 14: N-(5-bromopyrazin-2-yl)-2-(N-methylmethylsulfonamido)benzamide2-(N-methylmethylsulfonamido)benzoic acid (5.0 g, 21.83 mmol) was dissolved in SOCl2(20 mL), then the mixture was stirred at 80°C for 2 h. The reaction mixture was concentrated for the subsequent step without further purification. Step 2: N-(5-bromopyrazin-2-yl)-2-(N-methylmethylsulfonamido)benzamide To the solution of 5-bromopyrazin-2-amine (3.77 g, 21.83 mmol) in DCM (20 mL) was added TEA (6.61 g, 65.49 mmol), then the solution of 2-(N-methylmethylsulfonamido)benzoic acid (5.39 g, 21.83 mmol) in DCM (20 mL) was added dropwise at room temperature and the solution was stirred at room temperature overnight. It was poured into water, extracted with ethyl acetate, the combined organic layer was washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:1) to give N-(5-bromopyrazin-2-yl)-2-(N- methylmethylsulfonamido)benzamide (6.3 g, 75.1% yield) as a white solid. LCMS: Rt = 1.321 min, [M+H]+=385.0 Intermediate 15: N-((4-aminophenyl)(heptyl)(oxo)-l6-sulfanylidene)-2,2,2-trifluoroacetamideWSGR Ref: 60134-707.601To a solution of 4-(heptylthio)aniline (1 g, 4.48 mmol) in DCM (10 mL) were added (Boc)2O (1.47 g, 6.73 mmol) and TEA (0.95 g, 8.96 mmol). The mixture was allowed to room temperature for 3 hours. The mixture was filtrated and added water, extracted with EtOAc, the combined organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure, the residue was purified by silica gel chromatography (elute with ethyl acetate: petroleum ether =1:10) to give product (686 mg, 47% yield) as a white solid. LCMS: Rt = 2.34 min, [M+1-56]+= 268 Step 2: tert-butyl (4-(heptylsulfonimidoyl)phenyl)carbamate To a solution of tert-butyl (4-(heptylthio)phenyl)carbamate (686 mg, 2 mmol) in MeOH (10 mL) were added [bis(acetoxy)iodo]benzene (1.61 g, 5 mmol) and ammonium carbonate (480 mg, 5 mmol) , the mixture was stirred for 1 hour at room temperature. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (elute with ethyl acetate: petroleum ether =1:1) to give product (466 mg, 66% yield) as a white solid. LCMS: Rt =1.64 min, [M+1]+=355 Step 3: tert-butyl (4-(N-(2,2,2-trifluoroacetyl)heptylsulfonimidoyl)phenyl)carbamate To a solution of tert-butyl (4-(heptylsulfonimidoyl)phenyl)carbamate (466 mg, 1.32 mmol) in DCM (10 mL) was added TEA (400 mg, 3.96 mmol) and TFAA (443 mg, 2.11 mmol), the mixture was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure to give the product (450 mg, crude) as a colorless oil. Step 4: N-((4-aminophenyl)(heptyl)(oxo)-l6-sulfanylidene)-2,2,2-trifluoroacetamideWSGR Ref: 60134-707.601 To a solution of tert-butyl (4-(N-(2,2,2-trifluoroacetyl)heptylsulfonimidoyl)phenyl)carbamate (450 mg, 1 mmol) in DCM (2 mL) was added TFA (0.5 mL), the mixture was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by gel chromagraphy (MeOH / DCM=1 / 10) to give the product (198 mg, 57% yield) as a white solid. Intermediate 17: 4-bromo-N-(4-(heptylthio)phenyl)-2-(N- methylmethylsulfonamido)benzamideTo the solution of methyl 2-amino-4-bromobenzoate (25 g, 109 mmol) in DCM (250 mL) was added pyridine (21.6 g, 273 mmol), then MsCl (25 g, 218 mmol) was added at 0℃ and the solution was stirred at room temperature for 72 h. After removal of the solvent, the residue was purified by silica column (elute with ethyl acetate: petroleum ether =1:3) to give product (31 g, 93 % yield) as a white solid. TLC: PE / EA = 3:1, LCMS: Rt = 1.68 min, [M+H]+=308&310 Step 2: methyl 4-bromo-2-(N-methylmethylsulfonamido)benzoate To the solution of methyl 4-bromo-2-(methylsulfonamido)benzoate (31 g, 101 mmol) in DMF (130 mL) was added K2CO3 (28 g, 202 mmol) and MeI (36.6 g, 258 mmol) , then the mixture was heated to 50℃ and stirred for 16 h. Filtered and the filtrate added water, extracted with EtOAc, the combined organic layer was washed with brine, dried over sodium sulfate, then concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=3 / 22) to give the desired product (19.7 g, 65 % yield) as a yellow oil. LCMS: Rt = 1.64 min, [M+H]+=322 Step 3: 4-bromo-2-(N-methylmethylsulfonamido)benzoic acid To the solution of methyl 4-bromo-2-(N-methylmethylsulfonamido)benzoate (19.7 g, 62.1 mmol) in THF (65 mL) was added a solution of LiOH.H2O (10.41 g, 248 mmol) in H2O (65 mL), the mixture was stirred for 16 h at room temperature. Then the mixture was added water and neutralized with HC1 (2 N), and extracted with EtOAc, the combined organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure to give product (17 g, 92 % yield) as a yellow solid.WSGR Ref: 60134-707.601 LCMS: Rt = 1.34 min, [M+H]+=310 Step 4: 4-bromo-N-(4-(heptylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide To the mixture of TCFH (13.2 g, 47.1 mmol), NMI (6.44 g, 78.5 mmol) in ACN (65 mL) was added 4-bromo-2-(N-methylmethylsulfonamido)benzoic acid (10.6 g, 34.5 mmol) and 4- (heptylthio)aniline (7 g, 31.4 mmol), the mixture was stirred for 2 h at room temperature. Then water was added and extracted with EtOAc, the combined organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=1 / 1) to give the desired product (9.5 g, 56 % yield) as a white solid. LCMS: Rt = 2.093 min, [M+H]+=514 Intermediate 18: 4-bromo-N-(4-(heptylsulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamideTo a solution of 4-bromo-N-(4-(heptylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide (5 g, 9.74 mmol) in DCM (45 mL) was added m-CPBA (4.2 g, 24.3 mmol) at 0oC, the mixture was stirred at room temperature for 2 h. Then the mixture was added sodium sulfite and stirred for 30min at room temperature, water was added, extracted with DCM, the combined organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (MeOH / DCM=1 / 99) to give the desired product compound (4.2 g, 79 % yield) as a white solid. LCMS: Rt = 1.89 min, [M+H]+=545&547 Intermediate 19: 1-Methyl-3-(methylsulfonamido)-1H-pyrazole-4-carboxylic acidWSGR Ref: 60134-707.601 To a solution of ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate (1 g, 5.917 mmol) in DCM (40 mL) were added TEA (1.2 g, 11.834 mmol) and MsCl (746 mg, 6.509 mmol), the mixture was stirred for 3h at room temperature. The mixture was added water and extracted with DCM, combined the organic layer, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (10% MeOH in DCM / DCM=0~50 / 50) to give product (735 mg, 50.2%) as a yellow oil. LCMS: Rt = 1.187 min, [M+H]+=248

[0406] Step 2: 1-methyl-3-(methylsulfonamido)-1H-pyrazole-4-carboxylic acid To a solution of ethyl 1-methyl-3-(methylsulfonamido)-1H-pyrazole-4-carboxylate (735 mg, 2.976 mmol) in MeOH (10 mL) and THF (10 mL) was added a solution of NaOH (952 mg, 23.806 mmol) in H2O (10 mL), the mixture was heated to 50℃ and stirred for 4h. The mixture was concentrated under reduced pressure to remove THF and MeOH, the residue was neutralized with 2N HCl, the mixture was filtrated, and the product (537 mg, 82.3% yield) was collected as white solid. LCMS: Rt =0.405 min, [M+H]+=220.0 Example 1: N-(4-(hexylsulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamideTo the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (500 mg, 1.48 mmol) in MeCN (8 mL) were added K2CO3 (408 mg, 2.96 mmol) and 1-bromohexane (244 mg, 1.48 mmol) and the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product N-(4-(hexylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide (170 mg, Y:27.4%) as a white solid. TLC: PE / EA = 5:1, UV Rf (compound 2) = 0.2

[0408] Step 2: N-(4-(hexylsulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamideWSGR Ref: 60134-707.601 To the solution of N-(4-(hexylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide (170 mg, 0.40 mmol) in DCM (4 mL) was added m-CPBA (137 mg, 0.80 mmol) at 0°C and the solution was stirred at room temperature overnight It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product N-(4-(hexylsulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide (74.9 mg, Y: 41.6%) as a white solid.1H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.62 (dd, J = 7.4, 6.2 Hz, 3H), 7.55 – 7.46 (m, 1H), 3.26 (s, 3H), 3.23 (d, J = 7.9 Hz, 2H), 3.00 (s, 3H), 1.52 (dd, J = 9.5, 6.1 Hz, 2H), 1.36 – 1.26 (m, 2H), 1.26 – 1.15 (m, 4H), 0.83 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C21H28N2O5S2, 452.14; found, 453.1. Example 2: 2-(N-methylmethylsulfonamido)-N-(4-(pentylsulfonyl)phenyl)benzamideTo the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (500 mg, 1.48 mmol) in MeCN (8 mL) were added K2CO3 (408 mg, 2.96 mmol) and 1-bromopentane (224 mg, 1.48 mmol) and the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product 2-(N-methylmethylsulfonamido)-N-(4-(pentylthio)phenyl)benzamide (309 mg, Y:51.5%) as a white solid. TLC: PE / EA = 5:1, UV Rf (compound 2) = 0.2

[0410] Step 2: 2-(N-methylmethylsulfonamido)-N-(4-(pentylsulfonyl)phenyl)benzamide To the solution of 2-(N-methylmethylsulfonamido)-N-(4-(pentylthio)phenyl)benzamide (309 mg, 0.76 mmol) in DCM (4 mL) was added m-CPBA (269 mg, 1.52 mmol) at 0°C and the solution was stirred at room temperature overnight It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purifiedWSGR Ref: 60134-707.601 by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product 2-(N-methylmethylsulfonamido)-N-(4- (pentylsulfonyl)phenyl)benzamide (148.5 mg, Y: 44.5%) as a white solid.1H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.69 – 7.57 (m, 3H), 7.56 – 7.44 (m, 1H), 3.26 (s, 3H), 3.25 – 3.19 (m, 2H), 3.00 (s, 3H), 1.53 (d, J = 7.6 Hz, 2H), 1.35 – 1.18 (m, 4H), 0.81 (t, J = 7.1 Hz, 3H). MS(ESI) calculated for C20H26N2O5S2, 438.13; found, 439.1. Example 3: N-(4-((2-cyclopropylethyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide

[0411] Step 1: 2-(N-methylmethylsulfonamido)-N-(4-(pentylthio)phenyl)benzamide To the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (336 mg, 1.0 mmol) in MeCN (8 mL) were added K2CO3 (278 mg, 2.0 mmol) and (2- bromoethyl)cyclopropane (150 mg, 2.0 mmol), the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product 2-(N-methylmethylsulfonamido)-N-(4- (pentylthio)phenyl)benzamide (230 mg, Y:56.9%) as a white solid. TLC: PE / EA = 5:1, UV Rf(compound 2) = 0.2

[0412] Step 2: N-(4-((2-cyclopropylethyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide To the solution of 2-(N-methylmethylsulfonamido)-N-(4-(pentylthio)phenyl)benzamide (230 mg, 0.57 mmol) in DCM (4 mL) was added m-CPBA (202 mg, 1.14 mmol) at 0°C and the solution was stirred at room temperature overnight. It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product N-(4-((2-cyclopropylethyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide (71.3 mg, Y: 28.6%) as a white solid.WSGR Ref: 60134-707.6011H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.62 (dd, J = 9.2, 5.8 Hz, 3H), 7.51 (dd, J = 7.9, 3.7 Hz, 1H), 3.34 (s, 1H), 3.30 (s, 1H), 3.26 (s, 3H), 3.01 (s, 3H), 1.46 (dt, J = 10.5, 7.4 Hz, 2H), 0.80 – 0.66 (m, 1H), 0.37 (dd, J = 8.0, 1.6 Hz, 2H), 0.05 (dd, J = 4.8, 1.2 Hz, 2H). MS(ESI) calculated for C20H24N2O5S2, 436.11; found, 437.1. Example 4: N-(4-((2-cyclobutylethyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamidemethylmethylsulfonamido)benzamide To the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (350 mg, 1.04 mmol) in MeCN (8 mL) were added K2CO3 (287 mg, 2.08 mmol) and (2- bromoethyl)cyclobutane (170 mg, 1.04 mmol) and the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product N-(4-((2-cyclobutylethyl)thio)phenyl)- 2-(N-methylmethylsulfonamido)benzamide (240 mg, Y:55.2%) as a white solid. TLC: PE / EA = 5:1, UV Rf (compound 2) = 0.2

[0414] Step 2: N-(4-((2-cyclobutylethyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide To the solution of N-(4-((2-cyclobutylethyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (230 mg, 0.57 mmol) in DCM (4 mL) was added m- CPBA (202 mg, 1.14 mmol) at 0°C and the solution was stirred at room temperature overnight It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product N-(4-((2- cyclobutylethyl)sulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide (86.5 mg, Y: 33.5%) as a white solid.WSGR Ref: 60134-707.601 1H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.73 – 7.57 (m, 3H), 7.51 (dd, J = 7.9, 3.8 Hz, 1H), 3.26 (s, 3H), 3.16 – 3.07 (m, 2H), 3.01 (s, 3H), 2.34 – 2.20 (m, 1H), 2.02 – 1.88 (m, 2H), 1.84 – 1.69 (m, 2H), 1.67 – 1.45 (m, 4H). MS(ESI) calculated for C21H26N2O5S2, 450.13; found, 451.1. Example 5: N-(4-((5-methylhexyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamidemethylmethylsulfonamido)benzamide To the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (282 mg, 0.83 mmol) in MeCN (8 mL) were added K2CO3 (344 mg, 2.5 mmol) and 1-bromo-5- methylhexane (150 mg, 0.83 mmol), the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product N-(4-((5-methylhexyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (188 mg, Y:67.6%) as a white solid. TLC: PE / EA = 5:1, UV Rf(compound 2) = 0.2

[0416] Step 2: N-(4-((5-methylhexyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide To the solution of N-(4-((5-methylhexyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (188 mg, 0.43 mmol) in DCM (4 mL) was added m- CPBA (153 mg, 0.86 mmol) at 0°C and the solution was stirred at room temperature overnight It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product N-(4-((5- methylhexyl)sulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide (72.3 mg, Y: 36.0%) as a white solid.WSGR Ref: 60134-707.6011H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.62 (t, J = 6.5 Hz, 3H), 7.52 (d, J = 4.3 Hz, 1H), 3.26 (s, 3H), 3.25 – 3.21 (m, 2H), 3.00 (s, 3H), 1.47 (dd, J = 25.4, 7.1 Hz, 3H), 1.35 – 1.25 (m, 2H), 1.16 – 1.04 (m, 2H), 0.81 (d, J = 6.6 Hz, 6H). MS(ESI) calculated for C22H30N2O5S2, 466.16; found, 467.3. Example 6: N-(4-((3-cyclopentylpropyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamidemethylmethylsulfonamido)benzamide To the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (264 mg, 0.78 mmol) in MeCN (8 mL) were added K2CO3(323 mg, 2.34 mmol) and (3- bromopropyl)cyclopentane (150 mg, 0.78 mmol), the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product N-(4-((3- cyclopentylpropyl)thio)phenyl)-2-(N-methylmethylsulfonamido)benzamide (194 mg, Y:55.9%) as a white solid. TLC: PE / EA = 5:1, UV Rf (compound 2) = 0.2

[0418] Step 2: N-(4-((3-cyclopentylpropyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide To the solution of N-(4-((3-cyclopentylpropyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (194 mg, 0.43 mmol) in DCM (6 mL) was added m- CPBA (154 mg, 0.86 mmol) at 0°C and the solution was stirred at room temperature overnight It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product N-(4-((3- cyclopentylpropyl)sulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide (78.5 mg, Y: 38.0%) as a white solid.WSGR Ref: 60134-707.6011H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.9 Hz, 2H), 7.62 (dd, J = 8.6, 5.6 Hz, 3H), 7.56 – 7.46 (m, 1H), 3.26 (s, 3H), 3.23 (d, J = 7.8 Hz, 2H), 3.00 (s, 3H), 1.75 – 1.61 (m, 3H), 1.50 (tdd, J = 11.4, 7.8, 5.0 Hz, 6H), 1.38 – 1.26 (m, 2H), 0.99 (s, 2H). MS(ESI) calculated for C23H30N2O5S2, 478.16; found, 479.1. Example 7: N-(4-((7-hydroxyheptyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamidemethylmethylsulfonamido)benzamide To the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (258 mg, 0.77 mmol) in MeCN (8 mL) were added K2CO3(212 mg, 1.54 mmol) and 7-bromoheptan-1-ol (150 mg, 0.77 mmol), the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product N-(4-((7-hydroxyheptyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (167 mg, Y:48.2%) as a white solid. TLC: PE / EA = 5:1, UV Rf (compound 2) = 0.2

[0420] Step 2: N-(4-((7-hydroxyheptyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide To the solution of N-(4-((7-hydroxyheptyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (167 mg, 0.37 mmol) in DCM (6 mL) was added m- CPBA (131 mg, 0.74 mmol) at 0°C and the solution was stirred at room temperature overnight It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product N-(4-((7- hydroxyheptyl)sulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide (81.5 mg, Y: 45.5%) as a white solid.WSGR Ref: 60134-707.6011H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.89 – 7.81 (m, 2H), 7.66 – 7.57 (m, 3H), 7.56 – 7.46 (m, 1H), 4.31 (s, 1H), 3.35 (d, J = 4.6 Hz, 2H), 3.26 (s, 3H), 3.23 (d, J = 7.9 Hz, 2H), 3.01 (s, 3H), 1.61 – 1.47 (m, 2H), 1.41 – 1.26 (m, 4H), 1.22 (dd, J = 6.9, 3.6 Hz, 4H). MS(ESI) calculated for C22H30N2O6S2, 482.15; found, 483.2. Example 8: 3-(2-aminoethoxy)-N-(6-(heptylsulfonyl)pyridazin-3-yl)benzamideTo the solution of 6-bromopyridazin-3-amine (3 g, 17.2 mmol) in dioxane (15 mL) was added heptane-1-thiol (3.2 mL, 20.64 mmol), Pd2(dba)3 (1.8 g, 1.72 mmol), DPPF(1.9g, 3.3 mmol) and DIEA (8.5 mL, 51.6 mmol) under argon atmosphere. The mixture was heated to 110°C and stirred for 12 h. The reaction was concentrated by vacuo. The reside was purified by flash column chromatography on silica gel (eluted with PE / EA = 0%) to give product Y:64.3%) as a white solid. TLC: PE, UV Rf = 0.5

[0422] Step 2: tert-butyl (2-(3-((6-(heptylthio)pyridazin-3- yl)carbamoyl)phenoxy)ethyl)carbamate To a solution of 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoic acid (500.7 mg, 1.78 mmol) in MeCN (10 mL) were added TCFH (1.5 g, 5.34 mmol) and NMI (1.1 mL, 14.24 mmol), the mixture was stirring for 10 min. Then 6-(heptylthio)pyridazin-3-amine (200 mg, 0.89 mmol) was added. The reaction mixture was stirred at ambient temperature for another 4 h. After the reaction was completed, it was concentrated and purified with silica column (eluted with ethyl acetate: petroleum ether =1:1) to give the product tert-butyl (2-(3-((6-(heptylthio)pyridazin-3- yl)carbamoyl)phenoxy)ethyl)carbamate (500 mg) as a white solid. TLC: PE / EA = 1:1, UV Rf = 0.5WSGR Ref: 60134-707.601

[0423] Step 3: tert-butyl (2-(3-((6-(heptylsulfonyl)pyridazin-3- yl)carbamoyl)phenoxy)ethyl)carbamate To the solution of tert-butyl (2-(3-((6-(heptylthio)pyridazin-3- yl)carbamoyl)phenoxy)ethyl)carbamate (200 mg, 0.41 mmol) in dry DCM (5 mL) was added m- CPBA (177.75 mg, 1.03 mmol) at 0°C, then mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude product. The crude product was purified by flash chromatography eluted with PE / EA = 3:1 to give product tert-butyl (2-(3-((6-(heptylsulfonyl)pyridazin-3- yl)carbamoyl)phenoxy)ethyl)carbamate TLC: PE / EA = 3:1, UV Rf = 0.5

[0424] Step 4: 3-(2-aminoethoxy)-N-(6-(heptylsulfonyl)pyridazin-3-yl)benzamide To the solution of t tert-butyl (2-(3-((6-(heptylsulfonyl)pyridazin-3- yl)carbamoyl)phenoxy)ethyl)carbamate (100 mg, 0.29 mmol) in DCM (4 mL) was added TFA (1 mL), then mixture was stirred at room temperature for 1 h.The mixture was extracted with DCM and H2O. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with DCM / MeOH = 20:1 to give a crude product. Then the crude product was purified by prep. HPLC to give product 3-(2-aminoethoxy)-N-(6- (heptylsulfonyl)pyridazin-3-yl)benzamide (25.6 mg, 25.6% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 9.4 Hz, 1H), 8.33 (d, J = 9.4 Hz, 1H), 7.74 – 7.61 (m, 2H), 7.47 (t, J = 8.2 Hz, 1H), 7.23 (dd, J = 8.1, 1.9 Hz, 1H), 4.06 (t, J = 5.7 Hz, 2H), 3.62 – 3.52 (m, 2H), 2.96 (t, J = 5.7 Hz, 2H), 1.71 – 1.57 (m, 2H), 1.34 (d, J = 7.4 Hz, 2H), 1.30 – 1.14 (m, 6H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C20H28N4O4S,420.53, found, 421.WSGR Ref: 60134-707.601 Example 9: N-(4-((6-methylheptyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamideTo the solution of 6-methylheptan-1-ol (150 mg, 1.15 mmol) in DCM (8 mL) were added TEA (929 mg, 9.2 mmol), Cs2CO3 (2.99 g, 9.2 mmol) and MsCl (524 mg, 4.6 mmol) and the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =10:1) to give product 6- methylheptyl methanesulfonate (200 mg, Y:83.6%) as a white solid. TLC: PE / EA = 10:1, UV Rf (compound 2) = 0.2

[0426] Step 2: N-(4-((6-methylheptyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide To the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (320 mg, 0.96 mmol) in MeCN (8 mL) were added Cs2CO3(624 mg, 1.92 mmol) and 6-methylheptyl methanesulfonate (200 mg, 0.96 mmol), the solution was stirred at 80℃ overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product N-(4-((6-methylheptyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (100 mg, Y:23.0%) as a white solid. TLC: PE / EA = 5:1, UV Rf (compound 2) = 0.2WSGR Ref: 60134-707.601

[0427] Step 3: N-(4-((6-methylheptyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide To the solution of N-(4-((6-methylheptyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (100 mg, 0.22 mmol) in DCM (6 mL) was added m- CPBA (79 mg, 0.44 mmol) at 0°C and the solution was stirred at room temperature overnight It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product N-(4-((6- methylheptyl)sulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide (39.7 mg, Y: 37.1%) as a white solid.1H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.62 (t, J = 6.2 Hz, 3H), 7.52 (d, J = 4.4 Hz, 1H), 3.26 (s, 3H), 3.23 (d, J = 7.9 Hz, 2H), 3.00 (s, 3H), 1.60 – 1.40 (m, 3H), 1.34 – 1.14 (m, 4H), 1.13 – 1.02 (m, 2H), 0.82 (d, J = 6.6 Hz, 6H). MS(ESI) calculated for C23H32N2O5S2, 480.18; found, 481.2. Example 10: N-(4-((8-aminooctyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamidemethylmethylsulfonamido)benzamido)phenyl)thio)octyl)carbamate To the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (327 mg, 0.97 mmol) in MeCN (8 mL) were added K2CO3 (268 mg, 1.94 mmol) and tert-butyl (8- bromooctyl)carbamate (300 mg, 0.97 mmol), the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (eluteWSGR Ref: 60134-707.601 with ethyl acetate: petroleum ether =5:1) to give product tert-butyl (8-((4-(2-(N- methylmethylsulfonamido)benzamido)phenyl)thio)octyl)carbamate (400 mg, Y:73.2%) as a white solid. TLC: PE / EA = 5:1, UV Rf (compound 2) = 0.2

[0429] Step 2: tert-butyl (8-((4-(2-(N- methylmethylsulfonamido)benzamido)phenyl)sulfonyl)octyl)carbamate To the solution of tert-butyl (8-((4-(2-(N- methylmethylsulfonamido)benzamido)phenyl)thio)octyl)carbamate (400 mg, 0.71 mmol) in DCM (8 mL) was added m-CPBA (252 mg, 1.42 mmol) at 0°C and the solution was stirred at room temperature overnight After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product tert-butyl (8-((4-(2-(N- methylmethylsulfonamido)benzamido)phenyl)sulfonyl)octyl)carbamate (360 mg, Y:85.3%) as a white solid. LCMS: Rt = 1.808 min, [M+H-100]+=496.1.

[0430] Step 3: N-(4-((8-aminooctyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide To the solution of tert-butyl (8-((4-(2-(N- methylmethylsulfonamido)benzamido)phenyl)sulfonyl)octyl)carbamate (360 mg, 0.60 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 3 h. It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product N-(4-((8- aminooctyl)sulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide (92.7 mg, Y: 30.9%) as a white solid.1H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 5H), 7.66 – 7.58 (m, 3H), 7.51 (ddd, J = 7.3, 5.5, 3.5 Hz, 1H), 3.26 (s, 3H), 3.23 (d, J = 8.0 Hz, 2H), 3.01 (s, 3H), 2.73 (dd, J = 14.7, 6.1 Hz, 2H), 1.63 – 1.43 (m, 4H), 1.39 – 1.16 (m, 8H). MS(ESI) calculated for C23H33N3O5S2, 495.19; found, 496.2.WSGR Ref: 60134-707.601 Example 11: 2-(N-methylmethylsulfonamido)-N-(4-((6,6,6- trifluorohexyl)sulfonyl)phenyl)benzamidetrifluorohexyl)thio)phenyl)benzamide To the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (122 mg, 0.36 mmol) in MeCN (8 mL) were added K2CO3(100 mg, 0.72 mmol) and 6-bromo-1,1,1- trifluorohexane (80 mg, 0.36 mmol), the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product 2-(N-methylmethylsulfonamido)-N-(4-((6,6,6- trifluorohexyl)thio)phenyl)benzamide (94 mg, Y:54.9%) as a white solid. TLC: PE / EA = 5:1, UV Rf (compound 2) = 0.2

[0432] Step 2: 2-(N-methylmethylsulfonamido)-N-(4-((6,6,6- trifluorohexyl)sulfonyl)phenyl)benzamide To the solution of 2-(N-methylmethylsulfonamido)-N-(4-((6,6,6- trifluorohexyl)thio)phenyl)benzamide (100 mg, 0.21 mmol) in DCM (6 mL) was added m- CPBA (73 mg, 0.42 mmol) at 0°C and the solution was stirred at room temperature overnight It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product 2-(N- methylmethylsulfonamido)-N-(4-((6,6,6-trifluorohexyl)sulfonyl)phenyl)benzamide (53.4 mg, Y: 50.3%) as a white solid.1H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.62 (t, J = 6.3 Hz, 3H), 7.56 – 7.47 (m, 1H), 3.30 – 3.22 (m, 5H), 3.00 (s, 3H), 2.27 – 2.10 (m, 2H), 1.64 – 1.52 (m, 2H), 1.50 – 1.34 (m, 4H). MS(ESI) calculated for C21H25F3N2O5S2, 506.12; found, 507.1.WSGR Ref: 60134-707.601 Example 12: N-(4-((3-cyclopropylpropyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamidemethylmethylsulfonamido)benzamide To the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (311 mg, 0.92 mmol) in MeCN (8 mL) were added K2CO3 (254 mg, 1.84 mmol) and (3- bromopropyl)cyclopropane (150 mg, 0.92 mmol), the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product N-(4-((3- cyclopropylpropyl)thio)phenyl)-2-(N-methylmethylsulfonamido)benzamide (200 mg, Y:52.0%) as a white solid. TLC: PE / EA = 5:1, UV Rf(compound 2) = 0.2

[0434] Step 2 N-(4-((3-cyclopropylpropyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide To the solution of N-(4-((3-cyclopropylpropyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (100 mg, 0.21 mmol) in DCM (6 mL) was added m- CPBA (73 mg, 0.42 mmol) at 0°C and the solution was stirred at room temperature overnight It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product N-(4-((3- cyclopropylpropyl)sulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide (95.3 mg, Y: 45.0%) as a white solid.1H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.62 (dd, J = 8.9, 5.7 Hz, 3H), 7.51 (dd, J = 7.9, 3.6 Hz, 1H), 3.26 (s, 5H), 3.01 (s, 3H), 1.69 – 1.56 (m, 2H), 1.23 (dd, J = 14.6, 7.2 Hz, 2H), 0.63 (s, 1H), 0.37 (d, J = 1.7 Hz, 2H), -0.03 (dd, J = 4.9, 1.3 Hz, 2H). MS(ESI) calculated for C21H26N2O5S2, 450.13; found, 451.1.WSGR Ref: 60134-707.601 Example 13: (R)-3-(3-aminopyrrolidin-1-yl)-N-(6-(heptylsulfonyl)pyridazin-3- yl)benzamideyl)carbamoyl)phenyl)pyrrolidin-3-yl)carbamate To a solution of 1-((N-methylmethylsulfonamido)methyl)cyclopropane-1-carboxylic acid (400 mg, 1.78mmol) in MeCN (10 mL) were added TCFH (1.5 g, 5.34mmol) and NMI (1.2 g, 14.24mmol), the mixture was stirring for 10 min. Then tert-butyl 4-((4- aminophenyl)sulfonyl)piperazine-1-carboxylate (818 mg, 2.67 mmol) was added. The reaction mixture was stirred at ambient temperature for another 1 h. After the reaction was completed, it was concentrated and purified with silica column (eluted with ethyl acetate: petroleum ether =1:1) to give the product tert-butyl (R)-(1-(3-((6-(heptylthio)pyridazin-3- yl)carbamoyl)phenyl)pyrrolidin-3-yl)carbamate (500 mg) as a white solid. TLC: PE / EA = 1:1, UV Rf = 0.5

[0436] Step 2: tert-butyl (R)-(1-(3-((6-(heptylsulfonyl)pyridazin-3- yl)carbamoyl)phenyl)pyrrolidin-3-yl)carbamate To the solution of ethyl tert-butyl (R)-(1-(3-((6-(heptylthio)pyridazin-3- yl)carbamoyl)phenyl)pyrrolidin-3-yl)carbamate (100 mg, 0.19 mmol) in DCM (2 mL) was added m-CPBA (98 mg, 0.57 mmol) at 0°C, then mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with DCM, then the aqueous phase was acidified with aqueous to give product tert-butyl (R)-(1-(3-((6-(heptylsulfonyl)pyridazin-3- yl)carbamoyl)phenyl)pyrrolidin-3-yl)carbamate. LCMS: Rt = 1.45 min, [M+1]+=546

[0437] Step 3: (R)-3-(3-aminopyrrolidin-1-yl)-N-(6-(heptylsulfonyl)pyridazin-3- yl)benzamideWSGR Ref: 60134-707.601 To the solution of (R)-(1-(3-((6-(heptylsulfonyl)pyridazin-3-yl)carbamoyl)phenyl)pyrrolidin-3- yl)carbamate (100 mg, 0.2 mmol) in DCM (4 mL) was added TFA (1 mL) at 25°C. The mixture was stirred at room temperature for 1 h. The mixture was extracted with DCM and H2O. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with DCM / MeOH = 20:1 to give a crude product. Then the crude product was purified by prep. HPLC to give product (R)-3-(3-aminopyrrolidin-1-yl)-N-(6-(heptylsulfonyl)pyridazin-3- yl)benzamide (17 mg,17% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.73 – 8.64 (m, 2H), 8.37 (d, J = 8.1 Hz, 1H), 8.18 (d, J = 9.3 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 4.30 – 4.17 (m, 1H), 4.04 (dd, J = 7.3, 4.2 Hz, 1H), 3.76 – 3.65 (m, 1H), 3.63 – 3.55 (m, 1H), 3.42 (t, J = 9.1 Hz, 2H), 3.24 – 3.12 (m, 1H), 3.08 – 2.96 (m, 1H), 2.73 (dd, J = 27.0, 15.7 Hz, 1H), 1.80 – 1.67 (m, 2H), 1.50 – 1.32 (m, 2H), 1.25 (dd, J = 12.7, 6.1 Hz, 6H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C22H31N5O3S, 445.58; found, 446.1. Example 14: N-(6-(heptylsulfonyl)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine- 2-carboxamidepyrrolo[3,4-b]pyridine-6-carboxylate To the solution of 6-(heptylthio)pyridazin-3-amine (220 mg, 0.83 mmol), 6-(tert- butoxycarbonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-carboxylic acid (375 mg, 1.66 mmol), TCFH (351 mg, 1.24 mmol), NMI (239 mg, 2.90 mmol) and MeCN (20 mL), the reaction solution was stirred at room temperature for 2 hours. After completion, the solvent was removed under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel and eluted with EA: PE=20%~30% to afford product tert-butyl 2- ((6-(heptylthio)pyridazin-3-yl)carbamoyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (312.5 mg, Y:79%) as a yellow solid. LCMS: Rt = 2.350 min, [M+H]+= 472.0. TLC: PE / EA = 3:1, UVWSGR Ref: 60134-707.601 Rf = 0.8

[0439] Step 2: tert-butyl 2-((6-(heptylsulfonyl)pyridazin-3-yl)carbamoyl)-5,7-dihydro- 6H-pyrrolo[3,4-b]pyridine-6-carboxylate To the solution of tert-butyl 2-((6-(heptylthio)pyridazin-3-yl)carbamoyl)-5,7-dihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxylate (255.6mg, 0.54 mmol), m-CPBA (262 mg, 1.62 mmol) and DCM (25 mL), the reaction solution was stirred at room temperature for 2 hours. After completion, the reaction mixture was extracted with DCM (20 mL) and washed with 2% Sodium thiosulfate aqueous solution (20 mL), the combined organic layer was washed with brine and dried over sodium sulfate. Then filtered, the filtrate was concentrated and the resulting residue was purified by flash column chromatography on silica gel and eluted with EA: PE=40%~60% to afford product tert-butyl 2-((6-(heptylsulfonyl)pyridazin-3-yl)carbamoyl)-5,7-dihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxylate (188.9 mg, Y:69%) as a white solid. LCMS: Rt = 1.823 min, [M+H]+= 504.1. TLC: PE / EA = 1:1, UV Rf = 0.6

[0440] Step 3: N-(6-(heptylsulfonyl)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-2-carboxamide To the solution of tert-butyl 2-((6-(heptylsulfonyl)pyridazin-3-yl)carbamoyl)-5,7-dihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxylate (188.9 mg, 0.37 mmol) in DCM (10 mL) was added trifluoroacetic acid (2 mL) and stirred at room temperature for 1 h. It was concentrated under vacuum. The mixture was adjusted pH = 7~8 by Na2CO3, extracted with DCM (20 mL), washed with brine, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give product N-(6-(heptylsulfonyl)pyridazin-3-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridine-2-carboxamide (130 mg crude). The crude was purified by reverse phase prepration (ACN / 0.1% HCl H2O as the mobile phase) to afford product N-(6- (heptylsulfonyl)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-carboxamide (73.9 mg, 97.18% purity, Y:49%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.23 (s, 2H), 8.79 (d, J = 9.3 Hz, 1H), 8.40 (d, J = 9.3 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 4.69 (d, J = 22.2 Hz, 4H), 3.63-3.54 (m, 2H), 1.65 (p, J = 7.6 Hz, 2H), 1.36 (p, J = 7.2, 6.8 Hz, 2H), 1.30-1.14 (m, 6H), 0.89-0.79 (m, 3H). MS (ESI) calculated for C19H25N5O3S, 403.17; found, 404.2. TLC: DCM / MeOH = 40:1, UV Rf = 0.6WSGR Ref: 60134-707.601 Example 15: N-(4-((2-hydroxyheptyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamidemethylmethylsulfonamido)benzamide To the solution of N-(4-mercaptophenyl)-2-(N-methylmethylsulfonamido)benzamide (250 mg, 0.74 mmol) in dioxane and H2O (2 mL / 2 mL) were added Bu3P (15 mg, 0.074 mmol) and 2- pentyloxirane (100 mg, 0.74 mmol) and the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =5:1) to give product N-(4-((2-hydroxyheptyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (165 mg, Y:49.5%) as a colorless oil. TLC: PE / EA = 5:1, UV Rf(compound 2) = 0.2

[0442] Step 2: N-(4-((2-hydroxyheptyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide To the solution of N-(4-((2-hydroxyheptyl)thio)phenyl)-2-(N- methylmethylsulfonamido)benzamide (165 mg, 0.36 mmol) in DCM (6 mL) was added m- CPBA (126 mg, 0.72 mmol) at 0°C and the solution was stirred at room temperature overnight It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the crude product was purified by prep. HPLC(CH3CN / H2O) to give product N-(4-((2- hydroxyheptyl)sulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide (93.1 mg, Y: 53.7%) as a white solid.1H NMR (400 MHz, DMSO) δ 10.68 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.62 (t, J = 6.1 Hz, 3H), 7.55 – 7.47 (m, 1H), 4.81 (d, J = 6.0 Hz, 1H), 3.94 – 3.77 (m, 1H), 3.31 – 3.28 (m, 2H), 3.26 (s, 3H), 3.01 (s, 3H), 1.57 – 1.39 (m, 1H), 1.23 (s, 7H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C22H30N2O6S2, 482.15; found, 483.2.WSGR Ref: 60134-707.601 Example 16: N-(4-(heptylsulfonimidoyl)phenyl)-3-(piperazin-1-yl)benzamideTo a mixture of methyl 3-bromobenzoate (2 g, 9.3 mmol), tert-butyl piperazine-1-carboxylate (1.82 g, 9.765 mmol), Pd(OAc)2(209 mg, 0.93 mmol), BINAP (579 mg, 0.930 mmol) and Cs2CO3 (6.06 g, 18.6 mmoL) was added toluene (20 mL) , the mixture was degassed under vaccum, purged with Ar several times, and then heated to 100°C and stirred overnight. The mixture was filtered and the filter cake washed with toluene, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=0~8 / 92) to give product (2.8 g, 93.8% yield) as a yellow solid. LCMS: Rt = 1.621 min, [M+1-56]+= 265

[0444] Step 2: 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid To a solution of tert-butyl 4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.8 g, 8.723 mmol) in MeOH (70 mL) was added a solution of NaOH (1.4 g, 34.895 mmol) in H2O (23 mL), the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, the residue was neutralized with HCl, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was concentrated under reduced pressure to give product (2.63 g, 98.4% yield) as a yellowish solid. LCMS: Rt = 1.561 min, [M+1-56]+= 251

[0445] Step 3: tert-butyl 4-(3-((4-(heptylthio)phenyl)carbamoyl)phenyl)piperazine-1- carboxylate To a solution of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (274 mg, 0.895 mmol) in ACN (20 mL) were added 4-(heptylthio)aniline (200 mg, 0.895 mmol), TCFH (377 mg, 1.343WSGR Ref: 60134-707.601 mmol) and NMI (146 mg, 1.79 mmol), the mixture was stirred for 3h at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / DCM=0~10 / 90) to give product (480 mg, 94.5% yield) as a white solid. LCMS: Rt = 2.347 min, [M+1-56]+= 456

[0446] Step 4: tert-butyl 4-(3-((4- (heptylsulfonimidoyl)phenyl)carbamoyl)phenyl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3-((4-(heptylthio)phenyl)carbamoyl)phenyl)piperazine-1- carboxylate (330 mg, 0.645mmol) in MeOH (10 mL) were added (NH4)2CO3(124 mg, 1.29 mmol ) and [bis(acetoxy)iodo]benzene (519 mg, 1.613 mmol), the mixture was stirred for 2 h at 25°C. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (10% MeOH in DCM / DCM=0~15 / 85) to give product (220 mg, 62.9% yield) as a white solid. LCMS: Rt =1.801 min, [M+1]+= 543

[0447] Step 5: N-(4-(heptylsulfonimidoyl)phenyl)-3-(piperazin-1-yl)benzamide To a solution of tert-butyl 4-(3-((4-(heptylsulfonimidoyl)phenyl)carbamoyl)phenyl)piperazine- 1-carboxylate (21.2 mg, 0.039 mmol) in DCM (1 mL) was added TFA (0.2 mL), the mixture was stirred for 1h at 20°C. The mixture was concentrated under reduced pressure, the residue was added DCM, and washed with NaHCO3(aq.), the organic layer was dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by prep- HPLC to give product (79.1 mg, 44.1% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.04 – 7.93 (m, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.43 (s, 1H), 7.40 – 7.31 (m, 2H), 7.16 (d, J = 6.7 Hz, 1H), 4.07 (s, 1H), 3.12 (dd, J = 9.3, 4.2 Hz, 4H), 3.08 (d, J = 8.1 Hz, 2H), 2.92 – 2.75 (m, 4H), 1.56 – 1.44 (m, 2H), 1.29 – 1.13 (m, 8H), 0.82 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for: C24H34N4O2S, 442.2; found [M+H]+, 443.2.WSGR Ref: 60134-707.601 Example 17: N-(4-(heptylsulfonimidoyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide

[0448] Step 1: N-(4-(heptylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide 2-(N-methylmethylsulfonamido)benzoic acid (462 mg, 2.015 mmol) was dissolved into SOCl2(2 mL) in a 50 mL bottom flask, the mixture was heated to 80°C and stirred for 2 h. Then the mixture was concentrated under reduced pressure, the residue was added to a solution of 4- (heptylthio)aniline (300 mg, 1.344mmol) and TEA (679 mg, 6.715 mmol) in DCM (10 mL), the mixture was stirred for 1h at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=0~30 / 70) to give product (584 mg, 100% yield) as a white solid. LCMS: Rt = 1.796 min, [M+1]+=435

[0449] Step 2: N-(4-(heptylsulfonimidoyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide To a solution of N-(4-(heptylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide (560 mg, 1.289 mmol) in MeOH (20 mL) were added CH3COONH4 (199 mg, 2.578 mmol ) and [bis(acetoxy)iodo]benzene (1.04 g, 3.221 mmol), the mixture was stirred for 3h at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (10% MeOH in DCM / DCM=0~20 / 80) and prep-HPLC to give product (176.7 mg, 29.4% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.9 Hz, 2H), 7.66 – 7.56 (m, 3H), 7.54 – 7.46 (m, 1H), 4.05 (s, 1H), 3.25 (s, 3H), 3.12 – 3.04 (m, 2H), 3.01 (s, 3H), 1.58 – 1.41 (m, 2H), 1.30 – 1.12 (m, 8H), 0.83 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for: C22H31N3O4S2, 465.2; found [M+H]+, 466.2.WSGR Ref: 60134-707.601 Example 25 (R)-N-(4-(heptylsulfonimidoyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide:

[0450] 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.65 – 7.57 (m, 3H), 7.54 – 7.47 (m, 1H), 4.05 (s, 1H), 3.25 (s, 3H), 3.11 – 3.04 (m, 2H), 3.01 (s, 3H), 1.50 (dd, J = 15.6, 8.1 Hz, 2H), 1.28 – 1.12 (m, 8H), 0.83 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C22H31N3O4S2,465.2; found, 466.2. SFC retention time: 2.00 min. HPLC retention time: 4.908 min. Example 26 (S)-N-(4-(heptylsulfonimidoyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide:

[0451] 1H NMR (400 MHz, DMSO-d6) δ10.62 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.65 – 7.57 (m, 3H), 7.55 – 7.46 (m, 1H), 4.06 (s, 1H), 3.26 (s, 3H), 3.12 – 3.04 (m, 2H), 3.01 (s, 3H), 1.59 – 1.43 (m, 2H), 1.31 – 1.12 (m, 8H), 0.83 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C22H31N3O4S2,465.2; found, 466.2. SFC retention time: 2.713 min. HPLC retention time: 4.905 min. SFC method: Instrument: UPCC (Waters) Column: Daicel OZ-3 (4.6*100mm, 3.0 µm) Temperature: 40 ºC Mobile phase: CO2 / MeOH = 60:40 Flow rate: 3 mL / min Back pressure: 2000 psi HPLC method: Waters Acquity UPLC – BEH C18 (2.1*150mm, 1.7 µm) Mobile phase A: 0.05% TFA in water Mobile phase B: Acetonitrile Gradient Program: Time (min) MP A (%) MP B (%)WSGR Ref: 60134-707.601 9.5 90 10Column temperature: 40 ºC Flow rate: 0.4 mL / min Detector: DAD Wavelength: Range: 210-410 nm; channel: 214 nm, 254 nm, 280 nm Runtime: 10 min. Example 18: N-(6-(heptylsulfonimidoyl)pyridazin-3-yl)-2-(N- methylmethylsulfonamido)benzamide2-(N-methylmethylsulfonamido)benzoic acid was dissolved in SOCl2 (10 mL), then the mixture was stirred at 80°C for 2 h. The reaction mixture was concentrated for the subsequent step without further purification.

[0453] Step 2: N-(6-bromopyridazin-3-yl)-2-(N-methylmethylsulfonamido)benzamide To the solution of 6-bromopyridazin-3-amine (1 g, 4.4 mmol) in DCM (10 mL) was added pyridine (0.7mL, 8.8 mmol), then the solution of 2-(N-methylmethylsulfonamido)benzoyl chloride (765.6m g, 4.4 mmol) in DCM (2 mL) was added dropwise at room temperature and the solution was stirred at room temperature overnight. It was poured into water, extracted with ethyl acetate, the combined organic layer was washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:1) to give N-(6-bromopyridazin-3-yl)-2-(N- methylmethylsulfonamido)benzamide (500 mg, Y:51.5%) as a white solid.

[0454] Step 3: N-(6-(heptylthio)pyridazin-3-yl)-2-(N- methylmethylsulfonamido)benzamideWSGR Ref: 60134-707.601 To a 250 mL bottom flask were added N-(6-bromopyridazin-3-yl)-2-(N- methylmethylsulfonamido)benzamide (500 mg, 1.3 mmol), heptane-1-thiol (206 mg, 1.56 mmol), Pd2(dba)3(64 mg, 0.07 mmol), DPPF (144 mg, 0.26 mmol), DIEA (0.6 mL, 3.9mmol) and dioxane (15 mL) under argon atmosphere. The mixture was heated to 110°C and stirred for 12 h. The reaction was concentrated by vacuo. The reside was purified by flash column chromatography on silica gel (eluted with PE / EA = 0%) to give product N-(6- (benzylthio)pyridazin-3-yl)-2-(N-methylmethylsulfonamido)benzamide (400 mg, 80% yield) as an orange solid. LCMS: Rt = 2.5 min, [M+1]+=437.

[0455] Step 4: N-(6-(heptylsulfonimidoyl)pyridazin-3-yl)-2-(N- methylmethylsulfonamido)benzamide To a solution of N-(6-(heptylthio)pyridazin-3-yl)-2-(N-methylmethylsulfonamido)benzamide (150 mg, 0.34 mmol) in MeOH (10 mL) was added (NH4)2CO3(65.3 mg, 0.68 mmol) and phenyl-l3-iodanediyl diacetate(273.8 mg, 0.85 mmol).The mixture was stirred for 2h at 25°C. The reaction was concentrated under reduced pressure,the reside was purified by flash column chromatography on silica gel (eluted with MeOH / DCM = 10 / 1) to give product N-(6- (heptylsulfonimidoyl)pyridazin-3-yl)-2-(N-methylmethylsulfonamido)benzamide (76.7 mg, 51% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.60 (d, J = 9.3 Hz, 1H), 8.29 (d, J = 9.3 Hz, 1H), 7.70 – 7.63 (m, 3H), 7.54 – 7.46 (m, 1H), 3.43 – 3.35 (m, 1H), 3.31 (d, J = 11.3 Hz, 3H), 2.98 (s, 3H), 1.64 – 1.57 (m, 2H), 1.36 – 1.14 (m, 8H), 0.83 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C20H29N5O4S2, 467.17; found, 468.1. Example 19: N-(4-(heptylsulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamideWSGR Ref: 60134-707.601 To a mixture of 4-nitrobenzenethiol (1 g, 6.445 mmol), 1-bromoheptane (1.21 g, 6.764 mmol), KI (107 mg, 0.644 mmol) and K2CO3(2.67 g, 19.324 mmol) was added DMF (15 mL), then the mixture was heated to 85℃ and stirred for 2 hours. The mixture was added water, extracted with EtOAc, the combined organic layer was washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (EtOAc / PE=0~3 / 97) to give product (1.54g, 94.5% yield) as a yellow solid. LCMS: Rt =2.221 min, [M+H]+= 254.1.

[0457] Step 2: 4-(heptylthio)aniline To a solution of heptyl(4-nitrophenyl)sulfane (1.54 g, 5.289 mmol) in EtOH (75 mL) and H2O (25 mL) were added Fe (2.95 g, 52.89 mmol) and NH4Cl (2.83 g, 52.89 mmol), the mixture was heated to 70℃ and stirred for 2 hours. The mixture was filtered and the filtrate was added water, extracted with EtOAc, the combined organic layer was washed with brine, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=0~15 / 85) to give product (1.3 g, 100% yield) as a white solid. LCMS: Rt =1.738 min, [M+H]+= 224.

[0458] Step 3: N-(4-(heptylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide 2-(N-methylmethylsulfonamido)benzoic acid (462 mg, 2.015 mmol) was dissolved into SOCl2(2 mL) in a 50 mL bottom flask, the mixture was heated to 80℃ and stirred for 1 hour. Then the mixture was concentrated under reduced pressure, the residue was added to a solution of 4- (heptylthio)aniline (300 mg, 1.344 mmol) and TEA (679mg, 6.715 mmol) in DCM (10 mL), the mixture was stirred for 1 hours at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=0~30 / 70) to give product (450 mg, 77.1% yield) as a white solid.

[0459] Step 4: N-(4-(heptylsulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide To a solution of N-(4-(heptylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide (450 mg, 1.2 mmol) in DCM (10 mL) was m-CPBA (621 mg, 3.6 mmol) at 0℃, the mixture was stirred for 2 hours at room temperature. The mixture was added water, extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was concentrated under reduced pressure, the residue was purified by prep HPLC to give product (168 mg, 30.1% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ10.70 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.88 – 7.80 (m, 2H), 7.65 – 7.58 (m, 3H), 7.55 – 7.47 (m, 1H), 3.26 (s, 3H), 3.23 (d, J = 7.9 Hz, 2H), 3.00 (s, 3H), 1.53 (dt, J = 15.4, 7.5 Hz, 2H), 1.36 – 1.26 (m, 2H), 1.26 – 1.11 (m, 6H), 0.84 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for: C22H30N2O5S2, 466.2; found [M+H]+, 467.2WSGR Ref: 60134-707.601 Example 20: N-(4-(((2-ethoxyethoxy)methyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide

[0460] Step 1: (chloromethyl)(4-nitrophenyl)sulfane To the solution of methyl(4-nitrophenyl)sulfane (5 g, 29.55 mmol) in DCE (10 mL) was added N-Chlorosuccinimide (4.74 g, 35.46 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, then purified by silica column (elute with ethyl acetate: petroleum ether =1:10) to give product (chloromethyl)(4-nitrophenyl)sulfane (4.43 g, yield: 73.6% ) as a yellow solid. TLC: PE / EA = 10:1, UV 254 nm Rf = 0.65 LCMS: Rt = 1.674 min, [M+H]+= 204.0.

[0461] Step 2: ((2-ethoxyethoxy)methyl)(4-nitrophenyl)sulfane To the solution of 2-ethoxyethan-1-ol (1.80 g, 19.92 mmol) in DMF (30 mL) was added NaH (996 mg, 24.9 mmol) at 0oC portion wise under N2atmosphere. The resulting mixture was stirred at 0oC for 1.5 hours and then (chloromethyl)(4-nitrophenyl)sulfane (3.38 g, 16.6 mmol) was added portion wise at 0oC. The mixture was stirred at toom temperature overnight. The reaction mixture was quenched with water, extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, then purified with silica column (elute with ethyl acetate: petroleum ether = 1:7) to give product ((2-ethoxyethoxy)methyl)(4- nitrophenyl)sulfane (430 mg, purity:70 %, yield: 10% ) as a yellow oilWSGR Ref: 60134-707.601 TLC: PE / EA = 10:1, UV 254 nm Rf = 0.6

[0462] Step 3: 1-(((2-ethoxyethoxy)methyl)sulfonyl)-4-nitrobenzene To a solution of ((2-ethoxyethoxy)methyl)(4-nitrophenyl)sulfane (409 mg, 70% purity, 1.59 mmol) in DCM (4 mL) was added m-CPBA (822 mg, 4.77 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with DCM and water. The combined organic phase was washed with brine, dried over sodium sulfate, then purified with silica column (elute with ethyl acetate: petroleum ether = 35:65) to give product 1- (((2-ethoxyethoxy)methyl)sulfonyl)-4-nitrobenzene (305 mg, yield: 95 % ) as a peal yellow solid. TLC: PE / EA = 5:1, UV 254 nm Rf = 0.6

[0463] Step 4: 4-(((2-ethoxyethoxy)methyl)sulfonyl)aniline A mixture of 1-(((2-ethoxyethoxy)methyl)sulfonyl)-4-nitrobenzene (305 mg, 1.054 mmol), Fe (589 mg, 10.54 mmol) and saturated ammonium chloride solution (12 mL) in ethanol (12 mL) was stirred at 60oC overnight. The suspension was filtered through a pad of celite and the pad was washed with ethanol. The combined filtrates were concentrated in vacuo and then purified with silica column (elute with ethyl acetate: petroleum ether =85:15) to give product 4-(((2- ethoxyethoxy)methyl)sulfonyl)aniline (245 mg, Y: 89.6% ) as a yellow solid. TLC: PE / EA = 5:1, UV 254nm. Rf = 0.3

[0464] Step 5: N-(4-(((2-ethoxyethoxy)methyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide A mixture of 2-(N-methylmethylsulfonamido)benzoic acid (283 mg, 1.16 mmol) in sulfoxide chloride (4 mL) was stirred at 80oC under N2 for 2 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (2 mL) and then added to a mixture of 4-(((2-ethoxyethoxy)methyl)sulfonyl)aniline (150 mg, 0.58 mmol) and TEA (293 mg, 2.89 mmol) in DCM (4 mL) dropwise. The reaction mixture was quenched with water, extracted with DCM. The combined organic phase was washed with brine, dried over sodium sulfate, then purified with silica column (elute with ethyl acetate: petroleum ether = 73:27) to give crude product, it was further purified by reverse phase chromatography on silica gel (eluted with acetonitrile:H2O=1:1) to give product N-(4-(((2-ethoxyethoxy)methyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide (120.7 mg, yield: 44 % ) as a white solid.WSGR Ref: 60134-707.6011H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.66 – 7.58 (m, 3H), 7.54 – 7.48 (m, 1H), 4.82 (s, 2H), 3.87 – 3.82 (m, 2H), 3.47 – 3.43 (m, 2H), 3.38 (q, J = 7.0 Hz, 2H), 3.26 (s, 3H), 3.00 (s, 3H), 1.09 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C20H26N2O7S2, 471.1; found, 471.1. TLC: PE / EA = 0:1, UV 254 nm Rf = 0.75 Example 21: N-(4-((7-aminoheptyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide4-nitrobenzenethiol (212 mg, 1.36 mmol), tert-butyl (7-bromoheptyl)carbamate(400 mg, 1.36 mmol) was dissolved in DMF (10 mL) and NaH (109 mg, 2.72 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EtOAc and H2O. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE: EA=0-10% to give product tert-butyl (7-((4-nitrophenyl)thio)heptyl)carbamate (520 mg, 84.0%yield) as a yellow solid. TLC: PE: EA = 10:1, UV 254 nm Rf = 0.5

[0466] Step 2: tert-butyl (7-((4-nitrophenyl)sulfonyl)heptyl)carbamate tert-butyl (7-((4-nitrophenyl)thio)heptyl)carbamate (470 mg, 1.28 mmol) was dissolved in DCM (10 mL) and m-CPBA (661 mg, 3.83 mmol) was added slowly at 0oC. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EtOAc and H2O. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE: EA=0-WSGR Ref: 60134-707.601 30% to give product tert-butyl (7-((4-nitrophenyl)sulfonyl)heptyl)carbamate(450 mg, 79.7%yield) as a white solid. TLC: PE: EA = 3:1, UV 254 nm Rf = 0.5

[0467] Step 3: tert-butyl (7-((4-aminophenyl)sulfonyl)heptyl)carbamate tert-butyl (7-((4-nitrophenyl)sulfonyl)heptyl)carbamate (400 mg, 1 mmol), Fe(280 mg, 5 mmol) and NH4Cl (268 mg, 5 mmol) was dissolved in EtOH (12 mL) and H2O (4 mL) was added. The mixture was stirred at 60oC for 2 hours. The reaction mixture was filtered through a Celite pad and the filtrate cake was washed with MeOH (10 mL*3), then the filtrate was concentrated to give product tert-butyl (7-((4-aminophenyl)sulfonyl)heptyl)carbamate (430 mg, 100%yield) as a yellow solid. TLC: PE: EA = 3:1, UV 254 nm Rf = 0.4

[0468] Step 4: tert-butyl (7-((4-(2-(N- methylmethylsulfonamido)benzamido)phenyl)sulfonyl)heptyl)carbamate 2-(N-methylmethylsulfonamido) benzoic acid (353 mg, 1.538 mmol) was dissolved in SOCl2(2 mL), the mixture was stirred at 80oC for 2 hours. After the reaction was cooled down to room temperature, the mixture was concentrated and ressolved in dry DCM (2 mL). tert-butyl (7-((4- aminophenyl)sulfonyl)heptyl)carbamate (380 mg, 1.026 mmol) and TEA (310 mg, 3.09 mmol) was dissolved in dry DCM (20 mL). The solution of hypochlorous 2-(N- methylmethylsulfonamido)benzoic anhydride was added slowly. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EtOAc and H2O. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE:EtOAc=0-20% to give product N-(5-bromopyrimidin-2-yl)-2-(N- methylmethylsulfonamido)benzamide (420 mg, 70.4%yield) as a yellow solid. TLC: PE: EA = 3:1, UV 254 nm Rf = 0.6

[0469] Step 5: N-(4-((7-aminoheptyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide tert-butyl (7-((4-(2-(N-methylmethylsulfonamido)benzamido)phenyl)sulfonyl)heptyl)carbamate (380 mg, 0.65 mmol) was dissolved in DCM (10 mL) and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 h. The mixture was neutralized with NaHCO3(aq) to pH=8, and extracted with EA and H2O. The organic phase was concentrated and purified by prep. HPLC to give product N-(4-((7-aminoheptyl)sulfonyl)phenyl)-2-(N- methylmethylsulfonamido)benzamide as a white solid (49.8 mg, 16.0% yield).WSGR Ref: 60134-707.6011H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 7.94 – 7.82 (m, 5H), 7.59 (td, J = 7.6, 1.9 Hz, 1H), 7.56 – 7.51 (m, 1H), 7.37 (dd, J = 7.8, 1.2 Hz, 1H), 3.29 (s, 3H), 3.13 (s, 3H), 3.10 – 3.04 (m, 2H), 2.67 (t, J = 7.0 Hz, 2H), 1.72 – 1.66 (m, 2H), 1.42 (d, J = 6.8 Hz, 2H), 1.36 (dd, J = 12.5, 6.4 Hz, 2H), 1.29 (d, J = 6.8 Hz, 4H). MS(ESI) calculated for C22H31N3O5S2, 481.17; found, 482.1 Example 22: N-(4-(heptylsulfinyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide- 2-(N-methylmethylsulfonamido)benzoic acid (462 mg, 2.015 mmol) was dissolved into SOCl2(2 mL) in a 50 mL bottom flask, the mixture was heated to 80℃ and stirred for 2 h. Then the mixture was concentrated under reduced pressure, the residue was added to a solution of 4- (heptylthio)aniline (300 mg, 1.344mmol) and TEA (679 mg, 6.715 mmol) in DCM (10 mL), the mixture was stirred for 1h at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE = 0 ~ 30 / 70) to give the desired product (584 mg, 100% yield) as a white solid. LCMS: Rt = 1.796 min, [M+1]+=435.2

[0471] Step 2: N-(4-(heptylsulfinyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide To a solution of N-(4-(heptylthio)phenyl)-2-(N-methylmethylsulfonamido)benzamide (200 mg, 0.46mmol) in MeOH (10 mL) were added CH3COONH4 (53 mg, 0.69 mmol ) and [bis(acetoxy)iodo]benzene (371 mg, 1.15 mmol), the mixture was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (10% MeOH in DCM / DCM = 0 ~ 20 / 80) and prep-HPLC to give the desired product (11 mg, 5.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.66 – 7.56 (m, 5H), 7.54 – 7.46 (m, 1H), 3.25 (s, 3H), 3.01 (s, 3H), 2.89 (ddd, J = 13.2, 9.2, 6.1 Hz, 1H), 2.80 – 2.71WSGR Ref: 60134-707.601 (m, 1H), 1.61 (dt, J = 14.9, 9.2 Hz, 1H), 1.50 – 1.39 (m, 1H), 1.39 – 1.29 (m, 2H), 1.29 – 1.18 (m, 6H), 0.85 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C22H30N2O4S2, 450.2; found [M+H]+, 451.2. Example 23: N-(6-(heptylsulfonyl)pyridazin-3-yl)-2-(N- methylmethylsulfonamido)benzamide

[0472] Step 1: N-(6-(heptylthio)pyridazin-3-yl)-2-(N- methylmethylsulfonamido)benzamide The solution of N-(6-chloropyridazin-3-yl)-2-(N-methylmethylsulfonamido)benzamide (400 mg, 1.17 mmol), heptane-1-thiol (186 mg, 1.41 mmol), potassium iodide (19 mg, 0.117 mmol) and potassium carbonate (40 mg, 2.90 mmol) in i-PrOH (10 mL) was stirred at 100oC via microwave irradiation for 10 hours. The reaction mixture was concentrated under vacuum, and the residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:1) to give product methyl N-(6-(heptylthio)pyridazin-3-yl)-2-(N- methylmethylsulfonamido)benzamide (245 mg, yield:47.8%) as a white solid. TLC: PE / EA = 3:1, UV 254 nm Rf = 0.25 LCMS: Rt = 1.935 min, [M+1]+= 437.2.

[0473] Step 2: N-(6-(heptylsulfonyl)pyridazin-3-yl)-2-(N- methylmethylsulfonamido)benzamide The solution of N-(6-(heptylthio)pyridazin-3-yl)-2-(N-methylmethylsulfonamido)benzamide (245 mg, 0.56 mmol) in DCM (12 mL) was added m-CPBA (291 mg, 1.68 mmol), and stirred at room temperature for 1 hour. It was diluted with water, extracted with DCM, the combined organic phase was washed with brine and dried over sodium sulfate, concentrated under vacuum. And the residue was purified with silica column (elute with ethyl acetate: petroleumWSGR Ref: 60134-707.601 ether =63:37) to give crude product. It was further purified by prep-HPLC (eluted with acetonitrile:H2O (with 0.1 % NH3*H2O)=5:95~95:5) to give N-(6-(heptylsulfonyl)pyridazin-3- yl)-2-(N-methylmethylsulfonamido)benzamide (60.1 mg, yield: 22.9 %) as a white solid.1H NMR (400 MHz, DMSO) δ 11.78 (s, 1H), 8.67 (d, J = 9.2 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.67 – 7.63 (m, 2H), 7.54 – 7.48 (m, 1H), 3.62 – 3.52 (m, 2H), 3.31 (s, 3H), 2.99 (s, 3H), 1.70 – 1.59 (m, 2H), 1.40 – 1.30 (m, 2H), 1.30 – 1.16 (m, 6H), 0.84 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C20H28N4O5S2, 469.2; found, 469.2. TLC: PE / EA = 1:1, UV 254 nm Rf = 0.2 Example 24: 2-((Heptyl(4-(2-(N-methylmethylsulfonamido)benzamido)phenyl)(oxo)-l6- sulfanylidene)amino)acetic acid4-nitrobenzenethiol (2.0 g, 12.89 mmol) was dissolved into ACN (30 mL) in a 100 mL bottom flask, K2CO3 (2.7 mg, 19.34 mmol ) and 1-bromoheptane (2.8 g, 15.46 mmol) were added, the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was added ammonium chloride aqueous solution, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrateWSGR Ref: 60134-707.601 was concentrated under reduced pressure, and purified by silica gel chromatography (EtOAc / PE = 0 ~ 10 / 90) to give the desired product (2.8 g, 85.9% yield) as a yellow solid. LCMS: Rt = 2.306 min, [M+1]+=254.1 (weak signal).

[0475] Step 2: heptyl(imino)(4-nitrophenyl)-l6-sulfanone To a solution of heptyl(4-nitrophenyl)sulfane (2.5 g, 9.88 mmol) in MeOH (20 mL) were added ammonium carbomate (1.9 g, 24.7 mmol ) and [bis(acetoxy)iodo]benzene (6.4 g, 19.8 mmol), the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (10% MeOH in DCM / DCM = 0 ~ 30 / 70) to give the desired product (2.3 g, 81.0% yield) as a yellow solid. LCMS: Rt = 1.876 min, [M+1]+=285.1.

[0476] Step 3: tert-butyl 2-((heptyl(4-nitrophenyl)(oxo)-l6-sulfanylidene)amino)acetate To a solution of heptyl(imino)(4-nitrophenyl)-l6-sulfanone (900.0 mg, 3.17 mmol) in ACN (15 mL) were added K2CO3(874.9 mg, 6.34 mmol ) and tert-butyl 2-bromoacetate (928.0 mg, 4.76 mmol), the mixture was stirred at 80oC for 15h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (EtOAc / PE = 0 ~ 20 / 80) to give the desired product (470 mg, 37.3% yield) as a yellow solid. LCMS: Rt = 2.051 min, [M+1]+=399.2.

[0477] Step 4: tert-butyl 2-(((4-aminophenyl)(heptyl)(oxo)-l6- sulfanylidene)amino)acetate To a solution of tert-butyl 2-((heptyl(4-nitrophenyl)(oxo)-l6--sulfanylidene)amino)acetate (420 mg, 1.06 mmol) in EtOH (12 mL) and H2O (4 mL) were added Fe (295.5 mg, 5.28 mmol) and NH4Cl (282.3 mg, 5.28 mmol), the mixture was heated to 60℃ and stirred for 4 h. The mixture was filtered and the filtrate was added water, extracted with EtOAc, the combined organic layer was washed with brine, the filtrate was concentrated under reduced pressure to give product (370 mg, 95.3% yield) as a white solid. LCMS: Rt =1.702 min, [M+H]+= 369.2.

[0478] Step 5: tert-butyl tert-butyl 2-((heptyl(4-(2-(N- methylmethylsulfonamido)benzamido)phenyl)(oxo)-l6-sulfanylidene)amino)acetate 2-(N-methylmethylsulfonamido)benzoic acid (115 mg, 0.5 mmol) was dissolved into SOCl2(2 mL) in a 50 mL bottom flask, the mixture was heated to 80℃ and stirred for 2 h. Then the mixture was concentrated under reduced pressure, the residue was added to a solution of tert- butyl 2-((heptyl(4-nitrophenyl)(oxo)-l6-sulfanylidene)amino)acetate (160 mg, 0.435 mmol) and TEA (87.9 mg, 0.87 mmol) in DCM (5 mL), the mixture was stirred for 1h at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=0~40 / 60) to give product (155 mg, 61.5% yield) as a yellow solid.WSGR Ref: 60134-707.601 LCMS: Rt =1.816 min, [M+H]+= 580.3.

[0479] Step 6: 2-((heptyl(4-(2-(N-methylmethylsulfonamido)benzamido)phenyl)(oxo)-l6- sulfanylidene)amino)acetic acid To a solution of tert-butyl tert-butyl 2-((heptyl(4-(2-(N- methylmethylsulfonamido)benzamido)phenyl)(oxo)-l6-sulfanylidene)amino)acetate (155 mg, 0.27 mmol) in DCM (5 mL) was added TFA (2 mL), the mixture was stirred for 6h at room temperature. The mixture was added water, adjust pH to 3-4 with NaHCO3 aqueous, extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, and purified by prep.HPLC to give product (50.6 mg, 35.8% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.68 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.61 (t, J = 5.2 Hz, 3H), 7.54 – 7.47 (m, 1H), 3.54 – 3.39 (m, 2H), 3.26 (s, 3H), 3.23 (s, 2H), 3.01 (s, 3H), 1.53 (ddd, J = 21.6, 13.4, 7.0 Hz, 2H), 1.31 – 1.09 (m, 8H), 0.83 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C24H33N3O6S2, 523.2; found [M+H]+, 524.3. Example 27 N-(4-((3S)-3-methylheptylsulfonimidoyl)phenyl)-2-(N-methylmethylsulfonamido)-5- (piperazin-1-yl)benzamideWSGR Ref: 60134-707.601 To a solution of (R)-hexan-2-ol (3 g, 29.4 mmol) in DCM (30 mL) were added TsCl (6.73 g, 35.3 mmol), DMAP (0.72 g, 5.9 mmol) and TEA (3.86 g, 38.2 mmol), the mixture was stirred overnight at room temperature under Ar. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=5:95) to give product (3.5 g, 47% yield) as a white solid.

[0481] Step 2: dimethyl (S)-2-(hexan-2-yl)malonate To a solution of (R)-hexan-2-yl 4-methylbenzenesulfonate (3.5 g, 16.2 mmol) in DMF (50 mL) were added dimethyl malonate (10.69 g, 81 mmol) and NaH (3.24 g, 81 mmol) , the mixture was stirred for 5 hour at 90oC under Ar. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EA / PE=5:95) to give product (1.69 g, 48% yield) as a white solid.

[0482] Step 3: (S)-2-(hexan-2-yl)malonic acid To a solution of dimethyl (S)-2-(hexan-2-yl)malonate (1.7 g, 7.82 mmol) in MeOH (30 mL) were added NaOH (1.56 g, 39.12 mmol) in H2O (10 mL) , the mixture was stirred for 1 hour at 70oC under Ar. The mixture was concentrated under reduced pressure to give product (1.47 g, crude) as a white solid.

[0483] Step 4: (S)-3-methylheptanoic acid To a solution of (S)-2-(hexan-2-yl)malonic acid (1.47 g, 7.82 mmol) in xylenes (10 mL), the mixture was stirred for overnight at 140oC. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EA / PE=1:1) to give product (806 mg, 55% yield) as a white solid.

[0484] Step 5: (S)-3-methylheptan-1-ol To a solution of (S)-3-methylheptanoic acid (806 mg, 5.6 mmol) in THF (10 mL), was added LiAlH4(532 mg, 14 mmol).The mixture was stirred overnight at room temperature. The mixture was added Na2SO4H2O at 0oC and stirred for 1 h. The mixture was filtered to give product (728 mg, crude) as a white solid.

[0485] Step 6: (S)-3-methylheptyl methanesulfonate To a solution of (S)-3-methylheptan-1-ol (728 mg, 5.64 mmol) in DCM (10 mL) were added MsCl (1.93 g, 16.9 mmol), and TEA (1.71 g, 16.9 mmol), the mixture was stirred overnight at room temperature. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure to give product (1.13 g, 97% yield) as a white solid.

[0486] Step 7: (S)-4-((3-methylheptyl)thio)anilineWSGR Ref: 60134-707.601 To a solution of (S)-3-methylheptyl methanesulfonate (1.13 g, 5.47 mmol) in MeOH (10 mL) were added 4-aminobenzenethiol (3.42 g, 27.37 mmol) and K2CO3(2.26 g, 16.4 mmol), the mixture was stirred overnight at 60oC. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=5:1) to give product (671 mg, 52% yield) as a white solid. LCMS: Rt =1.81 min, [M+1]+=238

[0487] Step 8: tert-butyl (S)-4-(3-((4-((3-methylheptyl)thio)phenyl)carbamoyl)-4-(N- methylmethylsulfonamido)phenyl)piperazine-1-carboxylate To a solution of (S)-4-((3-methylheptyl)thio)aniline (335 mg, 1.42 mmol) in ACN (10 mL) were added 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(N-methylmethylsulfonamido)benzoic acid (492 mg, 1.42 mmol), TCFH (793 mg, 2.83 mmol) and NMI (348 mg, 4.25 mmol), the mixture was stirred 2 h at room temperature. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=5:1) to give product (692 mg, 77% yield) as a white solid. LCMS: Rt =2.31 min, [M+1]+= 633

[0488] Step 9: tert-butyl 4-(3-((4-((3S)-3-methylheptylsulfonimidoyl)phenyl)carbamoyl)- 4-(N-methylmethylsulfonamido)phenyl)piperazine-1-carboxylate To a solution of tert-butyl (S)-4-(3-((4-((3-methylheptyl)thio)phenyl)carbamoyl)-4-(N- methylmethylsulfonamido)phenyl)piperazine-1-carboxylate (692 mg, 1.1 mmol) in MeOH (5mL) were added [bis(acetoxy)iodo]benzene (706 mg, 2.2 mmol) and (NH4)2CO3(127 mg, 1.32 mmol), the mixture was stirred 0.5 h at room temperature. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (MeOH / DCM=1:100) to give product (292 mg, 40% yield) as a white solid. LCMS: Rt =1.72 min, [M+1]+=664 Step 10: N-(4-((3S)-3-methylheptylsulfonimidoyl)phenyl)-2-(N-methylmethylsulfonamido)-5- (piperazin-1-yl)benzamide To a solution of tert-butyl 4-(3-((4-((3S)-3-methylheptylsulfonimidoyl)phenyl)carbamoyl)-4-(N- methylmethylsulfonamido)phenyl)piperazine-1-carboxylate (292 mg, 0.44 mmol) in DCM (10 mL) was added TFA (2 mL), the mixture was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by gel chromagraphy (MeOH / DCM=100:1) and Prep-HPLC (ACN:H2O:HCl=12:20:1) to give the product (79.8 mg, yield: 32%) as a white solid.WSGR Ref: 60134-707.601 LCMS: Rt =1.31 min, [M+1]+= 564.1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.37 (s, 2H), 8.12 – 8.05 (m, 4H), 7.49 (d, J = 9.4 Hz, 1H), 7.22 – 7.17 (m, 2H), 4.51 (s, 1H), 4.02 (dt, J = 15.2, 7.5 Hz, 2H), 3.54 – 3.48 (m, 4H), 3.22 (s, 3H), 3.21 – 3.14 (m, 4H), 2.96 (s, 3H), 1.71 – 1.36 (m, 3H), 1.25 – 1.05 (m, 6H), 0.86 – 0.79 (m, 6H). MS(ESI) calculated for C27H41N5O4S2, 563.26; found, 563.78. Example 28 N-(4-((3R)-3-methylheptylsulfonimidoyl)phenyl)-2-(N-methylmethylsulfonamido)-5- (piperazin-1-yl)benzamideTo a solution of (S)-hexan-2-ol (3 g, 29.4 mmol) in DCM (30 mL) were added TsCl (6.73 g, 35.3 mmol), DMAP (0.72 g, 5.9 mmol) and TEA (3.86 g, 38.2 mmol), the mixture was stirred overnight at room temperature under Ar. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=5:95) to give product (4.86 g, 65% yield) as a white solid.

[0490] Step 2: dimethyl (R)-2-(hexan-2-yl)malonate To a solution of (S)-hexan-2-yl 4-methylbenzenesulfonate (4.86 g, 18.98 mmol) in DMF (50 mL) were added dimethyl malonate (12.53 g, 94.92 mmol) and NaH (3.8 g, 94.92 mmol) , the mixture was stirred for 5 hour at 90oC under Ar. The mixture was added water, and extractedWSGR Ref: 60134-707.601 with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EA / PE=5:95) to give product (1.96 g, 48% yield) as a white solid.

[0491] Step 3: (R)-2-(hexan-2-yl)malonic acid To a solution of dimethyl (R)-2-(hexan-2-yl)malonate (959 mg, 4.4 mmol) in MeOH (18 mL) were added NaOH (880 mg, 22 mmol) in H2O (6 mL) , the mixture was stirred for 1 hour at 70oC under Ar. The mixture was concentrated under reduced pressure to give product (800 mg, crude) as a white solid.

[0492] Step 4: (R)-3-methylheptanoic acid To a solution of (R)-2-(hexan-2-yl)malonic acid (800 mg, 4.26 mmol) in xylenes (10 mL), the mixture was stirred for overnight at 140oC. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EA / PE=1:1) to give product (320 mg, 52% yield) as a white solid.

[0493] Step 5: (R)-3-methylheptan-1-ol To a solution of (R)-3-methylheptanoic acid (320 mg, 2.2 mmol) in THF (10 mL), was added LiAlH4(211 mg, 5.56 mmol).The mixture was stirred overnight at room temperature. The mixture was added Na2SO4 H2O at 0oC and stirred for 1 h. The mixture was filtered to give product (309 mg, crude) as a white solid.

[0494] Step 6: (R)-3-methylheptyl methanesulfonate To a solution of (R)-3-methylheptan-1-ol (309 mg, 2.38 mmol) in DCM (5 mL) were added MsCl (814 mg, 7.14 mmol), and TEA (721 mg, 7.14 mmol), the mixture was stirred overnight at room temperature. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure to give product (495 mg, crude) as a white solid.

[0495] Step 7: (R)-4-((3-methylheptyl)thio)aniline To a solution of (R)-3-methylheptyl methanesulfonate (495 mg, 2.38 mmol) in MeOH (5 mL) were added 4-aminobenzenethiol (1.58 g, 12.65 mmol) and K2CO3(1 g, 7.59 mmol), the mixture was stirred overnight at 60oC. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=5:1) to give product (387 mg, 65% yield) as a white solid. LCMS: Rt =1.80 min, [M+1]+=238

[0496] Step 8: tert-butyl (R)-4-(3-((4-((3-methylheptyl)thio)phenyl)carbamoyl)-4-(N- methylmethylsulfonamido)phenyl)piperazine-1-carboxylateWSGR Ref: 60134-707.601 To a solution of (R)-4-((3-methylheptyl)thio)aniline (194 mg, 0.82 mmol) in ACN (5 mL) were added 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(N-methylmethylsulfonamido)benzoic acid (339 mg, 0.82 mmol), TCFH (459 mg, 1.64 mmol) and NMI (202 mg, 2.46 mmol), the mixture was stirred 2 h at room temperature. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=5:1) to give product (449 mg, 87% yield) as a white solid. LCMS: Rt =2.33 min, [M+1]+= 633

[0497] Step 9: tert-butyl 4-(3-((4-((3R)-3-methylheptylsulfonimidoyl)phenyl)carbamoyl)- 4-(N-methylmethylsulfonamido)phenyl)piperazine-1-carboxylate To a solution of tert-butyl (R)-4-(3-((4-((3-methylheptyl)thio)phenyl)carbamoyl)-4-(N- methylmethylsulfonamido)phenyl)piperazine-1-carboxylate (449 mg, 0.71 mmol) in MeOH (5mL) were added [bis(acetoxy)iodo]benzene (456 mg, 1.42 mmol) and (NH4)2CO3(68 mg, 0.71 mmol), the mixture was stirred 0.5 h at room temperature. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (MeOH / DCM=1:100) to give product (142 mg, 60% yield) as a white solid. LCMS: Rt =1.71 min, [M+1]+= 664

[0498] Step 10: N-(4-((3R)-3-methylheptylsulfonimidoyl)phenyl)-2-(N- methylmethylsulfonamido)-5-(piperazin-1-yl)benzamide To a solution of tert-butyl 4-(3-((4-((3R)-3-methylheptylsulfonimidoyl)phenyl)carbamoyl)-4-(N- methylmethylsulfonamido)phenyl)piperazine-1-carboxylate (142 mg, 0.21 mmol) in DCM (2 mL) was added TFA (0.5 mL), the mixture was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by gel chromagraphy (MeOH / DCM=1:100) and Prep-HPLC ( ACN:H2O:HCl=12:20:1) to give the product (34 mg, yield: 29%) as a white solid. LCMS: Rt =1.32 min, [M+1]+= 5641H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.17 (s, 2H), 8.06 (q, J = 9.1 Hz, 4H), 7.49 (d, J = 9.1 Hz, 1H), 7.21 – 7.16 (m, 2H), 3.87 (s, 1H), 3.65 (s, 2H), 3.49 (s, 4H), 3.22 (s, 3H), 3.21 (s, 4H), 2.96 (s, 3H), 1.67 – 1.35 (m, 3H), 1.26 – 1.06 (m, 6H), 0.83 (dd, J = 14.1, 6.8 Hz, 6H). MS(ESI) calculated for:C27H41N5O4S2, 563.2, found, 564.2 Example 29 5-((3S,4S)-4-amino-3-methoxypiperidin-1-yl)-N-(4-(((R)-5-methylheptyl)sulfonyl)phenyl)- 2-(N-methylmethylsulfonamido)benzamideWSGR Ref: 60134-707.6011- carboxylate To a solution of tert-butyl (3S,4S)-4-amino-3-hydroxypiperidine-1-carboxylate (250 mg, 1.157 mmol) in DCM (10 mL) were added CbzCl (197.27 mg, 1.157 mmol) and NaHCO3(2 ml)at room temperature. The mixture was stirred for 1h at room temperature. The mixture was added some water, and extracted with DCM, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (MeOH / DCM=1 / 99) to give product (350 mg, 70.3% yield) as a yellow oil.

[0500] Step 2: tert-butyl (3S,4S)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidine- 1-carboxylate To a solution of tert-butyl (3S,4S)-4-(((benzyloxy)carbonyl)amino)-3-hydroxypiperidine-1- carboxylate (350 mg, 0.999 mmol) in ACN (15 mL) were added dimethyl sulfate (125.87 mg, 0.999 mmol) 50% NaOH (3 ml) and Benzyltrimethylammonium chloride(18.55 mg, 0.1 mmol) at room temperature. The mixture was stirred for 3h at 60℃. The mixture was added some water, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (EA / PE=10 / 90) to give product (320 mg, 81.5% yield) as a yellow oil. LCMS: Rt =1.763 min, [M+1]+=365.1

[0501] Step 3: benzyl ((3S,4S)-3-methoxypiperidin-4-yl)carbamateWSGR Ref: 60134-707.601 To a solution of tert-butyl (3S,4S)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidine-1- carboxylate (320 mg, 0.877 mmol) in DCM (10 mL) were added TFA (999.78 mg, 8.77 mmol) at room temperature. The mixture was stirred for 12h at room temperature. The mixture was added some NaHCO3, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (MeOH / DCM=1 / 99) to give product (120 mg, 54.2% yield) as a yellow oil. LCMS: Rt =1.036 min, [M+1]+=265.1

[0502] Step 4: methyl 5-((3S,4S)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidin-1- yl)-2-(N-methylmethylsulfonamido)benzoate To a solution of benzyl ((3S,4S)-3-methoxypiperidin-4-yl)carbamate (120 mg, 0.455 mmol) in 1,4-Dioxane (8 mL) were added methyl 5-bromo-2-(N-methylmethylsulfonamido)benzoate (146.51 mg, 0.455 mmol) RuphosPdG4(39.12 mg, 0.046 mmol) and Cs2CO3(296.66 mg, 0.91 mmol) at room temperature. The mixture was stirred for 12h at 100℃. The mixture was added some NH4Cl, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (MeOH / DCM=1 / 99) to give product (150 mg, 42.8% yield) as a yellow oil. LCMS: Rt =1.683 min, [M+1]+=506.1

[0503] Step 5: 5-((3S,4S)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidin-1-yl)-2- (N-methylmethylsulfonamido)benzoic acid To a solution of methyl 5-((3S,4S)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidin-1-yl)-2- (N-methylmethylsulfonamido)benzoate (150 mg, 0.297 mmol) in THF (6 mL) were added LiOH (124.74 mg, 2.97 mmol) at room temperature. The mixture was stirred for 12h at room temperature. The mixture was added some 10%HCl, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (MeOH / DCM=1 / 99) to give product (120 mg, 80.6% yield) as a yellow solid. LCMS: Rt =1.263 min, [M+1]+=492.1

[0504] Step 6: benzyl ((3S,4S)-3-methoxy-1-(3-((4-(((R)-5- methylheptyl)thio)phenyl)carbamoyl)-4-(N-methylmethylsulfonamido)phenyl)piperidin-4- yl)carbamate To a solution of 5-((3S,4S)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidin-1-yl)-2-(N- methylmethylsulfonamido)benzoic acid (120 mg, 0.244 mmol) in Py (5 mL) were added POCl3 (56.18 mg, 0.366 mmol) at 0℃. The mixture was stirred for 2h at room temperature. TheWSGR Ref: 60134-707.601 mixture was added some 10%HCl, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (MeOH / DCM=1 / 99) to give product (90 mg, 53.7% yield) as a yellow oil. LCMS: Rt =2.206 min, [M+1]+=711.1

[0505] Step 7: (3S,4S)-4-(((benzyloxy)carbonyl)amino)-3-methoxy-1-(3-((4-(((R)-5- methylheptyl)sulfonyl)phenyl)carbamoyl)-4-(N-methylmethylsulfonamido)phenyl)piperidine 1- oxide To a solution of benzyl ((3S,4S)-3-methoxy-1-(3-((4-(((R)-5- methylheptyl)thio)phenyl)carbamoyl)-4-(N-methylmethylsulfonamido)phenyl)piperidin-4- yl)carbamate (90 mg, 0.127 mmol) in DCM (4 mL) were added m-CPBA (77.32 mg, 0.381 mmol) at 0℃. The mixture was stirred for 1h at room temperature. The mixture was added some NaHCO3, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (MeOH / DCM=1 / 99) to give product (50 mg, 61.7% yield) as a yellow oil. LCMS: Rt =1.632 min, [M+1]+=759.1

[0506] Step 8: benzyl ((3S,4S)-3-methoxy-1-(3-((4-(((R)-5- methylheptyl)sulfonyl)phenyl)carbamoyl)-4-(N-methylmethylsulfonamido)phenyl)piperidin-4- yl)carbamate To a solution of (3S,4S)-4-(((benzyloxy)carbonyl)amino)-3-methoxy-1-(3-((4-(((R)-5- methylheptyl)sulfonyl)phenyl)carbamoyl)-4-(N-methylmethylsulfonamido)phenyl)piperidine 1- oxide (50 mg, 0.066 mmol) in ACN (5 mL) were added B(pin)2(25.15 mg, 0.099 mmol) at room temperature. The mixture was stirred for 1h at room temperature. The mixture was added some NaHCO3, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (MeOH / DCM=1 / 99) to give product (30 mg, 70.5% yield) as a yellow oil. LCMS: Rt =1.935 min, [M+1]+=743.1

[0507] Step 9: 5-((3S,4S)-4-amino-3-methoxypiperidin-1-yl)-N-(4-(((R)-5- methylheptyl)sulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide To a solution of benzyl ((3S,4S)-3-methoxy-1-(3-((4-(((R)-5- methylheptyl)sulfonyl)phenyl)carbamoyl)-4-(N-methylmethylsulfonamido)phenyl)piperidin-4- yl)carbamate (30 mg, 0.040 mmol) in MeOH (4 mL) were added Pd / C (15 mg)at room temperature. The mixture was stirred for 2h at room temperature. The mixture was added someWSGR Ref: 60134-707.601 NaHCO3, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by prep-HPLC to give product (5 mg, 23.4% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.9 Hz, 2H), 7.38 (d, J = 8.7 Hz, 1H), 7.18 – 7.06 (m, 2H), 4.00 (dd, J = 12.3, 3.9 Hz, 1H), 3.70 (d, J = 12.4 Hz, 1H), 3.41 (s, 3H), 3.24 (s, 2H), 3.19 (s, 3H), 2.95 (s, 3H), 2.90 (dt, J = 9.1, 4.5 Hz, 1H), 2.86 – 2.76 (m, 1H), 2.64 – 2.53 (m, 1H), 1.82 (dd, J = 13.0, 4.2 Hz, 1H), 1.52 – 1.48 (m, 2H), 1.43 (d, J = 4.2 Hz, 2H), 1.24 (tt, J = 15.4, 5.1 Hz, 5H), 1.10 – 1.01 (m, 2H), 0.85 – 0.75 (m, 6H). MS(ESI) calculated for: C29H44N4O6S2, 401.18; found [M+H]+, 609.1 Example 30 5-((3S,4R)-4-amino-3-methoxypiperidin-1-yl)-N-(4-(((R)-5-methylheptyl)sulfonyl)phenyl)- 2-(N-methylmethylsulfonamido)benzamide1-carboxylate To a solution of ethyl tert-butyl (3S,4R)-4-amino-3-methoxypiperidine-1-carboxylate (400 mg, 1.74 mmol) and NaHCO3(292 mg, 3.48 mmol) in THF (5 mL) and H2O (5 mL) were added CbzCl (323 mg, 1.91 mmol). The reaction mixture was stirred at ambient temperature for 1 h. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organicWSGR Ref: 60134-707.601 phase was concentrated in vacuo and purified by flash chromatography eluted with PE / EA=1:2 to give the product tert-butyl (3S,4R)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidine-1- carboxylate (620 mg, yield :95.3% yield) as white solid. LCMS: Rt = 1.780 min, [M+H]+=309.1.

[0509] Step 2: benzyl ((3S,4R)-3-methoxypiperidin-4-yl)carbamate To the solution of tert-butyl (3S,4R)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidine-1- carboxylate (620 mg, 1.70 mmol) in DCM (4 mL) was added TFA (2 mL) into the mixture and the solution was stirred at room temperature for 2 h. The reaction mixture was quenched with H2O, extracted with DCM and washed with saturated brine. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to get the reside. The reside was purified with silica column (elute with ethyl acetate: petroleum ether =3:1) to give Product benzyl ((3S,4R)-3-methoxypiperidin-4-yl)carbamate (400 mg, yield: 89.2%) as white solid. LCMS: Rt = 1.062 min, [M+H]+=265.2.

[0510] Step 3: methyl 5-((3S,4R)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidin-1- yl)-2-(N-methylmethylsulfonamido)benzoate To the solution of methyl 5-bromo-2-(N-methylmethylsulfonamido)benzoate (200 mg, 0.75 mmol) in dioxane (6 mL) were added benzyl ((3S,4R)-3-methoxypiperidin-4-yl)carbamate (243 mg, 0.75 mmol), RuphosPdG4 (64 mg, 0.075 mmol), Cs2CO3(488 mg, 1.50 mmol) and the solution was stirred at 100℃ over night. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum. The residue was purified with silica column (elute with ethyl acetate: petroleum ether =1:1) to give product methyl 5-((3S,4R)- 4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidin-1-yl)-2-(N- methylmethylsulfonamido)benzoate (126 mg, yield:33.33%) as a white solid. LCMS: Rt = 1.937 min, [M+H]+=506.2.

[0511] Step 4: 5-((3S,4R)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidin-1-yl)-2- (N-methylmethylsulfonamido)benzoic acid To a 100 mL bottom flask were added methyl 5-((3S,4R)-4-(((benzyloxy)carbonyl)amino)-3- methoxypiperidin-1-yl)-2-(N-methylmethylsulfonamido)benzoate (116 mg, 0.023 mmol), NaOH (37 mg, 0.92 mmol), THF (2 mL) and H2O (2 mL) at 30°C. Then the reaction mixture was stirred at ambient temperature for 2 h. After the reaction was completed, the mixture was adjusted pH = 5~6 by 10%HCl and extracted with DCM. The combined organic extract was washed with brine, dried with Na2SO4, filtered and concentrated to give crude product 5-WSGR Ref: 60134-707.601 ((3S,4R)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidin-1-yl)-2-(N- methylmethylsulfonamido)benzoic acid (100 mg) as a yellow solid. LCMS: Rt = 1.588 min, [M+H-100]+=492.3.

[0512] Step 5: benzyl ((3S,4R)-3-methoxy-1-(3-((4-(((R)-5- methylheptyl)thio)phenyl)carbamoyl)-4-(N-methylmethylsulfonamido)phenyl)piperidin-4- yl)carbamate 5-((3S,4R)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidin-1-yl)-2-(N- methylmethylsulfonamido)benzoic acid (80 mg, 0.17 mmol) was dissolved into SOCl2 (2 mL) in a 50 mL bottom flask, the mixture was heated to 80℃ and stirred for 1 hour. Then the mixture was concentrated under reduced pressure, the residue was added to a solution of (R)-4-((5- methylheptyl)thio)aniline (35 mg, 0.16 mmol) and TEA (51 mg, 0.51 mmol) in DCM (5 mL), the mixture was stirred for 1 hours at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc / PE=1:1) to give produc...

Claims

WSGR Ref: 60134-707.601 CLAIMS We claim:

1. A compound of Formula (I-a-0),or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; wherein B is substituted with one or more substituent selected from the group consisting of3-aminopiperidin-1-yl, optionally substituted 4-aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of B are substituted by the divalent group consisting of ;WSGR Ref: 60134-707.601 L is -N(Rj)-, -C(Rn)2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3- C6 carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6- membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3- C6carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; W is N or C-R; X is N or C-R; Y is N or C-R; Z is N or C-R; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3 alkyl;WSGR Ref: 60134-707.601 or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1- C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted -(C1-C3 alkylene)-NH(C1-C6 alkyl), optionally substituted C4- C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl; provided the compound is not2. A compound of Formula (I-a),WSGR Ref: 60134-707.601or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; wherein B is substituted with one or more substituent selected from the group consisting ofby the divalent group consisting of ; L is -N(Rj)-, -C(Rn)2-, or -O-;RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH;WSGR Ref: 60134-707.601 or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3- C6carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6- membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3- C6carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; W is N or C-R; X is N or C-R; Y is N or C-R; Z is N or C-R; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1- C10alkyl), optionally substituted -(C1-C3alkylene)-N(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl; provided the compound is notWSGR Ref: 60134-707.6013. A compound of Formula (I-b-0),or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted 4- to 6-membered heterocyclyl; wherein B is substituted with one or more substituent selected from the group consistingWSGR Ref: 60134-707.6013-aminopiperidin-1-yl, optionally substituted 4-aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of B are substituted by the divalent group consisting of L is2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3- C6carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; each Rmis independently optionally substituted C1-C3alkyl;WSGR Ref: 60134-707.601 or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6- membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3- C6 carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; W is N or C-R; X is N or C-R; Y is N or C-R; Z is N or C-R; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5alkyl; each R9is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1- C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted -(C1-C3alkylene)-NH(C1-C6alkyl), optionally substituted C4- C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted 4-membered carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl; provided the compound of Formula (I-b-0) is not .

4. A compound of Formula (I-b),WSGR Ref: 60134-707.601or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted 4- to 6-membered heterocyclyl; wherein B is substituted with one or more substituent selected from the group consistingsubstituted 3-aminopyrrolidin-1-yl, andor two adjacent atoms of B are substituted by the divalent group consisting of L is2-, or -O-; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPindependently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH;WSGR Ref: 60134-707.601 or two Rkgroups attached to the same carbon atom are optionally cyclized to form a C3- C6carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6- membered heterocyclyl; each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a C3- C6carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; W is N or C-R; X is N or C-R; Y is N or C-R; Z is N or C-R; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1- C10alkyl), optionally substituted -(C1-C3alkylene)-N(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted 4-membered carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C- heterocyclyl.

5. A compound of Formula (II-a),WSGR Ref: 60134-707.601or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; X is N or C-R; W is N or C-R; Y is N or C-R; Z is N or C-R; wherein at least one of W, X, Y, and Z is N; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5alkyl; each R9is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1- C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

6. A compound of Formula (II-b),WSGR Ref: 60134-707.601or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted 4- to 6-membered heterocyclyl; X is N or C-R; W is N or C-R; Y is N or C-R; Z is N or C-R; wherein at least one of W, X, Y, and Z is N; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5alkyl; each R9is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RLis optionally substituted C5-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1- C10 alkyl), optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

7. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein B is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted 4 to 6-membered heterocyclyl.

8. The compound of claim 5 or claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein B is optionally substituted aryl, optionally substituted heteroaryl,WSGR Ref: 60134-707.601 optionally substituted carbocyclyl, or optionally substituted 4 to 6-membered C- heterocyclyl.

9. The compound of any one of claims 5-7, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C5-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

10. The compound of any one of claims 5-8, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C5-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3alkylene)-N(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4 to 6-membered C-heterocyclyl.

11. A compound of claim 5, wherein the compound is a compound of Formula (II-c),or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl;WSGR Ref: 60134-707.601 or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1- C10 alkyl), optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

12. A compound of claim 11, wherein the compound is a compound of Formula (II-d),or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted 4- to 6-membered heterocyclyl; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1- C10alkyl), optionally substituted -(C1-C3alkylene)-N-(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

13. A compound of claim 11, wherein the compound is a compound of Formula (II-e),WSGR Ref: 60134-707.601or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O or N-R1; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1- C10alkyl), optionally substituted -(C1-C3alkylene)-N-(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

14. A compound of Formula (III), or a pharmaceuticallywherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;WSGR Ref: 60134-707.601 W is N or C-R; X is N or C-R; Y is N or C-R; Z is N or C-R; each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3alkyl; R1is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8is optionally substituted C1-C5 alkyl; each R9is independently hydrogen or optionally substituted C1-C3alkyl; or two R9groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1- C10alkyl), optionally substituted -(C1-C3alkylene)-N-(C1-C3alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3alkylene)-N-(C1-C3alkyl)(heteroaryl), optionally substituted -(C1-C3 alkylene)-NH(C1-C6 alkyl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted C4-C10carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

16. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted C4-C10carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.WSGR Ref: 60134-707.601 17. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3alkylene)-N-(C1-C3alkyl)(heteroaryl), optionally substituted -(C1-C3 alkylene)-NH(C1-C6 alkyl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted C5-C10carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

18. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted C5-C10carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted carbocyclyl.

20. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 3- to 6-membered carbocyclyl.

21. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 3-membered carbocyclyl.

22. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4-membered carbocyclyl.

23. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5-membered carbocyclyl.

24. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 6-membered carbocyclyl.

25. The compound of any one of claims 1, 2, 5, 9-11, or 13-18, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4- to 8- membered heterocyclyl.WSGR Ref: 60134-707.601 26. The compound of claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4- to 8-membered C-heterocyclyl.

27. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4 to 6-membered heterocyclyl.

28. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4 to 6-membered C-heterocyclyl.

29. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5-membered C-heterocyclyl.

30. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted pyrrolidinyl.

31. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted pyrazolidinyl.

32. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 6-membered C-heterocyclyl.

33. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted heteroaryl.

34. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5-membered heteroaryl.

35. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted pyrazolyl, optionally substituted thiazolyl, or optionally substituted triazolyl.

36. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 6-membered heteroaryl.

37. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted pyridinyl.

38. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 9-membered heteroaryl.WSGR Ref: 60134-707.601 39. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted pyrazolopyrimidinyl.

40. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 10-membered heteroaryl.

41. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted aryl.

42. The compound of claim 41, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted phenyl.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:optionally substituted 4-aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.

44. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:WSGR Ref: 60134-707.6011-yl.

45. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: .

46. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

47. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; L is -N(Rj)-, -C(Rn)2-, or -O-; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each Rjis hydrogen or -CH3; each Rnis independently hydrogen, -F, -Cl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3.

48. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, or optionally substituted C2-C5 alkynyl; each Rjis independently hydrogen or -CH3.WSGR Ref: 60134-707.601 49. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; RSis optionally substitutedeach Rjis independently hydrogen or -CH3.

50. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; RSis -CH3, -CH2F, -CHF2,-CH2NH2, or -CH2CH2NH2; Rjis hydrogen or -CH3.

51. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; RSis -CH3, -CH2F, -CHF2,-CH2NH2, or -CH2CH2NH2.

52. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

53. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; RSis -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2.

54. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:.WSGR Ref: 60134-707.601 55. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

56. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, or optionally substituted C2-C5 alkynyl.

57. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; RSis -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2.

58. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

59. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; RSis -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl.

60. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: .WSGR Ref: 60134-707.601 61. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, or optionally substituted C2-C5 alkynyl; and each Rnis independently hydrogen, -F, -Cl, or -CH3.

62. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; RSis -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2; and each Rnis independently hydrogen, -F, or -CH3.

63. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: RSis -CH3, -CH2F, -CHF2,-CH2NH2, or -CH2CH2NH2.

64. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

65. The compound of any one of claims 1-42, wherein B is substituted with one or more substituents selected from: ; RSis -ORj, or -N(Rj)2; each Rnis independently hydrogen, -F, -Cl, or -CH3; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl.WSGR Ref: 60134-707.601 66. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

67. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:, -N(CH3)-, -CH2-, or -O-; wherein each RPindependently optionally substituted C1-C3 alkyl; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl.

68. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:, -N(CH3)-, or -CH2-; wherein each RPindependently optionally substituted C1-C3 alkyl; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl.

69. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

70. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:WSGR Ref: 60134-707.601 71. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:substituted 3-aminopiperidin-1-yl, optionally substituted 4-aminopiperidin-1-yl, optionally substituted azepan-1-yl, optionally substituted diazepan-1-yl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.

72. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:1-yl.

73. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:hydrogen or -CH3.

74. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

75. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .WSGR Ref: 60134-707.601 76. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

77. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

78. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

79. he compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

80. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .WSGR Ref: 60134-707.601 81. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

82. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

83. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

84. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

85. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: ; each Rkis independently hydrogen, -F, or -CH3.WSGR Ref: 60134-707.601 86. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

87. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

88. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:hydrogen or -CH3. each Rkis independently hydrogen, -F, -Cl, -CH3, or -OH.

89. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

90. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: optionally substituted optionally substituted azetidine-1-yl.

91. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:WSGR Ref: 60134-707.601 92. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

93. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: optionally substituted 3-aminopyrrolidin-1-yl.

94. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

95. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

96. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

97. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .WSGR Ref: 60134-707.601 98. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

99. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

100. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: optionally substituted C-piperidinyl, optionally substituted 3-aminopiperidin-1-yl, and optionally substituted 4-aminopiperidin-1-yl.

101. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .The compound of any one of claims 1-33, or athereof, wherein B is substituted with one or more substituents selected from: optionally substituted piperazin-1-yl.

102. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .WSGR Ref: 60134-707.601 103. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

104. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: optionally substituted azepan-1-yl.

105. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

106. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: optionally substituted diazepan-1-yl 107. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

108. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .WSGR Ref: 60134-707.601 109. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

110. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6- membered heterocyclyl.

111. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: .

112. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein two adjacent atoms of B are substituted by the divalent group consisting of ; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl.

113. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein two adjacent atoms of B are substituted by the divalent group consisting each Rjisor optionally substituted C1-C3 alkyl;WSGR Ref: 60134-707.601 or two Rjgroups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl.

114. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein two adjacent atoms of B are substituted by the divalent group consisting<img src='' class="img-anchor img-center" img-id="IMGF000443_0001" / >115. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:WSGR Ref: 60134-707.601116. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

117. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:WSGR Ref: 60134-707.601118. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C4-C12alkyl, optionally substituted - (C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted -(C1-C3 alkylene)-NH(C1-C6 alkyl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.

119. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C4-C12alkyl, optionally substituted - (C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.

120. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C4-C12alkyl, optionally substituted C4-C12 alkenyl, or optionally substituted C4-C12 alkynyl.

121. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C5-C12alkyl, optionally substituted C5-C12alkenyl, or optionally substituted C5-C12alkynyl.

122. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C6-C12 alkyl, optionally substituted C6-C12alkenyl, or optionally substituted C6-C12alkynyl.

123. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C12 alkyl.WSGR Ref: 60134-707.601 124. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C10alkyl.

125. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted, linear C4-C10 alkyl.

126. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an unsubstituted, linear C4-C10alkyl.

127. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C12 alkenyl.

128. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C10alkenyl.

129. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C12alkynyl.

130. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C10 alkynyl.

131. The compound of any one of claims 1-2 or 5-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted carbocyclyl.

132. The compound of any one of claims 1-2 or 5-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C3-C8 carbocyclyl.

133. The compound of any one of claims 1-2 or 5-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C8carbocyclyl.

134. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 4-membered carbocyclyl.

135. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted aralkyl.

136. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted heteroarylalkyl.WSGR Ref: 60134-707.601 137. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted carbocyclylalkyl.

138. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted heterocyclylalkyl.

139. The compound of any one of claims 1-2 or 5-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C-heterocyclyl.

140. The compound of any one of claims 1-2 or 5-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 4 to 8-membered C- heterocyclyl.

141. The compound of any one of claims 1-2 or 5-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 5 to 6-membered C- heterocyclyl.

142. The compound of any one of claims 1-2 or 5-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 4 to 5-membered C- heterocyclyl.

143. The compound of any one of claims 1-2 or 5-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 4 to 6-membered C- heterocyclyl.

144. The compound of any one of claims 1-2 or 5-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 5 membered C-heterocyclyl.

145. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted oxetanyl.

146. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C-azetidinyl.

147. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted -(C1-C3alkylene)-N-(C1-C3alkyl)(heteroaryl).

148. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted -(C1-C2alkylene)-O-(C1-C10alkyl).WSGR Ref: 60134-707.601 149. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted -(C1alkylene)-O-(C1-C10alkyl).

150. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted -CH2O(C1-C10 alkyl).

151. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis selected from the group consisting of: ,152. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis selected from the group consisting of: ,, .WSGR Ref: 60134-707.601 153. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis selected from the group consisting of: ,WSGR Ref: 60134-707.601154. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis selected from the group consisting of: ,WSGR Ref: 60134-707.601155. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis selected from the group consisting of: ,WSGR Ref: 60134-707.601 156. The compound of any one of claims 1-10 or 14-155, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N.

157. The compound of any one of claims 1-10 or 14-155, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C-R.

158. The compound of any one of claims 1-10 or 14-157, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N.

159. The compound of any one of claims 1-10 or 14-157, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C-R.

160. The compound of any one of claims 1-10 or 14-159, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

161. The compound of any one of claims 1-10 or 14-159, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-R.

162. The compound of any one of claims 1-10 or 14-161, or a pharmaceutically acceptable salt or solvate thereof, wherein W is N.

163. The compound of any one of claims 1-10 or 14-161, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C-R.

164. The compound of any one of claims 1-10 or 14-155, or a pharmaceutically acceptable salt or solvate thereof, wherein165. The compound of any one of claims 1-10 or 14-155, or a pharmaceutically acceptable salt or solvate thereof, wherein166. The compound of any one of claims 1-10 or 14-155, or a pharmaceutically acceptable salt or solvate thereof, whereinWSGR Ref: 60134-707.601 167. The compound of any one of claims 1-10 or 14-155, or a pharmaceutically acceptable salt or solvate thereof, wherein168. The compound of any one of claims 1-10 or 14-155, or a pharmaceutically acceptable salt or solvate thereof, wherein169. The compound of any one of claims 1-10 or 14-155, or a pharmaceutically acceptable salt or solvate thereof, wherein170. The compound of any one of acceptable salt or solvate thereof, wherein171. The compound of any one of acceptable salt or solvate thereof, wherein each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1 alkyl.

172. The compound of any one of claims 1-170, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen, deuterium, halogen, -CN, or -CH3.

173. The compound of any one of claims 1-170, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen, deuterium, or halogen.

174. The compound of any one of claims 1-170, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen, deuterium, or chloro.

175. The compound of any one of claims 1-170, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen or deuterium.

176. The compound of any one of claims 1-12 or 14-175, or a pharmaceutically acceptable salt or solvate thereof, wherein E is absent.WSGR Ref: 60134-707.601 177. The compound of any one of claims 1-175, or a pharmaceutically acceptable salt or solvate thereof, wherein E is O.

178. The compound of any one of claims 1-175, or a pharmaceutically acceptable salt or solvate thereof, wherein E is N-R1.

179. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen.

180. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted alkyl.

181. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C5alkyl substituted with one or more group selected from -CO2H.

182. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -H, -CH2CO2H, or -CH(CH3)CO2H.

183. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH2CO2H or -CH(CH3)CO2H.

184. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH2CO2H.

185. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH(CH3)CO2H.

186. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH.

187. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -C(O)R8.

188. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -C(O)CH3.

189. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -C(O)N(R9)2.WSGR Ref: 60134-707.601 190. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -C(O)N(CH3)2.

191. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, wherein192. A compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 1 or Table 2.

193. A compound, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 1.

194. A compound, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 2.

195. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1-194 and a pharmaceutically acceptable excipient.

196. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of claims 1-194, and a pharmaceutically acceptable carrier.

197. A compound of any one of claims 1-194, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

198. A compound of any one of claims 1-194, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of infection by at least one Gram-negative pathogen.

199. Use of a compound of any one of claims 1-194, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of bacterial infection by at least one Gram-negative pathogen.

200. A method of treating bacterial infection by at least one Gram-negative pathogen in a patient in need thereof, comprising administering to the patient a compound as described in any one of claims 1-194, or pharmaceutically acceptable salt or solvate thereof.WSGR Ref: 60134-707.601 201. A method of treating bacterial infection by at least one Gram-negative pathogen in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-194, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

202. The use of claim 199, or the method of claim 200 or 201, wherein the at least one Gram- negative pathogen is selected from the group consisting of Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, Haemophilus influenzae, Neisseria gonorrhoeae, Morganella morganii, Proteus mirabilis, Yersinia pestis, Citrobacter freundii, Citrobacter koseri, Enterobacter cloacae, Serratia marcescens, Achromobacter xylosoxidans, Salmonella typhi, Salmonella enterica, Moraxella catarrhalis, Helicobacter pylori, Stenotrophomonas maltophilia, Neisseria meningitis, Burkholderia cepacian, and Stenotrophomonas maltophilia.

203. The use of claim 199, or the method of claim 200 or 201, wherein the Gram-negative pathogen is selected from the group consisting of Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Citrobacter freundii or Proteus mirabilis.

204. A method of inhibiting LpxH enzyme comprising contacting the enzyme with a compound of any one of claims 1-194 wherein the LpxH enzyme is contacted in an in vitro setting.

205. A method of inhibiting LpxH enzyme comprising contacting the enzyme with a compound of any one of claims 1-194, wherein the LpxH enzyme is contacted in an in vivo setting.

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