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: 60134-709.601 ANTIBACTERIAL COMPOUNDS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 641,795, 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), or a pharmaceutically acceptable salt or solvate thereof,(I-a) wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; 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; 1WSGR Ref: 60134-709.601 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; G is a bivalent radical selected from:*-C(R4)2-C(R5)2-N(R3)-; where the * denotes the bond to N; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl; each R6is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R6groups together form an oxo; or two R6groups together form a 3- or 4-membered carbocyclyl; or two R6groups together form 4-membered heterocyclyl; each R7is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7groups together form an oxo; or two R7groups together form a 3- or 4-membered carbocyclyl; or two R7groups together form 4-membered heterocyclyl; and R3is hydrogen or optionally substituted C1-C3 alkyl; with the proviso that B is not. 2WSGR Ref: 60134-709.601

[0005] 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-a), 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

[0006] 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

[0007] 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 intended 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

[0008] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0009] "Amino" refers to the –NH2radical.

[0010] "Cyano" refers to the -CN radical.

[0011] "Nitro" refers to the -NO2 radical.

[0012] "Oxa" refers to the -O- radical.

[0013] "Oxo" refers to the =O radical.

[0014] "Thioxo" refers to the =S radical.

[0015] "Imino" refers to the =N-H radical.

[0016] "Oximo" refers to the =N-OH radical. 3WSGR Ref: 60134-709.601

[0017] "Hydrazino" refers to the =N-NH2 radical.

[0018] "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-C15alkyl). 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-C15alkyl). In certain embodiments, an alkyl comprises six to fifteen carbon atoms (e.g., C6-C15alkyl). 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-C15alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8alkyl). 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-C2alkyl). 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-C5alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 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, - 4WSGR Ref: 60134-709.601 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.

[0019] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.

[0020] "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, and 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, 5WSGR Ref: 60134-709.601 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, 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).

[0021] "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, 6WSGR Ref: 60134-709.601 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, 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 7WSGR Ref: 60134-709.601 substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl).

[0022] "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-C8alkylene). 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., C1 alkylene). 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, - 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 8WSGR Ref: 60134-709.601 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, 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] "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., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5alkenylene). 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, 9WSGR Ref: 60134-709.601 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] "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-C8alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4alkynylene). 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., C2 alkynylene). 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-C5alkynylene). 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 10WSGR Ref: 60134-709.601 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] "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 from 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), - 11WSGR Ref: 60134-709.601 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, 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 , , , ,12WSGR Ref: 60134-709.601, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of the aryl are substituted by the divalent group consisting ofL 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 RPis independently 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-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-C6 carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0026] "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 13WSGR Ref: 60134-709.601 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.

[0027] "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.

[0028] "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.

[0029] "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.

[0030] "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, a 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 14WSGR Ref: 60134-709.601 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, 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 15WSGR Ref: 60134-709.601 indicated. In some embodiments, “Carbocyclyl” is optionally substituted with a substituentaminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of the carbocyclyl are substituted by the divalent group consisting ofL 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 RPis independently 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-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 C3-C6 carbocyclyl; 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. 16WSGR Ref: 60134-709.601 "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.

[0031] "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.

[0032] "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.

[0033] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0034] "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.

[0035] "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. The 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, - 17WSGR Ref: 60134-709.601 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 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, 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, “Heterocyclyl” is optionally substituted with a substituent 18WSGR Ref: 60134-709.6011-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of the heterocyclyl are substituted by the divalent group consisting ofL 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 RPis independently 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; 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 C3-C6 carbocyclyl; 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-C6 carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. 19WSGR Ref: 60134-709.601

[0036] "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.

[0037] "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.

[0038] "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.

[0039] "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 substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0040] "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, 20WSGR Ref: 60134-709.601 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 the 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 21WSGR Ref: 60134-709.601 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, 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 substituentaminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; 22WSGR Ref: 60134-709.601 or two adjacent atoms of the heteroaryl are substituted by the divalent group consisting ofL 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 RPis independently 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-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 C3-C6 carbocyclyl; 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.

[0041] "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.

[0042] "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 23WSGR Ref: 60134-709.601 heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0043] "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.

[0044] "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.

[0045] 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 double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0046] 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: 24WSGR Ref: 60134-709.601

[0047] The compounds disclosed herein, in some embodiments, are used in different enriched 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.

[0048] 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.

[0049] 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,13N,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.

[0050] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H 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. 25WSGR Ref: 60134-709.601

[0051] 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.

[0052] 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.

[0053] 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.

[0054] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4is illustrated, by way of example only, in the reaction schemes below.

[0055] 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.26WSGR Ref: 60134-709.601

[0056] In one embodiment, the compounds disclosed herein contain one deuterium atom. 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.

[0057] "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.

[0058] "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, 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 27WSGR Ref: 60134-709.601 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.

[0059] "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.

[0060] "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.

[0061] 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, 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.

[0062] 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 28WSGR Ref: 60134-709.601 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

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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 29WSGR Ref: 60134-709.601 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.

[0068] 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).

[0069] 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

[0070] In one aspect, provided herein is a LpxH inhibitory compound.

[0071] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein, 30WSGR Ref: 60134-709.601 B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; 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-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; G is a bivalent radical selected from: *-C(R4)2-C(R5)2-; *-C(R4)2-C(R5)2-C(R6)2-; *-C(R4)2-C(R7)2-O-; *-C(R4)2-C(R5)2-N(R3)-; where the * denotes the bond to N; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl; each R6is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; 31WSGR Ref: 60134-709.601 or two R6groups together form an oxo; or two R6groups together form a 3- or 4-membered carbocyclyl; or two R6groups together form 4-membered heterocyclyl; each R7is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7groups together form an oxo; or two R7groups together form a 3- or 4-membered carbocyclyl; or two R7groups together form 4-membered heterocyclyl; and R3is hydrogen or optionally substituted C1-C3 alkyl.

[0072] One embodiment provides a compound of Formula (I-a), or a pharmaceutically acceptable salt or solvate thereof,(I-a) wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; 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; 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 32WSGR Ref: 60134-709.601 substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl; G is a bivalent radical selected from: *-C(R4)2-C(R5)2-; *-C(R4)2-C(R5)2-C(R6)2-; *-C(R4)2-C(R7)2-O-; *-C(R4)2-C(R5)2-N(R3)-; where the * denotes the bond to N; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl; each R6is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R6groups together form an oxo; or two R6groups together form a 3- or 4-membered carbocyclyl; or two R6groups together form 4-membered heterocyclyl; each R7is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; or two R7groups together form an oxo; or two R7groups together form a 3- or 4-membered carbocyclyl; or two R7groups together form 4-membered heterocyclyl; and R3is hydrogen or optionally substituted C1-C3alkyl; with the proviso that B is not.

[0073] One embodiment provides a compound of Formula (I-b), or a pharmaceutically acceptable salt or solvate thereof, 33WSGR Ref: 60134-709.601(I-b) wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 4- to 10-membered carbocyclyl, or optionally substituted heterocyclyl; 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; G is a bivalent radical selected from:*-C(R4)2-C(R5)2-N(R3)-; where the * denotes the bond to N; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; 34WSGR Ref: 60134-709.601 or two R4groups together form a 4-membered heterocyclyl; each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl; each R6is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R6groups together form an oxo; or two R6groups together form a 3- or 4-membered carbocyclyl; or two R6groups together form 4-membered heterocyclyl; each R7is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; or two R7groups together form an oxo; or two R7groups together form a 3- or 4-membered carbocyclyl; or two R7groups together form 4-membered heterocyclyl; and R3is hydrogen or optionally substituted C1-C3alkyl.

[0074] One embodiment provides a compound of Formula (I-c), or a pharmaceutically acceptable salt or solvate thereof,(I-c) wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5- to 10-membered carbocyclyl, or optionally substituted heterocyclyl; 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; 35WSGR Ref: 60134-709.601 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 C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-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; G is a bivalent radical selected from: *-C(R4)2-C(R5)2-; *-C(R4)2-C(R5)2-C(R6)2-; *-C(R4)2-C(R7)2-O-; *-C(R4)2-C(R5)2-N(R3)-; where the * denotes the bond to N; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl; each R6is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3alkyl; or two R6groups together form an oxo; or two R6groups together form a 3- or 4-membered carbocyclyl; or two R6groups together form 4-membered heterocyclyl; each R7is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; or two R7groups together form an oxo; or two R7groups together form a 3- or 4-membered carbocyclyl; or two R7groups together form 4-membered heterocyclyl; and R3is hydrogen or optionally substituted C1-C3 alkyl.

[0075] In some embodiments, G is *-C(R4)2-C(R5)2-; where the * denotes the bond to N. 36WSGR Ref: 60134-709.601

[0076] In some embodiments, G is *-CH2-C(R5)2-; where the * denotes the bond to N.

[0077] In some embodiments, G is *-C(R4)2-CH2-; where the * denotes the bond to N.

[0078] In some embodiments, G is -CH2-CH2-.

[0079] In some embodiments, G is *-C(R4)2-C(R5)2-C(R6)2-; where the * denotes the bond to N.

[0080] In some embodiments, G is -CH2-CH2-CH2-, *-CH2-CH2-CHF-, or *-CH2-CH2-CF2-; where the * denotes the bond to N.

[0081] In some embodiments, G is -CH2-CH2-CH2-.

[0082] In some embodiments, G is *-C(R4)2-C(R7)2-O-; where the * denotes the bond to N.

[0083] In some embodiments, G is *-CH2-CH2-O-; where the * denotes the bond to N.

[0084] In some embodiments, G is *-C(R4)2-C(R5)2-N(R3)-; where the * denotes the bond to N.

[0085] In some embodiments, G is *-CH2-CH2-NH-, or *-CH2-C(=O)-NH-; where the * denotes the bond to N.

[0086] One embodiment provides a compound of Formula (II),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; 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; 37WSGR Ref: 60134-709.601 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; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; and each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl.

[0087] One embodiment provides a compound of Formula (II-a),(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; 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; 38WSGR Ref: 60134-709.601 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; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; and each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl; with the proviso that B is not .

[0088] One embodiment provides a compound of Formula (II-b),(II-b) or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 4- to 10-membered carbocyclyl, or optionally substituted heterocyclyl; 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; 39WSGR Ref: 60134-709.601 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; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; and each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl.

[0089] One embodiment provides a compound of Formula (II-c),(II-c) or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5- to 10-membered carbocyclyl, or optionally substituted heterocyclyl; X is N or C-R; Y is N or C-R; Z is N or C-R; 40WSGR Ref: 60134-709.601 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-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; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; and each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl.

[0090] In some embodiments, each R4is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; and each R5is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl.

[0091] In some embodiments, each R4is independently hydrogen, deuterium, or C1-C3alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2; and each R5is independently hydrogen, deuterium, or C1-C3alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2.

[0092] In some embodiments, each R4is independently hydrogen, deuterium, or optionally substituted C1alkyl; and each R5is independently hydrogen, deuterium, or optionally substituted C1 alkyl. 41WSGR Ref: 60134-709.601

[0093] In some embodiments, each R4is independently hydrogen, deuterium, or optionally substituted C1alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2; and each R5is independently hydrogen, deuterium, or optionally substituted C1 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2.

[0094] In some embodiments, each R4is independently hydrogen, deuterium, or -CH3; and each R5is independently hydrogen, deuterium, or -CH3.

[0095] In some embodiments, each R4is independently hydrogen or deuterium; and each R5is independently hydrogen, deuterium, or halogen. In some embodiments, each R4is independently hydrogen or deuterium; and each R5is independently hydrogen, deuterium, or fluorine.

[0096] In some embodiments, each R4is independently hydrogen or deuterium; and each R5is independently hydrogen or deuterium.

[0097] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.

[0098] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted C-heterocyclyl.

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

[0100] 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.

[0101] 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.

[0102] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 4 to 10-membered carbocyclyl, or optionally substituted 4 to 10-membered heterocyclyl.

[0103] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5 to 10-membered carbocyclyl, or optionally substituted 5 to 10-membered heterocyclyl.

[0104] 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. 42WSGR Ref: 60134-709.601

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered carbocyclyl.

[0112] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered heterocyclyl.

[0113] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered C-heterocyclyl.

[0114] In some embodiments, B is an optionally substituted aryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 5 to 8-membered heterocyclyl.

[0115] In some embodiments, B is an optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 5 to 8-membered heterocyclyl.

[0116] In some embodiments, B is an optionally substituted aryl or optionally substituted heteroaryl.

[0117] In some embodiments, B is an optionally substituted carbocyclyl.

[0118] In some embodiments, B is an optionally substituted 4- to 8-membered carbocyclyl. 43WSGR Ref: 60134-709.601

[0119] In some embodiments, B is an optionally substituted 5- to 8-membered carbocyclyl.

[0120] In some embodiments, B is an optionally substituted 5- to 6-membered carbocyclyl.

[0121] In some embodiments, B is an optionally substituted 4-membered carbocyclyl.

[0122] In some embodiments, B is an optionally substituted 5-membered carbocyclyl.

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

[0124] In some embodiments, B is an optionally substituted heterocyclyl.

[0125] In some embodiments, B is an optionally substituted 4 to 8-membered heterocyclyl.

[0126] In some embodiments, B is an optionally substituted 5 to 8-membered heterocyclyl.

[0127] In some embodiments, B is an optionally substituted 4 to 6-membered heterocyclyl.

[0128] In some embodiments, B is an optionally substituted 5 to 6-membered heterocyclyl.

[0129] In some embodiments, B is an optionally substituted 4-membered heterocyclyl.

[0130] In some embodiments, B is an optionally substituted 5-membered heterocyclyl.

[0131] In some embodiments, B is an optionally substituted 6-membered heterocyclyl.

[0132] In some embodiments, B is an optionally substituted C-heterocyclyl.

[0133] In some embodiments, B is an optionally substituted 4 to 8-membered C- heterocyclyl.

[0134] In some embodiments, B is an optionally substituted 5 to 8-membered C- heterocyclyl.

[0135] In some embodiments, B is an optionally substituted 4 to 6-membered C- heterocyclyl.

[0136] In some embodiments, B is an optionally substituted 5 to 6-membered C- heterocyclyl.

[0137] In some embodiments, B is an optionally substituted 4-membered C-heterocyclyl.

[0138] In some embodiments, B is an optionally substituted 5-membered C-heterocyclyl.

[0139] In some embodiments, B is an optionally substituted 6-membered C-heterocyclyl.

[0140] In some embodiments, B is an optionally substituted heteroaryl.

[0141] In some embodiments, B is an optionally substituted 5- to 10-membered heteroaryl. 44WSGR Ref: 60134-709.601

[0142] In some embodiments, B is an optionally substituted 6- to 10-membered heteroaryl.

[0143] In some embodiments, B is an optionally substituted 5- to 6-membered heteroaryl.

[0144] In some embodiments, B is an optionally substituted 5-membered heteroaryl.

[0145] In some embodiments, B is an optionally substituted substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, or optionally substituted thiophenyl. In some embodiments, B is an optionally substituted substituted pyrrolyl. In some embodiments, B is an optionally substituted substituted pyrazolyl. In some embodiments, B is an optionally substituted substituted imidazolyl. In some embodiments, B is an optionally substituted substituted thiophenyl.

[0146] In some embodiments, B is an optionally substituted 6-membered heteroaryl.

[0147] In some embodiments, B is an optionally substituted pyridinyl, or optionally substituted pyrimidinyl. In some embodiments, B is an optionally substituted pyridinyl. In some embodiments, B is an optionally substituted pyrimidinyl.

[0148] In some embodiments, B is an optionally substituted 9-membered heteroaryl.

[0149] In some embodiments, B is an optionally substituted pyrazolopyrimidinyl.

[0150] In some embodiments, B is an optionally substituted 10-membered heteroaryl.

[0151] In some embodiments, B is an optionally substituted aryl.

[0152] In some embodiments, B is an optionally substituted phenyl.

[0153] In some embodiments, B is not.

[0154] In some embodiments, B is not.

[0155] In some embodiments, B is not.

[0156] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: 45WSGR Ref: 60134-709.601cyano, halogen, optionally substituted morpholinyl, 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 RPis independently 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-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; 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. 46WSGR Ref: 60134-709.601

[0157] 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 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-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each RPis independently 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-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. 47WSGR Ref: 60134-709.601

[0158] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:cyano, halogen, optionally substituted morpholinyl, 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-C5alkynyl, -ORj, or -N(Rj)2; each RPis independently 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-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; 48WSGR Ref: 60134-709.601 or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0159] 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 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 RPis independently 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; 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; 49WSGR Ref: 60134-709.601 or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0160] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:optionally substituted morpholinyl, 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-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPis independently 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-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; 50WSGR Ref: 60134-709.601 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.

[0161] 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 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-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RPis independently 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-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; 51WSGR Ref: 60134-709.601 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.

[0162] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:optionally substituted morpholinyl, 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 RPis independently 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; 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.

[0163] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: 52WSGR Ref: 60134-709.601, 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-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each RPis independently 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; 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.

[0164] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:,alkyl, amino, cyano, halogen, optionally substituted morpholinyl, 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 ofL is -N(Rj)-, -C(Rn)2-, or -O-; 53WSGR Ref: 60134-709.601 RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -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.

[0165] 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 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-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.

[0166] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:optionally substituted morpholinyl; 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 Rjis independently hydrogen or optionally substituted C1-C3alkyl; 54WSGR Ref: 60134-709.601 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.

[0167] 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 -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-C3 alkyl, or -OH; each Rmis independently optionally substituted C1-C3 alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl.

[0168] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:optionally substituted morpholinyl; 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 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.

[0169] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: 55WSGR Ref: 60134-709.601L 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 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.

[0170] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:halogen, and optionally substituted morpholinyl; 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 Rjis independently hydrogen or optionally substituted C1-C3 alkyl; each Rmis independently optionally substituted C1-C3 alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl.

[0171] 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 -O-; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; each Rmis independently optionally substituted C1-C3 alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3alkyl.

[0172] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: 56WSGR Ref: 60134-709.601amino, cyano, halogen, optionally substituted morpholinyl; 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 independently hydrogen or optionally substituted C1-C3 alkyl; each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C3 alkyl.

[0173] 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 -O-; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5alkynyl, -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-C3alkyl.

[0174] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:optionally substituted morpholinyl; L is -N(Rj)-, -C(Rn)2-, or -O-; RSis optionally substituted C1-C3 alkyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C2 alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C2alkyl.

[0175] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: 57WSGR Ref: 60134-709.601L is -N(Rj)-, -C(Rn)2-, or -O-; RSis optionally substituted C1-C3 alkyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or optionally substituted C1-C2 alkyl; and each Rnis independently hydrogen, halogen, or optionally substituted C1-C2alkyl.

[0176] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:alkyl, amino, cyano, halogen, and optionally substituted morpholinyl; L is -N(Rj)-, -C(Rn)2-, or -O-; RSis optionally substituted C1-C2 alkyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or -CH3; and each Rnis independently hydrogen, halogen, or -CH3.

[0177] 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 -O-; RSis optionally substituted C1-C2alkyl, -ORj, or -N(Rj)2; each Rjis independently hydrogen or -CH3; and each Rnis independently hydrogen, halogen, or -CH3.

[0178] In some embodiments, B is substituted with one or more substituent selected from the group consisting of:amino, cyano, halogen, and optionally substituted morpholinyl; 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; 58WSGR Ref: 60134-709.601 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 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.

[0179] 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 -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; 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; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0180] In some embodiments, B is substituted with one or more substituents selected from:alkyl, amino, cyano, halogen, and optionally substituted morpholinyl.

[0181] In some embodiments, B is substituted with one or more substituents selected from:. 59WSGR Ref: 60134-709.601

[0182] In some embodiments, B is substituted with one or more substituents selected ,

[0183] In some embodiments, B is substituted with one or more substituents selected

[0184] In some embodiments, B is substituted with one or more substituents selectedfrom:

[0185] In some embodiments, B is substituted with one or more substituents selected from:.

[0186] In some embodiments, B is substituted with one or more substituents selected from:.

[0187] In some embodiments, B is substituted with one or more substituents selected from:.

[0188] 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; 60WSGR Ref: 60134-709.601 each Rjis hydrogen or -CH3; and each Rnis independently hydrogen, -F, -Cl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3.

[0189] In some embodiments, B is substituted with one or more substituents selected from: ; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5alkynyl; and each Rjis independently hydrogen or -CH3.

[0190] 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.

[0191] In some embodiments, B is substituted with one or more substituents selected from: ; RSis -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2; and Rjis hydrogen or -CH3.

[0192] 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, or -CF3.

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

[0194] 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, - 61WSGR Ref: 60134-709.601 CH2F, -CHF2, or -CF3. In some embodiments, RSis -CH3. In some embodiments, RSis - CF3. In some embodiments, RSis -CHF2. In some embodiments, RSis -CH2F.

[0195] In some embodiments, B is substituted with one or more substituents selectedfrom:. In some embodiments, B is substituted with one or more substituents selectedfrom:some embodiments, Bis substituted with one or more substituents selected from:.

[0196] In some embodiments, B is substituted with one or more substituents selectedfrom:In some embodiments, B is substituted with one or more substituents selected from:

[0197] In some embodiments, B is substituted with one or more substituents selected from: ; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl. In some embodiments RSis -CH3, -CH2F, -CHF2, -CF3, - CH2OCH3, -CH2NH2, or -CH2CH2NH2.

[0198] In some embodiments, B is substituted with one or more substituents selected from:. 62WSGR Ref: 60134-709.601

[0199] 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.

[0200] 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.

[0201] 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.

[0202] In some embodiments, B is substituted with one or more substituents selected from:.

[0203] 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. each Rnis independently hydrogen, -F, -Cl, or -CH3.

[0204] 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. 63WSGR Ref: 60134-709.601

[0205] 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, or -CF3.

[0206] In some embodiments, B is substituted with one or more substituents selected from:.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] In some embodiments, B is substituted with one or more substituents selected. 64WSGR Ref: 60134-709.601

[0211] In some embodiments, B is substituted with one or more substituents selected from:L is -NH-, -N(CH3)-, -CH2-, or -O-; wherein each RPis independently optionally substituted C1-C3alkyl; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl.

[0212] In some embodiments, B is substituted with one or more substituents selected from: ; L is -NH-, -N(CH3)-, or -CH2-; wherein each RPis independently optionally substituted C1-C3alkyl; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl.

[0213] In some embodiments, B is substituted with one or more substituents selected from:L is -NH-, -N(CH3)-, or -CH2-; wherein each RPis independently optionally substituted C1-C3alkyl.

[0214] In some embodiments, B is substituted with one or more substituents selected.

[0216] In some embodiments, B is substituted with one or more substituents selected from: 65WSGR Ref: 60134-709.601alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.

[0217] In some embodiments, B is substituted with one or more substituents selected from:optionallysubstituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.

[0218] In some embodiments, B is substituted with one or more substituents selected from:alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.

[0219] In some embodiments, B is substituted with one or more substituents selected from:aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl. 66WSGR Ref: 60134-709.601

[0220] In some embodiments, B is substituted with one or more substituents selected from:alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.

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

[0222] In some embodiments, B is substituted with one or more substituents selected from:alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3- aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.

[0223] In some embodiments, B is substituted with one or more substituents selected from:, optionally substituted 3-aminopyrrolidin-1-yl, andoptionally substituted piperazin-1-yl. 67WSGR Ref: 60134-709.601

[0224] In some embodiments, B is substituted with one or more substituents selectedoptionally substituted morpholinyl, 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 optionally substituted piperazin-1-yl.

[0225] 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; 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; and 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.

[0226] In some embodiments, B is substituted with one or more substituents selected from: 68WSGR Ref: 60134-709.601aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; 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.

[0227] In some embodiments, B is substituted with one or more substituents selected from:alkyl, amino, cyano, halogen, and optionally substituted morpholinyl; each Rjis independently hydrogen or optionally substituted C1-C3alkyl; and each Rkis independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH.

[0228] In some embodiments, B is substituted with one or more substituents selected from:each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; and each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH. 69WSGR Ref: 60134-709.601

[0229] In some embodiments, B is substituted with one or more substituents selected from:alkyl, amino, cyano, halogen, optionally substituted morpholinyl; each Rjis independently hydrogen, -CH3, -CH2F, -CHF2, or -CF3; and each Rkis independently hydrogen, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, or -OH.

[0230] In some embodiments, B is substituted with one or more substituents selected from:each Rjis independently hydrogen, -CH3, -CH2F, -CHF2, or -CF3; and each Rkis independently hydrogen, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, or -OH.

[0231] In some embodiments, B is substituted with one or more substituents selected from:alkyl, amino, cyano, halogen, and optionally substituted morpholinyl; each Rjis independently hydrogen or -CH3; and each Rkis independently hydrogen, -F, -CH3, or -OH.

[0232] In some embodiments, B is substituted with one or more substituents selected from: 70WSGR Ref: 60134-709.601each Rjis independently hydrogen or -CH3; and each Rkis independently hydrogen, -F, -CH3, or -OH.

[0233] In some embodiments, B is substituted with one or more substituents selected from:each Rjis independently hydrogen or -CH3.

[0234] In some embodiments, B is substituted with one or more substituents selected from:.

[0235] In some embodiments, B is substituted with one or more substituents selected from:.

[0236] In some embodiments, B is substituted with one or more substituents selected from:. each Rkis independently hydrogen, -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.

[0237] In some embodiments, B is substituted with one or more substituents selected from:.

[0238] In some embodiments, B is substituted with one or more substituents selected from:each Rjis independently hydrogen or -CH3.

[0239] In some embodiments, B is substituted with one or more substituents selected from:each Rjis independently hydrogen or -CH3. 71WSGR Ref: 60134-709.601

[0240] In some embodiments, B is substituted with one or more substituents selected from:each Rjis independently hydrogen or -CH3.

[0241] In some embodiments, B is substituted with one or more substituents selected from:each Rjis independently hydrogen or -CH3.

[0242] In some embodiments, B is substituted with one or more substituents selected from:each Rjis independently hydrogen or -CH3; and each Rkis independently hydrogen, -F, -Cl, -CH3, or -OH.

[0243] In some embodiments, B is substituted with one or more substituents selected from: ; each Rjis independently hydrogen or -CH3; and each Rkis independently hydrogen, -F, or -CH3.

[0244] In some embodiments, B is substituted with one or more substituents selected from:.

[0245] In some embodiments, B is substituted with one or more substituents selected from: optionally substituted 3-aminopyrrolidin-1-yl.

[0246] 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.

[0247] In some embodiments, B is substituted with one or more substituents selected from:.

[0248] In some embodiments, B is substituted with one or more substituents selected from: optionally substituted piperazin-1-yl. 72WSGR Ref: 60134-709.601

[0249] 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.

[0250] In some embodiments, B is substituted with one or more substituents selected from:.

[0251] In some embodiments, B is substituted with one or more substituents selected from: ; each Rmis independently optionally substituted C1-C3alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl.

[0252] In some embodiments, B is substituted with one or more substituents selected from: ; each Rmis independently optionally substituted C1-C3 alkyl.

[0253] In some embodiments, B is substituted with one or more substituents selectedeach Rmis independently unsubstituted C1-C3alkyl.

[0254] In some embodiments, B is substituted with one or more substituents selected from:.

[0255] In some embodiments, two adjacent atoms of B are substituted by the divalent group consistingeach 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. 73WSGR Ref: 60134-709.601

[0256] In some embodiments, two adjacent atoms of B are substituted by the divalent group consistingeach Rjis independently hydrogen or -CH3.

[0257] In some embodiments, two adjacent atoms of B are substituted by the divalent group consistingeach 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.

[0258] In some embodiments, two adjacent atoms of B are substituted by the divalent group consisting.

[0259] In some embodiments, B is substituted with one or more substituents selected from:

[0260] In some embodiments, B is substituted with one or more substituents selected from: 74WSGR Ref: 60134-709.601

[0261] In some embodiments, B is substituted with one or more substituents selected

[0262] In some embodiments, B is substituted with one or more substituents selectedfro,75WSGR Ref: 60134-709.601

[0263] In some embodiments, B is substituted with one or more substituents selected

[0264] In some embodiments, B is substituted with one or more substituents selected76WSGR Ref: 60134-709.601

[0265] In some embodiments, B is substituted with one or more substituents selected.

[0266] In some embodiments, B is substituted with one or more substituents selected77WSGR Ref: 60134-709.601

[0267] In some embodiments, B is substituted with one or more substituents selected

[0268] In some embodiments, B is substituted with one or more substituents selected

[0269] In some embodiments, B is substituted with one or more substituents selected78WSGR Ref: 60134-709.601

[0270] In some embodiments, B is substituted with one or more substituents selected

[0271] In some embodiments, B is substituted with one or more substituents selected

[0272] In some embodiments, B is substituted with one or more substituents selected79WSGR Ref: 60134-709.601

[0274] In some embodiments, X is N.

[0275] In some embodiments, X is C-R. 80WSGR Ref: 60134-709.601

[0276] In some embodiments, Y is N.

[0277] In some embodiments, Y is C-R.

[0278] In some embodiments, Z is N.

[0279] In some embodiments, Z is C-R.

[0280] In some embodiments, X is CR; Y is CR; and Z is CR.

[0281] In some embodiments, X is CH; Y is CH; and Z is CH.

[0282] In some embodiments, X is N; Y is CR; and Z is CR.

[0283] In some embodiments, X is N; Y is CH; and Z is CH.

[0284] In some embodiments, each R is independently hydrogen, deuterium, halogen, - CN, or optionally substituted C1-2alkyl.

[0285] In some embodiments, each R is independently hydrogen, deuterium, halogen, - CN, or optionally substituted C1alkyl.

[0286] In some embodiments, each R is independently hydrogen, deuterium, halogen, - CN, or -CH3.

[0287] In some embodiments, each R is independently hydrogen, deuterium, or halogen.

[0288] In some embodiments, each R is independently hydrogen, deuterium, or -F.

[0289] In some embodiments, each R is independently hydrogen or deuterium.

[0290] In some embodiments, E is absent.

[0291] In some embodiments, E is O or N-R1.

[0292] In some embodiments, E is O.

[0293] In some embodiments, E is N-R1.

[0294] In some embodiments, E is O or absent.

[0295] In some embodiments, E is N-R1or absent.

[0296] In some embodiments, R1is hydrogen, optionally substituted C1-C5 alkyl, -OH, - CN, -C(O)R8, or -C(O)N(R9)2.

[0297] In some embodiments, R1is hydrogen, optionally substituted C1-C5alkyl, -OH, - CN, -C(O)CH3, -C(O)NH2, -C(O)NH(CH3), or -C(O)N(CH3)2.

[0298] In some embodiments, R1is hydrogen, optionally substituted C1-C5 alkyl, -OH, - CN, -C(O)CH3, or -C(O)N(CH3)2.

[0299] In some embodiments, R1is hydrogen, -CH3, -CH2CO2H, -CH(CH3)CO2H, -OH, -CN, -C(O)CH3, or -C(O)N(CH3)2.

[0300] In some embodiments, R1is hydrogen, optionally substituted C1-C5 alkyl, -OH, or -CN.

[0301] In some embodiments, R1is hydrogen or optionally substituted C1-C5 alkyl. In some embodiments, R1is hydrogen or optionally substituted C1-C4 alkyl. In some embodiments, 81WSGR Ref: 60134-709.601 R1is hydrogen or optionally substituted C1-C3 alkyl. In some embodiments, R1is hydrogen or optionally substituted C1-C2alkyl. In some embodiments, R1is hydrogen or optionally substituted C1alkyl. In some embodiments, R1is hydrogen or -CH3.

[0302] In some embodiments, R1is hydrogen.

[0303] In some embodiments, R1is optionally substituted alkyl. In some embodiments, R1is optionally substituted C1-C5alkyl. In some embodiments, R1is optionally substituted C1- C4 alkyl. In some embodiments, R1is optionally substituted C1-C3 alkyl. In some embodiments, R1is optionally substituted C1-C2 alkyl. In some embodiments, R1is optionally substituted C1 alkyl. In some embodiments, R1is C1-C5alkyl 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.

[0304] In some embodiments, R1is -OH.

[0305] In some embodiments, R1is -C(O)R8.

[0306] In some embodiments, R1is -C(O)CH3.

[0307] In some embodiments, R1is -C(O)N(R9)2.

[0308] In some embodiments, R1is -C(O)N(CH3)2.

[0309] 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 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.

[0310] In some embodiments, the compound of Formula (I), Formula (I-a), Formula (I- b), Formula (I-c), Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), has the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof,wherein: 82WSGR Ref: 60134-709.601 each Rw is independently hydrogen, , ,, , ,alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and E is O or NH.

[0311] In some embodiments, the compound of Formula (I), Formula (I-a), Formula (I- b), Formula (I-c), Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), has the structure of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof,wherein: each Rw is independently hydrogen,, , , , ,alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and 83WSGR Ref: 60134-709.601 E is O or NH.

[0312] In some embodiments, the compound of Formula (I), Formula (I-a), Formula (I- b), Formula (I-c), Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), has the structure of Formula (V), or a pharmaceutically acceptable salt or solvate thereof,wherein: each Rw is independently hydrogen,, , , , ,alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and E is O or NH.

[0313] In some embodiments, the compound of Formula (I), Formula (I-a), Formula (I- b), Formula (I-c), Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), has the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof,wherein: 84WSGR Ref: 60134-709.601alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl;optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and E is O or NH.

[0314] In some embodiments, the compound of Formula (I), Formula (I-a), Formula (I- b), Formula (I-c), Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), has the structure of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof,wherein: 85WSGR Ref: 60134-709.601alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl;optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and E is O or NH.

[0315] In some embodiments, the compound of Formula (I), Formula (I-a), Formula (I- b), Formula (I-c), Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), has the structure of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof,, wherein: 86WSGR Ref: 60134-709.601 each Rw is independently hydrogen, , ,, , ,alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and E is O or NH.

[0316] In some embodiments, the compound of Formula (I), Formula (I-a), Formula (I- b), Formula (I-c), Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), has the structure of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof,wherein: each Rw is independently hydrogen,, , , , ,alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and 87WSGR Ref: 60134-709.601 E is O or NH.

[0317] In some embodiments, the compound of Formula (I), Formula (I-a), Formula (I- b), Formula (I-c), Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), has the structure of Formula (X), or a pharmaceutically acceptable salt or solvate thereof,wherein:alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and E is O or NH.

[0318] In some embodiments, the compound of Formula (I), Formula (I-a), Formula (I- b), Formula (I-c), Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), or a pharmaceutically acceptable salt or solvate thereof,wherein: 88WSGR Ref: 60134-709.601 each Rw is independently hydrogen, , ,, , ,alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and E is O or NH.

[0319] In some embodiments, the compound of Formula (I), Formula (I-a), Formula (I- b), Formula (I-c), Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), has the structure of Formula (XII), or a pharmaceutically acceptable salt or solvate thereof,wherein: each Rw is independently hydrogen,, , , , ,alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and 89WSGR Ref: 60134-709.601 E is O or NH.

[0320] In some embodiments, the compound of Formula (I), Formula (I-a), Formula (I- b), Formula (I-c), Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), or a pharmaceutically acceptable salt or solvate thereof,wherein: V is O, NH, or N(C1-C6alkyl); each Rw is independently hydrogen,, , , , ,alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl;optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; each Rvis independently hydrogen or C1-C6alkyl; and E is O or NH. 90WSGR Ref: 60134-709.601

[0321] 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 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, wherein RLis not 4-piperidinyl.

[0322] 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 carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4- to 5-membered C-heterocyclyl.

[0323] 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, optionally substituted 4- to 5-membered carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4- to 5-membered C-heterocyclyl.

[0324] 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 4-membered carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl.

[0325] 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 C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl.

[0326] 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 3- to 6-membered carbocyclyl, optionally substituted aralkyl, optionally 91WSGR Ref: 60134-709.601 substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl.

[0327] 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, optionally substituted 3- to 5-membered carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl.

[0328] 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 3- to 4-membered carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl.

[0329] 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 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.

[0330] 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 C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted 4- to 6-membered carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl.

[0331] 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-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted 5- to 6-membered carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl.

[0332] 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, 92WSGR Ref: 60134-709.601 optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.

[0333] In some embodiments, RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.

[0334] In some embodiments, RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted aralkyl or optionally substituted carbocyclylalkyl.

[0335] In some embodiments, RLis optionally substituted C4-C12alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted C4-C12alkenyl, optionally substituted C4-C12 alkynyl, or optionally substituted carbocyclylalkyl.

[0336] In some embodiments, RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted C4-C12alkenyl, or optionally substituted C4-C12 alkynyl.

[0337] In some embodiments, RLis optionally substituted C4-C12 alkyl or optionally substituted -(C1-C3alkylene)-O-(C1-C10alkyl).

[0338] In some embodiments, RLis optionally substituted C4-C10alkyl or optionally substituted -(C1-C3 alkylene)-O-(C1-C8 alkyl).

[0339] 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 aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.

[0340] 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-C12alkenyl, optionally substituted C4-C12alkynyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.

[0341] In some embodiments, RLis optionally substituted C5-C10 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C8 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C5-C10alkenyl, optionally substituted C5-C10alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted 93WSGR Ref: 60134-709.601 heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0342] In some embodiments, RLis optionally substituted C4-C10alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C10 alkenyl, optionally substituted C4-C10 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

[0343] 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 C5-C12alkenyl, optionally substituted C5-C12alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.

[0344] In some embodiments, RLis optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C12 alkenyl, or optionally substituted C4-C12alkynyl.

[0345] In some embodiments, RLis optionally substituted C4-C12 alkyl, optionally substituted C4-C12 alkenyl, or optionally substituted C4-C12 alkynyl.

[0346] In some embodiments, RLis optionally substituted C5-C12alkyl, optionally substituted C5-C12alkenyl, or optionally substituted C5-C12alkynyl.

[0347] In some embodiments, RLis optionally substituted C6-C12 alkyl, optionally substituted C6-C12alkenyl, or optionally substituted C6-C12alkynyl.

[0348] In some embodiments, RLis an optionally substituted C4-C12alkyl.

[0349] In some embodiments, RLis an optionally substituted C5-C12 alkyl.

[0350] In some embodiments, RLis an optionally substituted, linear C4-C10 alkyl.

[0351] In some embodiments, RLis an optionally substituted, linear C5-C10alkyl.

[0352] In some embodiments, RLis an optionally substituted C4-C12alkenyl.

[0353] In some embodiments, RLis an optionally substituted C4-C10 alkenyl.

[0354] In some embodiments, RLis an optionally substituted C4-C12alkynyl.

[0355] In some embodiments, RLis an optionally substituted C4-C10alkynyl.

[0356] In some embodiments, RLis an optionally substituted carbocyclyl.

[0357] In some embodiments, RLis an optionally substituted C3-C8 carbocyclyl.

[0358] In some embodiments, RLis an optionally substituted C4-C8carbocyclyl.

[0359] In some embodiments, RLis an optionally substituted C5-C8 carbocyclyl.

[0360] In some embodiments, RLis an optionally substituted C5-C7 carbocyclyl. 94WSGR Ref: 60134-709.601

[0361] In some embodiments, RLis an optionally substituted C5-C6 carbocyclyl.

[0362] In some embodiments, RLis an optionally substituted 4-membered carbocyclyl.

[0363] In some embodiments, RLis an optionally substituted aralkyl.

[0364] In some embodiments, RLis an optionally substituted heteroarylalkyl.

[0365] In some embodiments, RLis an optionally substituted carbocyclylalkyl.

[0366] In some embodiments, RLis an optionally substituted heterocyclylalkyl.

[0367] In some embodiments, RLis an optionally substituted C-heterocyclyl.

[0368] In some embodiments, RLis an optionally substituted 4 to 8-membered C- heterocyclyl.

[0369] In some embodiments, RLis an optionally substituted 5 to 6-membered C- heterocyclyl.

[0370] In some embodiments, RLis an optionally substituted 4 to 5-membered C- heterocyclyl.

[0371] In some embodiments, RLis an optionally substituted 4 to 6-membered C- heterocyclyl.

[0372] In some embodiments, RLis an optionally substituted 6 membered C- heterocyclyl.

[0373] In some embodiments, RLis an optionally substituted C-pyperidinyl.

[0374] In some embodiments, RLis a substituted C-pyperidinyl.

[0375] In some embodiments, RLis an optionally substituted 5 membered C- heterocyclyl.

[0376] In some embodiments, RLis an optionally substituted 4 membered C- heterocyclyl.

[0377] In some embodiments, RLis an optionally substituted oxetanyl.

[0378] In some embodiments, RLis an optionally substituted C-azetidinyl.

[0379] In some embodiments, RLis optionally substituted -(C1-C3alkylene)-N-(C1-C3alkyl)(heteroaryl).

[0380] 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).

[0381] In some embodiments, RLis optionally substituted -(C1-C2 alkylene)-O-(C1-C10 alkyl).

[0382] In some embodiments, RLis optionally substituted -(C1 alkylene)-O-(C1-C10 alkyl). 95WSGR Ref: 60134-709.601

[0383] In some embodiments, RLis optionally substituted -CH2O(C1-C10 alkyl).

[0384] In some embodiments, RLis selected from the group consisting of:

[0385] In some embodiments, RLis selected from the group consisting of:

[0386] In some embodiments, RLis selected from the group consisting of:96WSGR Ref: 60134-709.60197WSGR Ref: 60134-709.60198WSGR Ref: 60134-709.601

[0389] In some embodiments, RLis selected from the group consisting of:99WSGR Ref: 60134-709.601

[0390] In some embodiments, RLis selected from the group consisting of:100WSGR Ref: 60134-709.601 ,, ,[101WSGR Ref: 60134-709.601.

[0392] In some embodiments, RLis selected from the group consisting of:102WSGR Ref: 60134-709.601103WSGR Ref: 60134-709.601.

[0394] In some embodiments, L is -N(Rj)-, -C(Rn)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)-.

[0395] In some embodiments, RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, optionally substituted C2-C5alkynyl, -ORj, or -N2. In some embodiments, RSis optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -ORj, or -N(Rj)2. In some embodiments, RSis optionally substituted C1-C4alkyl, -ORj, or -N2. In some embodiments, RSis optionally substituted C1- C4alkyl. In some embodiments, RSis optionally substituted C1-C3alkyl. In some embodiments, RSis optionally substituted C1-C2 alkyl. In some embodiments, RSis optionally substituted C1 alkyl. 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.

[0396] In some embodiments, each RPis independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or - N(Rj)2. In some embodiments, each RPis independently optionally substituted C1-C3alkyl, -ORj, or -N(Rj)2. In some embodiments, each RPis independently optionally substituted C1-C3 alkyl. In some embodiments, each RPis independently C1-C3 alkyl 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- 104WSGR Ref: 60134-709.601 membered heterocyclyl. In some embodiments, two RPare taken together to form an optionally substituted 5 to 6-membered heterocyclyl.

[0397] 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-C7 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl.

[0398] 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.

[0399] 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-C6 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl.

[0400] In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C5carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 5-membered heterocyclyl.

[0401] 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-C4 carbocyclyl; or two Rjgroups are optionally cyclized to form an optionally substituted 4-membered heterocyclyl.

[0402] In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3-C4carbocyclyl.

[0403] In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted C3carbocyclyl.

[0404] In some embodiments, each Rjis independently hydrogen or optionally substituted C1-C3 alkyl. In some embodiments, each Rjis independently hydrogen or optionally 105WSGR Ref: 60134-709.601 substituted C1-C2 alkyl. In some embodiments, each Rjis independently hydrogen or optionally substituted C1alkyl. In some embodiments, each Rjis independently hydrogen or -CH3.

[0405] 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.

[0406] 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-C5 carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 3 to 5- membered heterocyclyl.

[0407] 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-C4 carbocyclyl; or two Rkgroups attached to the same carbon atom are optionally cyclized to form a 4- membered heterocyclyl.

[0408] 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.

[0409] 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.

[0410] In some embodiments, each Rkis independently hydrogen, halogen, optionally substituted C1-C3alkyl, or -OH. In some embodiments, each Rkis independently hydrogen, halogen, optionally substituted C1-C2 alkyl, or -OH. In some embodiments, each Rkis independently hydrogen, halogen, optionally substituted C1 alkyl, or -OH.

[0411] In some embodiments, each Rkis independently hydrogen, -F, -OH, or -CH3. In some embodiments, each Rkis independently hydrogen, -F, or -CH3. In some embodiments, 106WSGR Ref: 60134-709.601 each Rkis independently hydrogen or -CH3.In some embodiments, each Rkis independently hydrogen.

[0412] In some embodiments, each Rmis independently optionally substituted C1-C3alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl.

[0413] In some embodiments, each Rmis independently optionally substituted C1-C3 alkyl;

[0414] or two Rmgroups are optionally cyclized to form an optionally substituted 5 to 6-membered heterocyclyl.

[0415] 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.

[0416] In some embodiments, each Rmis independently optionally substituted C1-C3 alkyl. In some embodiments, each Rmis independently optionally substituted C1-C2alkyl. In some embodiments, each Rmis independently optionally substituted C1 alkyl. In some embodiments, each Rmis independently -CH3.

[0417] 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-C6 carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.

[0418] 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-C4carbocyclyl; or two Rngroups attached to the same carbon atom are optionally cyclized to form a 4- membered heterocyclyl.

[0419] In some embodiments, 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-C4carbocyclyl. 107WSGR Ref: 60134-709.601

[0420] 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-C2alkyl. In some embodiments, each Rnis independently hydrogen, halogen, or optionally substituted C1 alkyl. In some embodiments, each Rnis independently hydrogen, -F, or -CH3.

[0421] In some embodiments, R8is optionally substituted C1-C5alkyl. In some embodiments, R8is optionally substituted C1-C4 alkyl. In some embodiments, R8is optionally 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.

[0422] 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.

[0423] 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.

[0424] 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 5 to 6-membered heterocyclyl.

[0425] 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. In some embodiments, each R9is independently hydrogen or optionally substituted C1alkyl. In some embodiments, each R9is independently hydrogen or -CH3.

[0426] One embodiment provides a LpxH inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1. Table 1108WSGR Ref: 60134-709.601109WSGR Ref: 60134-709.601110WSGR Ref: 60134-709.601111WSGR Ref: 60134-709.601112WSGR Ref: 60134-709.601113WSGR Ref: 60134-709.601114WSGR Ref: 60134-709.601115WSGR Ref: 60134-709.601116WSGR Ref: 60134-709.601117WSGR Ref: 60134-709.601

[0427] Another embodiment provides a LpxH inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 2.118WSGR Ref: 60134-709.601119WSGR Ref: 60134-709.601120WSGR Ref: 60134-709.601121WSGR Ref: 60134-709.601122WSGR Ref: 60134-709.601 Preparation of Compounds

[0428] The compounds used in the synthetic chemistry reactions described herein are made 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).

[0429] 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, 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 123WSGR Ref: 60134-709.601 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.

[0430] 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

[0431] 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 on 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)).

[0432] Another embodiment provides a pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-a), (I-b), (I- c), (II), (II-a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), and a pharmaceutically acceptable excipient.

[0433] Another embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), and a pharmaceutically acceptable carrier.

[0434] Provided herein is a pharmaceutical composition comprising at least one LpxH inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, 124WSGR Ref: 60134-709.601 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.

[0435] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II- a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), or a pharmaceutically acceptable salt or solvate thereof.

[0436] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0437] In certain embodiments, the LpxH inhibitory compound as described by Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), 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.

[0438] 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.

[0439] 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.

[0440] 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.

[0441] 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, 125WSGR Ref: 60134-709.601 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)).

[0442] In some embodiments, the LpxH inhibitory compound as described by Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), 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.

[0443] 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.

[0444] 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.

[0445] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. Methods of Treatment

[0446] One embodiment provides a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II- a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0447] One embodiment provides a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II- a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of infection by at least one Gram-negative pathogen. 126WSGR Ref: 60134-709.601

[0448] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), 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.

[0449] One embodiment provides a use of a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), 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.

[0450] 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), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), 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), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0451] 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.

[0452] 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.

[0453] 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.

[0454] 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.

[0455] 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 127WSGR Ref: 60134-709.601 composition comprising a compound of Table 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0456] 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.

[0457] 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.

[0458] 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.

[0459] One embodiment provides a method of inhibiting LpxH comprising contacting the LpxH enzyme with a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII), or Table 1 or 2. Another embodiment provides the method of inhibiting a LpxH enzyme, wherein the LpxH enzyme is 128WSGR Ref: 60134-709.601 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.

[0460] 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

[0461] 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 AcOH Acetic acid ACN Acetonitrile d doublet (spectral) dba dibenzylideneacetone DCM dichloromethane (CH2Cl2) DIPEA Diisoproylethylamine DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate ESI electrospray ionization Et ethyl EA or EtOAc Ethyl acetate FA Formic acid g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertz coupling constant (in NMR spectrometry) LCMS liquid chromatography mass spectrometry μ micro m multiplet (spectral); meter(s); milli 129WSGR Ref: 60134-709.601 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 mass spectrometry MsCl methyl sulfonyl chloride NCS N-Chlorosuccinimide nm nanometer(s) NMR nuclear magnetic resonance NMI 1-methylimidazole 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 s singlet (spectral) t triplet (spectral) T temperature TBAF tetrabutylammonium fluoride TCFH N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate TFA trifluoroacetic acid THF tetrahydrofuran

[0462] Intermediate 1 130WSGR Ref: 60134-709.601Step 1: methyl 2-(methylsulfonamido)benzoate To the solution of methyl 2-aminobenzoate (30 g, 198.67 mmol) in DCM (200 mL) was added pyridine (31.39 g, 397.34 mmol), then cooled to 0°C and MsCl (36.7 g, 238.41 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 (44.5 g, Y:97.8%) as a white solid. TLC: PE / EA = 5:1, UV Rf = 0.3 Step 2: methyl 2-(N-methylmethylsulfonamido)benzoate To the solution of methyl 2-(methylsulfonamido)benzoate (44.5 g, 194.11 mmol) in DMF (150 mL) was added potassium carbonate (53.66 g, 388.22 mmol) then added MeI (32.84 g, 232.93 mmol) into the mixture and stirred at room temperature overnight. It was poured into water, extracted with ethyl acetate, the combined organic phase 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 (45.8 g, Y:97%) as a white solid. TLC: PE / EA = 5:1, UV Rf = 0.2 Step 3: 2-(N-methylmethylsulfonamido)benzoic acid To the solution of ethyl 2-(N-methylmethylsulfonamido)benzoate (45.8 g, 188.26 mmol) in THF (100 mL) was added the solution of NaOH (37.65 g, 941.30 mmol) in H2O (100 mL), then mixture was stirred at room temperature overnight. The reaction mixture was concentrated and washed with DCM, then the aqueous phase was acidified with aqueous HCl till pH = 3 and 131WSGR Ref: 60134-709.601 extracted with DCM to give product 2-(N-methylmethylsulfonamido)benzoic acid (41.7 g, Y:96.6%) as a white solid. Step 4: tert-butyl N-(2-(5-bromoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide The solution of 2-(N-methylmethylsulfonamido)benzoic acid (41g, 184.09 mmol) in SOCl2 (250 mL) was stirred at 80°C for 2 h. The reaction mixture was concentrated and added into the mixture of 5-bromoindoline (25 g, 126.22 mmol) and TEA(38.3 g, 378.66 mmol) in DCM (150 mL), then the solution was stirred at room temperature for 30 min. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: DCM =8:1) to give product N-(2-(5-bromoindoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide (36.4 g, P: 80%, Y:56.4%) as a yellow solid. TLC: PE / EA = 5:1, UV Rf = 0.2 MS(ESI) calculated for: C17H17BrN2O3S, 409.0; found [M+H]+, 409.0. Step 5: N-(2-(5-(benzylthio)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide To the solution of N-(2-(5-bromoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (10 g, 24.45 mmol) in 1,4-dioaxane (90 mL) were added phenylmethanethiol (4.56 g, 36.65 mmol), Pd2(dba)3 (1.8 g, 1.96 mmol), Xant-phos (2.26 g, 3.91 mmol) and DIPEA (9.46 g, 73.30 mmol) at 25°C. The mixture was stirred at 100oC overnight. 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=1:1 to give product N-(2-(5-(benzylthio)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide (9.8g, 88.6 % yield) as a yellow solid. TLC: PE / EA = 1:1, UV Rf = 0.6 Step 6: N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide To a solution of N-(2-(5-(benzylthio)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (5 g, 11.05 mmol) in toluene (8 mL) was added AlCl3 (4.4 g, 33.14 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give crude product . It was further purified with silica column (elute with ACN: H2O =2:1) to give N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide (1.4 g, Y:35.0%) as a white solid. TLC: PE / EA = 1:1, UV 132WSGR Ref: 60134-709.601 Rf = 0.3

[0463] Intermediate 2Step 1: tert-butyl 5-(heptylthio)indoline-1-carboxylate tert-butyl 5-bromoindoline-1-carboxylate (200 mg, 1.15 mmol), heptane-1-thiol (157 mg, 1.26 mmol), Pd2(dba)3(105 mg, 0.12 mmol) and Xant-Phos(133 mg, 0.23 mmol) was dissolved in dry dioxane (10 mL) and DIPEA(291 mg, 2.88 mmol) was added. The mixture was stirred at 100oC for 3 h. The reaction mixture was quenched with water and extracted with EA (50 mLx3), the organic phase was separated, washed with brine (50 mLx3) and dried with Na2SO4 then concentrated and purified by flash chromatography eluted with PE:EA = 1:9 to give product tert-butyl 5-(heptylthio)indoline-1-carboxylate (230 mg, 84.0% yield) as a light yellow solid. TLC: PE:EA = 1:1, UV Rf = 0.2 Step 2: tert-butyl 5-(heptylsulfonyl)indoline-1-carboxylate tert-butyl 5-(heptylthio)indoline-1-carboxylate (670 mg, 1.92 mmol) was dissolved in DCM (15 mL) and m-CPBA (992 mg, 5.75 mmol) was added slowly at 0oC. The reaction mixture was quenched with water and extracted with EA (50 mLx3), the organic phase was separated, washed with brine (50 mLx3) and dried with Na2SO4then concentrated and purified by flash chromatography eluted with PE:EA = 3:1 to give product tert-butyl 5-(heptylsulfonyl)indoline- 1-carboxylate (670 mg, 91.5%yield) as a yellow oil. TLC: PE:EA = 3:1, UV Rf = 0.4 Step 3: 5-(heptylsulfonyl)indoline tert-butyl 5-(heptylsulfonyl)indoline-1-carboxylate (620 mg, 1.63 mmol) was dissolved in DCM (8 mL) and TFA (2 mL) was added. The mixture was stirred at RT for 1 h. The reaction mixture was poured into water (10 mL) and neutralized with NaHCO3 (aq.) to pH=8, then extracted with EA (30 mLx3), the organic phase was separated, washed with brine (30 mLx3) and dried with 133WSGR Ref: 60134-709.601 Na2SO4 then concentrated to give product 5-(heptylsulfonyl)indoline (440 mg, 96.1% yield) as a brown solid. TLC: DCM:MeOH = 10:1, UV Rf = 0.3

[0464] Intermediate 3Step 1: tert-butyl 4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate To 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 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

[0465] Intermediate 4Step 1: methyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate 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 134WSGR Ref: 60134-709.601 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 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

[0466] Intermediate 5Step 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 Step 2: 6-(tert-butyl) 2-methyl 5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-2,6-dicarboxylate 135WSGR Ref: 60134-709.601 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 was 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 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

[0467] Intermediate 6Step :1 tert-butyl 5-(heptylthio)indoline-1-carboxylate tert-butyl 5-bromoindoline-1-carboxylate (200 mg, 1.15 mmol), heptane-1-thiol (157 mg, 1.26 mmol), Pd2(dba)3(105 mg, 0.12 mmol) and Xant-Phos(133 mg, 0.23 mmol) was dissolved in dry dioxane (10 mL) and DIPEA(291 mg, 2.88 mmol) was added. The mixture was stirred at 100oC for 3 h. The reaction mixture was quenched with water and extracted with EA (50 mL*3), the organic phase was separated, washed with brine (50 mL*3) and dried with Na2SO4 then 136WSGR Ref: 60134-709.601 concentrated and purified by flash chromatography eluted with PE:EA = 1:9 to give product tert-butyl 5-(heptylthio)indoline-1-carboxylate (230 mg, 84.0% yield) as a light yellow solid. TLC: PE:EA = 1:1, UV Rf = 0.2 Step 2: 5-(heptylthio)indoline tert-butyl 5-(heptylthio)indoline-1-carboxylate (230 mg, 0.92 mmol) was dissolved in DCM (4 mL) and TFA (1 mL) was added. The mixture was stirred at RT for 1 h. The reaction mixture was poured into water (10 mL) and neutralized with NaHCO3 (aq.) to pH=8, then extracted with EA (30 mL*3), the organic phase was separated, washed with brine (30 mL*3) and dried with Na2SO4then concentrated to give product 5-(heptylthio)indoline (150 mg, 93.1% yield) as a brown solid. TLC: DCM:MeOH = 10:1, UV Rf = 0.3Step 1: methyl 2-(methylsulfonamido)benzoate To the solution of methyl 2-aminobenzoate (30 g, 198.67 mmol) in DCM (200 mL) was added pyridine (31.39 g, 397.34 mmol), then cooled to 0°C and MsCl (36.7 g, 238.41 mmol) was added dropwise into the mixture. The mixture 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 =1:1) to give product methyl 2-(methylsulfonamido)benzoate (45.8 g, yield : 97.8%) as a white solid. TLC: PE / EA = 5:1, UV Rf = 0.3 137WSGR Ref: 60134-709.601 Step 2: 2-(N-methylmethylsulfonamido)benzoic acid To the solution of methyl 2-(methylsulfonamido)benzoate (45.8 g, 188.26 mmol) in THF (100 mL) was added the solution of NaOH (37.65 g, 941.30 mmol) in H2O (100 mL), then mixture was stirred at room temperature overnight. 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 to give the product 2-(N-methylmethylsulfonamido)benzoic acid (41.7 g, yield :96.6%) as a white solid. Step 3: N-(2-(5-bromoindoline-1-carbonyl)phenyl)methanesulfonamide The solution of 2-(N-methylmethylsulfonamido)benzoic acid (41g, 184.09 mmol) in SOCl2(250 mL) was stirred at 80°C for 2 h. The reaction mixture was concentrated and added into the mixture of 5-bromoindoline (25 g, 126.22 mmol) and TEA(38.3 g, 378.66 mmol) in DCM (150 mL), then the solution was stirred at room temperature for 30 mins. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: DCM =8:1) to give product N-(2-(5-bromoindoline-1- carbonyl)phenyl)methanesulfonamide (36.4 g, yield:56.4%) as a yellow solid. TLC: PE / EA = 5:1, UV Rf = 0.2 MS(ESI) calculated for: C17H17BrN2O3S, 409.0; found [M+H]+, 410.1. Step 4: N-(2-(5-(benzylthio)indoline-1-carbonyl)phenyl)methanesulfonamide To the solution of N-(2-(5-bromoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (10 g, 24.45 mmol) in 1,4-dioaxane (90 mL) were added phenylmethanethiol (4.56 g, 36.65 mmol), Pd2(dba)3(1.8 g, 1.96 mmol), Xant-phos (2.26 g, 3.91 mmol) and DIPEA (9.46 g, 73.30 mmol) at 25°C. The mixture was stirred at 100oC overnight. 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=1:1 to give product N-(2-(5-(benzylthio)indoline-1- carbonyl)phenyl)methanesulfonamide (9.8g, 88.6 % yield) as a yellow solid. TLC: PE / EA = 1:1, UV Rf = 0.6 Step 5: N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)methanesulfonamide To a solution of N-(2-(5-(benzylthio)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (5 g, 11.05 mmol) in toluene (8 mL) was added AlCl3(4.4 g, 33.14 mmol). The resulting mixture was stirred at room temperature overnight. Water was added, the mixture was extracted with ethyl acetate and water, the combined organic layer was washed with brine and dried over 138WSGR Ref: 60134-709.601 sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give crude product . It was further purified with silica column (elute with ACN: H2O =2:1) to give N-(2-(5-mercaptoindoline-1- carbonyl)phenyl)methanesulfonamide (1.4 g, yield:35.0%) as a white solid. TLC: PE / EA = 1:1, UV Rf = 0.3

[0469] Intermediate 8Step 1: methyl (R)-5-methylheptanoate. 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) was stirred at 50℃for 30 min.Then cooled to room temperature, and (R)-1-bromo-2-methylbutane (15.0 g, 10.0 mmol) was added, the reaction mixture were stirred at room temperature for 3 h under Ar atmosphere. 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 to give product methyl (R)-5-methylheptanoate (10.0 g, crude) as a colorless oil oil. Step 2: (R)-5-methylheptan-1-ol. To the solution of (R)-5-methylheptanoate (4.0 g, 25.31 mmol) in THF(50 mL) was added LiAlH4(25 mL, 50.62 mmol), the reaction mixture was stirred at RT for 3 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=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. 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) was stirred at 0℃ for 30 min. Then MsCl(1.75 g, 15.38 mmol) was added, 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).

[0470] Intermediate 9 139WSGR Ref: 60134-709.601Step 1: methyl 2-bromo-5-methyl-4-nitrobenzoate. To a solution of methyl 3-methyl-4-nitrobenzoate(10 g, 51.282 mmol) and NBS(11.9 g, 66.667 mmol) in DCM (100 mL) were added Pd(OAc)2(1.1 g, 5.128 mmol), TfOH(36 ml) and N- fluoropyridinium triflate(12.7 g, 51.282 mmol). The mixture was stirred at 65oC overnight. The mixture was added NaHCO3 aqueous solution, 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 silica gel chromatography (EA / PE=1 / 9) to give product (3.2 g, 22.9% yield) as a white solid. LCMS: [M+1]+=274.1 / 276.1. Step 2: methyl 2-bromo-5-(bromomethyl)-4-nitrobenzoate. To a solution of methyl 2-bromo-5-methyl-4-nitrobenzoate(3.2 g, 11.679 mmol) in CCl4 (90 mL) were added NBS(3.1 g, 17.519 mmol) and BPO(2.0 g, 8.175 mmol). The mixture was stirred at 80oC overnight. 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 purified silica gel chromatography (EA / PE=1 / 9) to give product (2.1 g, 51.2% yield) as a white solid. LCMS: [M+1]+=354.1 / 356.1. Step 3: methyl 2-bromo-5-((methylamino)methyl)-4-nitrobenzoate. To a solution of methyl 2-bromo-5-(bromomethyl)-4-nitrobenzoate (2.1 g, 5.949 mmol) in THF (30 mL) were added methylamine MeOH (1.3 mL). The mixture was stirred for 1 h at room temperature. The mixture was added some NH4Cl, 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 silica gel chromatography (MeOH / DCM=1 / 9) to give product (1.5 g, 83.3% yield) as a yellow oil. LCMS: [M+1]+=303.1 / 305.1. Step 4: methyl 4-amino-2-bromo-5-((methylamino)methyl)benzoate. The solution of methyl 2-bromo-5-((methylamino)methyl)-4-nitrobenzoate(1.5 g, 4.950 mmol) in EtOH (20 mL) were added Fe (1.1 g, 19.800 mmol) and HOAc (2 mL). The mixture was stirred for 1h at 70oC. The mixture was added NaHCO3 aqueous solution, and extracted with 140WSGR Ref: 60134-709.601 EtOAc, 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=5 / 95) to give product (1.0 g, 74.1% yield) as a yellow oil. LCMS: [M+1]+=273.1 / 275.1 Step 5: methyl 7-bromo-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate. To a solution of methyl 4-amino-2-bromo-5-((methylamino)methyl)benzoate (1.0 g 3.663 mmol) in THF (50 mL) were added Triphosgene (1.1 g, 3.663 mmol) and TEA (1.8 g, 18.315 mmol). The mixture was stirred for 2h at room temperature. The mixture was added NH4Cl aqueous solution, 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 silica gel chromatography (EA / PE=1 / 1) to give product (470 mg, 42.7% yield) as a yellow solid. LCMS: [M+1]+=299.1 / 301.1

[0471] Intermediate 10Step 1: tert-butyl 5-(heptylthio)indoline-1-carboxylate To the solution of tert-butyl 5-bromoindoline-1-carboxylate (500 mg, 1.677 mmol, bide) in dry dioxane (20 mL) were added heptane-1-thiol (266 mg, 2.012 mmol, bide), Pd2(dba)3(156 mg, 0.17 mmol, bide), dppf (189 mg, 0.34 mmol, bide) and DIEA(650 mg, 5.031 mmol, energy). The reaction mixture, flushed with argon, and stirred at 100oC overnight. The mixture reaction was quenched by water, extracted with EA, washed with brine, dried with Na2SO4 and concentrated. The residue was purified by flash choromatography elute with PE / EA = 99:1 to afford the title compound tert-butyl 5-(heptylthio)indoline-1-carboxylate (670 mg, 100% yield) as a yellow solid. TLC: PE / EA = 20:1, UV, Rf = 0.6 Step 2: tert-butyl 5-(heptylsulfonyl)indoline-1-carboxylate To the solution of tert-butyl 5-(heptylthio)indoline-1-carboxylate (670 mg, 1.92 mmol) in DCM (10 mL) was added m-CPBA (992 mg, 5.75 mmol) slowly at 0oC. The mixture was stirred at RT for 1 h. The reaction mixture was quenched by water, extracted with EA, washed with brine, and dried with Na2SO4then concentrated and purified by flash choromatography elute with PE / EA = 3:1 to afford the title compound tert-butyl 5-(heptylsulfonyl)indoline-1-carboxylate (670 mg, 91.5%yield) as a yellow solid. TLC: PE / EA = 3:1, UV, Rf= 0.6 141WSGR Ref: 60134-709.601 Step 3: 5-(heptylsulfonyl)indoline To the solution of tert-butyl 5-(heptylsulfonyl)indoline-1-carboxylate (620 mg, 1.63 mmol) in DCM (8 mL) was added TFA (2 mL) and stirred at room temperature for 2 h. The mixture was poured into water and neutralized with NaHCO3(aq) to pH=8, the mixture was extracted with EA, washed with brine, and dried with Na2SO4 then concentrated to afford the title compound 5- (heptylsulfonyl)indoline (440 mg, 96.1% yield) as a brown solid. TLC: DCM:MeOH=20:1, UV, Rf = 0.4

[0472] Intermediate 11Step 1: tert-butyl 4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate To a solution of methyl 3-bromobenzoate (2.0 g, 9.3 mmol), RuphosPdG4 (791 mg, 0.93 mmol), Cs2CO3 (6.04 g, 18.6 mmol) in dioxane (40 mL) was added tert-butyl piperazine-1-carboxylate (2.08 g, 11.2 mmol), the mixture was degassed under vacuum, purged with Ar several times, and then heated to 100oC 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 (PE / EA=10:1) to give product tert-butyl 4-(3- (methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.5 g, 83.9% yield) as a white solid. TLC: PE:EA=10:1, UV, Rf = 0.3 Step 2: 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid To the solution of tert-butyl 4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.8 g, 7.83 mmol) in MeOH (30 mL) was added the solution of NaOH (3.13 g, 78.3 mmol) in H2O (10 mL), then mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with EA, then the aqueous phase was acidified with aqueous HCl till pH = 3 and extracted with EA and concentrated to give product 3-(4-(tert- butoxycarbonyl)piperazin-1-yl)benzoic acid (2.0 g, 83.5%) as a white solid. TLC: DCM:MeOH=20:1, UV, Rf = 0.4

[0473] Intermediate 12Step 1: methyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate 142WSGR Ref: 60134-709.601 To a solution of methyl 3-bromobenzoate (2.0 g, 9.3 mmol), RuphosPdG4 (791 mg, 0.93 mmol), Cs2CO3(6.04 g, 18.6 mmol) in dioxane (40 mL) was added tert-butyl piperazine-1-carboxylate (1.8 g, 11.2 mmol), the mixture was degassed under vacuum, purged with Ar several times, and then heated to 100oC 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 (PE / EA=5:1) to give product methyl 3-(2-((tert- butoxycarbonyl)amino)ethoxy)benzoate (2.1 g, 76.5% yield) as a yellow solid. TLC: PE:EA=5:1, UV, Rf = 0.3 Step 2: 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoic acid To the solution of methyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate (2.1 g, 7.12 mmol) in MeOH (30 mL) was added the solution of NaOH (2.85 g, 71.2 mmol) in H2O (10 mL), then mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with EA, then the aqueous phase was acidified with aqueous HCl till pH = 3 and extracted with EA and concentrated to give product 3-(4-(tert-butoxycarbonyl)piperazin-1- yl)benzoic acid (1.5 g, 75.0% yield) as a white solid. TLC: DCM:MeOH=20:1, UV, Rf= 0.4

[0474] Intermediate 13Step 1: tert-butyl 5-(heptylsulfonimidoyl)indoline-1-carboxylate To the solution of tert-butyl 5-(heptylthio)indoline-1-carboxylate (1.0 g, 2.86 mmol) in DCM(20 mL) and (NH4)2CO3(550 mg, 5.72 mmol) and phenyl-l3-iodanediyl diacetate (1.84 g, 5.72 mmol) was added at 0oC. The mixture was stirred at RT for 1 h. The reaction mixture was added water, extracted with EA, washed with brine and dried with Na2SO4then concentrated and purified by flash chromatography eluted with PE / EA=5:1 to afford the title compound tert-butyl 5-(heptylsulfonimidoyl)indoline-1-carboxylate (900 mg, 82.7% yield) as a yellow solid. TLC: PE:EA=5:1, UV, Rf= 0.5 Step 2: tert-butyl 5-(N-(2,2,2-trifluoroacetyl)heptylsulfonimidoyl)indoline-1-carboxylate To the solution of tert-butyl 5-(heptylsulfonimidoyl)indoline-1-carboxylate (900 mg, 2.36 mmol) in THF (10 mL) were added TEA (717 mg, 7.09 mmol) and 2,2,2-trifluoroacetic anhydride (991 mg, 4.72 mmol). The mixture was stirred at RT for 2 h. The reaction mixture was quenched by water, extracted with EA, washed with brine, and dried with Na2SO4 then concentrated and purified by flash choromatography elute with PE / EA=10:1 to afford the title 143WSGR Ref: 60134-709.601 compound tert-butyl 5-(N-(2,2,2-trifluoroacetyl)heptylsulfonimidoyl)indoline-1-carboxylate (800 mg, 71.1% yield) as a yellow oil. TLC: PE:EA=10:1, UV, Rf= 0.5 Step 3: 2,2,2-trifluoro-N-(heptyl(indolin-5-yl)(oxo)-l6-sulfanylidene)acetamide To the solution of tert-butyl 5-(N-(2,2,2-trifluoroacetyl)heptylsulfonimidoyl)indoline-1- carboxylate (800 mg, 1.68 mmol) in DCM (8 mL) was added TFA (2 mL) and stirred at room temperature for 2 h. The mixture was poured into water and neutralized with NaHCO3(aq) to pH=8, the mixture was extracted with EA, washed with brine, and dried with Na2SO4 then concentrated to afford the title compound 2,2,2-trifluoro-N-(heptyl(indolin-5-yl)(oxo)-l6- sulfanylidene)acetamide (580 mg, 91.8% yield) as a brown solid. TLC: DCM:MeOH=20:1, UV, Rf = 0.4

[0475] Example 1: (5-(heptylsulfonyl)indolin-1-yl)(pyrazolo[1,5-a]pyrimidin-3- yl)methanoneStep 1: (5-(heptylsulfonyl)indolin-1-yl)(pyrazolo[1,5-a]pyrimidin-3-yl)methanone Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (159 mg, 0.8 mmol) was dissolved in SOCl2(2 mL), the mixture was stirred at 80oC for 2 h. After the reaction was cooled down to RT, concentrated and ressolved in dry DCM (5 mL), 5-(heptylsulfonyl)indoline (150 mg, 0.53 mmol) and pyridine (126 mg, 1.59 mmol) was dissolved in dry DCM (2 mL). The solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride was added slowly. The mixture was stirred at room temperature for 2h. The mixture was extracted with EA and H2O. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE:EA=1:9 to give a light yellow solid. Then the crude product was purified by prep. HPLC to give product (5- (heptylsulfonyl)indolin-1-yl)(pyrazolo[1,5-a]pyrimidin-3-yl)methanone as a white solid (70 mg, 31.0% yield). TLC: PE: EA = 1:1, UV Rf = 0.21H NMR (400 MHz, DMSO-d6) δ 9.29 (dd, J = 7.0, 1.7 Hz, 1H), 8.76 (dd, J = 4.1, 1.7 Hz, 1H), 8.62 (s, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 13.5, 5.0 Hz, 2H), 7.26 (dd, J = 7.0, 4.1 Hz, 144WSGR Ref: 60134-709.601 1H), 4.39 (t, J = 8.6 Hz, 2H), 3.23 (dd, J = 16.6, 8.6 Hz, 4H), 1.52 (dd, J = 15.4, 7.9 Hz, 2H), 1.36 – 1.27 (m, 2H), 1.26 – 1.15 (m, 6H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C22H26N4O3S, 426.17; found, 427.1.

[0476] Example 2: (5-(heptylsulfonyl)indolin-1-yl)(3-(piperazin-1- yl)phenyl)methanoneStep 1: tert-butyl 4-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)phenyl)piperazine-1-carboxylate 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (135 mg, 0.44 mmol), 5- (heptylsulfonyl)indoline (124 mg, 0.44 mmol) was dissolved in ACN (5 mL) and TCFH (186 mg, 0.66 mmol) and NMI (109 mg, 1.72 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with EA (50 mLx3), the organic phase was separated, washed with brine (50 mLx3) and dried with Na2SO4 then concentrated and purified by flash chromatography eluted with PE:EA = 3:2 to give product 4-(3-(5- (heptylsulfonyl)indoline-1-carbonyl)phenyl)piperazine-1-carboxylate (250 mg, 87.8% yield) as a yellow solid. TLC: PE:EA = 3:1, UV Rf = 0.5 Step 2: (5-(heptylsulfonyl)indolin-1-yl)(3-(piperazin-1-yl)phenyl)methanone 4-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)phenyl)piperazine-1-carboxylate (200 mg, 0.35 mmol) was dissolved in DCM (8 mL) and TFA (2 mL) was added. The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep. HPLC to give product (5-(heptylsulfonyl)indolin-1-yl)(3-(piperazin-1-yl)phenyl)methanone as a white solid (60.5mg, 30.0% yield).1H NMR (400 MHz, DMSO-d6) δ10.72 (s, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 5.2 Hz, 3H), 7.52 (d, J = 3.9 Hz, 1H), 3.75 – 3.62 (m, 4H), 3.25 (s, 3H), 3.14 – 3.05 (m, 4H), 3.00 (s, 3H). MS(ESI) calculated for C26H35N3O3S, 469.24; found, 470.3. 145WSGR Ref: 60134-709.601

[0477] Example 3: (3-(2-aminoethoxy)phenyl)(5-(heptylsulfonyl)indolin-1-Step 1: tert-butyl (2-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)phenoxy)ethyl)carbamate 5-(heptylsulfonyl)indoline (210 mg, 0.75 mmol), 3-(2-((tert- butoxycarbonyl)amino)ethoxy)benzoic acid (231 mg, 0.82 mmol) was dissolved in DMF (10 mL) and TCFH(315 mg, 1.12 mmol) and NMI(106 mg, 2.24 mmol) was added. The mixture was stirred at 120oC overnight. The mixture was extracted with EA and H2O. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE:EA=5:1 to give product tert-butyl (2-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)phenoxy)ethyl)carbamate (240 mg, 58.8%yield) as a yellow oil. TLC: PE:EA = 3:1, UV Rf = 0.6 Step 2: (3-(2-aminoethoxy)phenyl)(5-(heptylsulfonyl)indolin-1-yl)methanone tert-butyl (2-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)phenoxy)ethyl)carbamate (270 mg, 0.50 mmol) was dissolved in DCM (6 mL) and TFA (2 mL) was added. The reaction mixture was neutralized with NaHCO3(aq.) to pH=8, the mixture was extracted with EA (50 mLx3), the organic phase was separated, washed with brine (30 mLx3) and dried with Na2SO4then concentrated to purified by prep. HPLC to give product (3-(2-aminoethoxy)phenyl)(5- (heptylsulfonyl)indolin-1-yl)methanone as a white solid (104.4 mg, 42.7% yield).1H NMR (400 MHz, DMSO-d6) δ7.97 (s, 1H), 7.76 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.21 – 7.06 (m, 3H), 4.08 (t, J = 8.4 Hz, 2H), 3.97 (dd, J = 12.0, 6.2 Hz, 2H), 3.25 – 3.21 (m, 2H), 3.17 (t, J = 8.3 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H), 1.59 – 1.44 (m, 2H), 1.36 – 1.26 (m, 2H), 1.26 – 1.11 (m, 6H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C24H32N2O4S2, 444.21; found, 445.3.

[0478] Example 4: 2-(5-(heptylsulfonyl)indoline-1-carbonyl)benzoic acid 146WSGR Ref: 60134-709.601Step 1: 2-(5-(heptylsulfonyl)indoline-1-carbonyl)benzoic acid phthalic acid (200 mg, 1.08 mmol), 5-(heptylsulfonyl)indoline (300 mg, 1.08 mmol) was dissolved in ACN (10 mL) and TCFH (452 mg, 1.60 mmol) and NMI (396 mg, 4.84 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with EA (50 mLx3), the organic phase was separated, washed with brine (50 mLx3) and dried with Na2SO4 then concentrated and purified by prep. HPLC to give product 2-(5-(heptylsulfonyl)indoline-1-carbonyl)benzoic acid as a white solid (65.3 mg, 14.1% yield). TLC: PE:EA = 3:1, UV Rf = 0.31H NMR (400 MHz, DMSO-d6) δ13.28 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.75 (dd, J = 12.9, 8.3 Hz, 3H), 7.61 (t, J = 7.7 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H), 3.72 (t, J = 8.5 Hz, 2H), 3.28 – 3.20 (m, 2H), 3.15 (t, J = 8.4 Hz, 2H), 1.58 – 1.49 (m, 2H), 1.35 – 1.27 (m, 2H), 1.26 – 1.17 (m, 6H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C23H27NO5S, 429.16; found, 430.2.

[0479] Example 5: N-(2-(5-((3-(cyanomethyl)azetidin-1-yl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamideStep 1: N-(2-(5-(hexylthio)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (250 mg, 0.69 mmol) and K2CO3 (191 mg, 1.38 mmol) in MeCN (5 mL ) was added 1- bromohexane (114 mg, 0.69 mmol)) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give product N-(2-(5-(hexylthio)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (229 mg, 74.3 % yield) as a colorless oil. 147WSGR Ref: 60134-709.601 MS(ESI) calculated for :C23H30N2O3S2, 446.17; found, 447.2. Step 2: N-(2-(5-(hexylsulfonyl)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide To a solution of N-(2-(5-(hexylthio)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (229 mg, 0.51 mmol) in DCM (6 ml) was added m-CPBA (266 mg, 1.54 mmol). The resulting mixture was stirred at room temperature for 1 h. 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 = 28:72) to give crude product . The crude was purified by Prep-HPLC (CH3CN / H2O, 0.1% NH3•H2O) to give product N-(2-(5-(hexylsulfonyl)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (147.7 mg, Y: 60.2 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.4 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 3.98 (t, J = 7.8 Hz, 2H), 3.27 – 3.21 (m, 2H), 3.19 (s, 3H), 3.11 (t, J = 8.0 Hz, 2H), 3.06 (s, 3H), 1.60 – 1.49 (m, 2H), 1.38 – 1.28 (m, 2H), 1.26 – 1.18 (m, 4H), 0.83 (t, J = 6.8 Hz, 3H). MS(ESI) calculated for C23H30N2O5S2, 478.16; found, 479.2.

[0480] Example 6: N-(2-(5-((2-cyclobutylethyl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamideStep 1: N-(2-(5-((2-cyclobutylethyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (113 mg, 0.312 mmol) and K2CO3 (86 mg, 0.624 mmol) in MeCN (4 mL ) was added (2- bromoethyl)cyclobutane (52 mg, 0.312 mmol)) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give product N-(2-(5-((2-cyclobutylethyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide (72 mg, 52 % yield) as a colorless oil. MS(ESI) calculated for: C23H28N2O3S2, 444.15; found, 445.2. Step 2: N-(2-(5-((2-cyclobutylethyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide 148WSGR Ref: 60134-709.601 To a solution of N-(2-(5-((2-cyclobutylethyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide (72 mg, 0.16 mmol) in DCM (3 ml) was added m-CPBA (82 mg, 0.44 mmol). The resulting mixture was stirred at room temperature for 1 h. 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 crude product. The crude was purified by Prep-HPLC (CH3CN / H2O, 0.1% NH3•H2O) to give product N-(2-(5-((2-cyclobutylethyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide (41 mg, Y: 53.1 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.2 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 3.99 (t, J = 7.8 Hz, 2H), 3.19 (s, 3H), 3.15 – 3.09 (m, 4H), 3.06 (s, 3H), 2.31 – 2.23 (m, 1H), 2.01 – 1.91 (m, 2H), 1.81 – 1.70 (m, 2H), 1.68 – 1.60 (m, 2H), 1.58 – 1.50 (m, 2H). MS(ESI) calculated for: C23H28N2O5S2, 476.14; found, 477.2.

[0481] Example 7: N-methyl-N-(2-(5-(pentylsulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamideStep 1: N-methyl-N-(2-(5-(pentylthio)indoline-1-carbonyl)phenyl)methanesulfonamide To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (300 mg, 0.828 mmol) and K2CO3 (229 mg, 1.656 mmol) in MeCN (6 mL ) was added 1- bromopentane (125 mg, 0.828 mmol)) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give product N-methyl-N-(2-(5-(pentylthio)indoline-1-carbonyl)phenyl)methanesulfonamide (276 mg, 77.1 % yield) as a colorless oil. MS(ESI) calculated for: C22H28N2O3S2, 432.15; found, 433.2. Step 2: N-methyl-N-(2-(5-(pentylsulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide To a solution of N-methyl-N-(2-(5-(pentylthio)indoline-1-carbonyl)phenyl)methanesulfonamide (276mg, 0.638 mmol) in DCM (6 ml) was added m-CPBA (330 mg, 1.914 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with DCM and water. The combined organic phase was washed with brine, dried over sodium sulfate, then 149WSGR Ref: 60134-709.601 purified with silica column (elute with ethyl acetate: petroleum ether = 1:1) to give crude product . The crude was purified by Prep-HPLC (CH3CN / H2O, 0.1% NH3•H2O) to give product N-methyl-N-(2-(5-(pentylsulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide (168.5 mg, Y: 56.7 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 7.3 Hz, 2H), 7.65 (t, J = 7.1 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 3.98 (t, J = 7.6 Hz, 2H), 3.27 – 3.21 (m, 2H), 3.18 (s, 3H), 3.15 – 3.09 (m, 2H), 3.06 (s, 3H), 1.60 – 1.50 (m, 2H), 1.33 – 1.21 (m, 4H), 0.82 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for: C22H28N2O5S2, 464.14; found, 465.2.

[0482] Example 8: N-methyl--(2-(5-((5-methylhexyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamideStep 1: N-methyl-N-(2-(5-((5-methylhexyl)thio)indoline-1-carbonyl)phenyl)methanesulfonamide To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (128 mg, 0.353 mmol) and Cs2CO3(230 mg, 0.706 mmol) and KI (6 mg, 0.0353 mmol) in MeCN (4 mL ) was added 1-bromo-5-methylhexane (63 mg, 0.353 mmol)) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give product N-methyl-N-(2-(5-((5- methylhexyl)thio)indoline-1-carbonyl)phenyl)methanesulfonamide (150 mg, 93.4 % yield) as a colorless oil. MS(ESI) calculated for: C24H32N2O3S2, 460.19; found, 461.2. Step 2: N-methyl-N-(2-(5-((5-methylhexyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide To a solution of N-methyl-N-(2-(5-((5-methylhexyl)thio)indoline-1- carbonyl)phenyl)methanesulfonamide (150 mg, 0.33 mmol) in DCM (5 ml) was added m-CPBA (168 mg, 0.98 mmol). The resulting mixture was stirred at room temperature for 1 h. 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 = 2:3) to give crude product . The crude was purified by Prep-HPLC 150WSGR Ref: 60134-709.601 (CH3CN / H2O, 0.1% NH3•H2O) to give product N-methyl-N-(2-(5-((5- methylhexyl)sulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide (83.7 mg, Y: 52.2 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 8.0 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 3.28 – 3.22 (m, 2H), 3.19 (s, 3H), 3.15 – 3.09 (m, 2H), 3.06 (s, 3H), 1.57 – 1.49 (m, 2H), 1.48 – 1.42 (m, 1H), 1.35 – 1.27 (m, 2H), 1.15 – 1.07 (m, 2H), 0.82 (d, J = 6.4 Hz, 6H). MS(ESI) calculated for: C24H32N2O5S2, 492.18; found, 493.2.

[0483] Example 9: N-(2-(5-((2-cyclopropylethyl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamideStep 1: N-(2-(5-((2-cyclopropylethyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (269 mg, 0.742 mmol) and Cs2CO3 (484 mg, 1.484 mmol) and KI (12 mg, 0.0742 mmol) in MeCN (6 mL) was added (2-bromoethyl)cyclopropane (111 mg, 0.742 mmol)) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give product N-(2-(5-((2- cyclopropylethyl)thio)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (213 mg, 66.7 % yield) as a colorless oil. MS(ESI) calculated for: C22H26N2O3S2, 430.14; found, 431.1. Step 2: N-(2-(5-((2-cyclopropylethyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide To a solution of N-methyl-N-(2-(5-((5-methylhexyl)thio)indoline-1- carbonyl)phenyl)methanesulfonamide (213 mg, 0.495 mmol) in DCM (6 ml) was added m- CPBA (261 mg, 1.484 mmol). The resulting mixture was stirred at room temperature for 1 h. 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 = 3:7) to give crude product. The crude was purified by Prep-HPLC 151WSGR Ref: 60134-709.601 (CH3CN / H2O, 0.1% NH3•H2O) to give product N-(2-(5-((2-cyclopropylethyl)sulfonyl)indoline- 1-carbonyl)phenyl)-N-methylmethanesulfonamide (124.2 mg, Y: 54.3 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 6.8 Hz, 2H), 7.65 (t, J = 7.2 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.53 – 7.48 (m, 1H), 3.98 (t, J = 7.8 Hz, 2H), 3.36 – 3.32 (m, 1H), 3.32 – 3.28 (m, 1H), 3.19 (s, 3H), 3.11 (t, J = 8.2 Hz, 2H), 3.06 (s, 3H), 1.53 – 1.41 (m, 2H), 0.82 – 0.70 (m, 1H), 0.42 – 0.33 (m, 2H), 0.08 – 0.03 (m, 2H). MS(ESI) calculated for: C22H26N2O5S2, 462.13; found, 463.1.

[0484] Example 10: N-(2-(5-((3-cyclopentylpropyl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamideStep 1: N-(2-(5-((3-cyclopentylpropyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (230 mg, 0.635 mmol) and Cs2CO3(417 mg, 1.269 mmol) and KI (11 mg, 0.0635 mmol) in MeCN (6 mL ) was added (3-bromopropyl)cyclopentane (121 mg, 0.635 mmol)) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give product N-(2-(5-((3- cyclopentylpropyl)thio)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (227 mg, 75.7 % yield) as a colorless oil. MS(ESI) calculated for: C25H32N2O3S2, 472.19; found, 473.2. Step 2: N-(2-(5-((3-cyclopentylpropyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide To a solution of N-(2-(5-((3-cyclopentylpropyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide (227 mg, 0.48 mmol) in DCM (6 ml) was added m-CPBA (249 mg, 1.44 mmol). The resulting mixture was stirred at room temperature for 1 h. 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 = 2:3) to give crude product. The crude was purified by Prep-HPLC (CH3CN / H2O, 0.1% 152WSGR Ref: 60134-709.601 NH3•H2O) to give product N-(2-(5-((3-cyclopentylpropyl)sulfonyl)indoline-1-carbonyl)phenyl)- N-methylmethanesulfonamide (106.3 mg, Y: 43.9 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.0 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 3.98 (t, J = 7.5 Hz, 2H), 3.27 – 3.21 (m, 2H), 3.19 (s, 3H), 3.11 (t, J = 8.1 Hz, 2H), 3.06 (s, 3H), 2.07 (s, 1H), 1.72 – 1.63 (m, 3H), 1.60 – 1.51 (m, 4H), 1.49 – 1.41 (m, 2H), 1.37 – 1.29 (m, 2H), 1.05 – 0.94 (m, 2H). MS(ESI) calculated for: C25H32N2O5S2, 504.18; found, 505.2.

[0485] Example 11: N-(2-(6-((4-(4-cyano-6-methylpyrimidin-2-yl) piperazin-1-yl) sulfonyl)-3-oxo-1,2,3,4 -tetrahydroquinoxaline-1-carbonyl)phenyl)-N- methylmethanesulfonamideStep 1: N-(2-(5-bromo-2, 3-dihydro-1H-pyrrolo [3, 2-b] pyridine-1-carbonyl) phenyl)-N- methylmethanesulfonamide To a solution of 5-bromo-2, 3-dihydro-1H-pyrrolo [3, 2-b] pyridine (150 mg, 0.753 mmol) in MeCN (10 mL) was added 2-(N-methylmethylsulfonamido) benzoic acid (258 mg, 1.13 mmol), TCFH (316 mg, 1.129 mmol) and NMI (185 mg, 2.259 mmol). The mixture was stirred at 50oC for 3 h. The reaction was concentrated and residue was purified by flash column chromatography (PE / EA =100 / 0-70 / 30) to afford product (300 mg, 81%) as yellow solid. LCMS: RT = 1.509 min, [M+H]+=410.2. Step 2: N-(2-(5-(heptylthio)-2, 3-dihydro-1H-pyrrolo [3, 2-b] pyridine-1-carbonyl) phenyl)-N- methylmethanesulfonamide To a solution of N-(2-(5-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carbonyl)phenyl)-N- methylmethanesulfonamide (238 mg, 0.58 mmol) in dioxane (8 mL) was added heptane-1-thiol (91 mg, 0.696 mmol) and Pd2(dba)3(53 mg, 0.058 mmol), DPPF(64 mg, 0.116 mmol), 153WSGR Ref: 60134-709.601 DIEA(224 mg , 1.74 mmol) under Ar. The mixture was stirred at 100oC for 4 h. The reaction was purified by flash column chromatography (PE / EA =100 / 0-60 / 40) to afford product (260 mg, 98%) as yellow solid. LCMS: RT = 2.019 min, [M+H]+=462.2. Step 3: N-(2-(5-(heptylsulfonyl)-2, 3-dihydro-1H-pyrrolo [3,2-b] pyridine-1-carbonyl)phenyl)- N-methylmethanesulfonamide To a solution of N-(2-(5-(heptylthio)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carbonyl)phenyl)-N-methylmethanesulfonamide (125 mg, 0.271 mmol) in DCM(5 mL) was added m-CPBA(140 mg, 0.813 mmol). The mixture was stirred at room temperature for 1 h. The reaction was added H2O and extracted by EA, the crude product was purified by prep-HPLC to afford product (89 mg, 54%) as white solid. LCMS: RT = 1.809 min, [M+H]+=494.2.1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 8.5 Hz, 2H), 7.61 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 4.04 (d, J = 7.8 Hz, 2H), 3.38 – 3.33 (m, 2H), 3.22 (t, J = 6.9 Hz, 2H), 3.19 (s, 3H), 3.07 (s, 3H), 1.58 (dt, J = 15.0, 7.6 Hz, 2H), 1.38 – 1.29 (m, 2H), 1.27 – 1.16 (m, 6H), 0.84 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C23H31N3O5S2,493.17; found, 494.2.

[0486] Example 12: Heptyl (imino) (1-(3-(piperazin-1-yl) benzoyl) indolin-5-yl)-l6- sulfanoneStep 1: tert-butyl 4-(3-(5-bromoindoline-1-carbonyl) phenyl) piperazine-1-carboxylate To a solution of 5-bromoindoline (90 mg, 0.454 mmol) in MeCN (5 mL) was added 3-(4-(tert- butoxycarbonyl) piperazin-1-yl) benzoic acid (139 mg, 0.454 mmol), TCFH (190 mg, 0.681 mmol) and NMI (111 mg, 1.362 mmol). The mixture was stirred at 50oC for 1 h. The reaction was concentrated and residue was purified by flash column chromatography (PE / EA =100 / 0- 70 / 30) to afford product (180 mg, 83 %) as a white solid. 154WSGR Ref: 60134-709.601 LCMS: RT = 2.066 min, [M+H]+=430.1. Step 2: tert-butyl 4-(3-(5-(heptylthio) indoline-1-carbonyl) phenyl) piperazine-1-carboxylate To a solution of tert-butyl 4-(3-(5-bromoindoline-1-carbonyl) phenyl) piperazine-1-carboxylate (180 mg, 0.37 mmol) in dioxane (5 mL) was added heptane-1-thiol (58 mg, 0.444 mmol) and Pd2 (dba)3 (33 mg, 0.037 mmol), DPPF(40 mg, 0.074 mmol), DIEA(143 mg , 1.11 mmol) under Ar. The mixture was stirred at 100oC overnight. The reaction was purified by flash column chromatography (PE / EA =100 / 0-60 / 40) to afford product (110 mg, 56%) as a white solid. LCMS: RT = 2.526 min, [M+H]+=538.2. Step 3: tert-butyl 4-(3-(5-(heptylsulfonimidoyl) indoline-1-carbonyl) phenyl) piperazine-1- carboxylate To a solution of tert-butyl 4-(3-(5-(heptylthio) indoline-1-carbonyl) phenyl) piperazine-1- carboxylate (100 mg, 0.186 mmol) in MeOH (3 mL) was added phenyl-l3-iodanediyl diacetate (149 mg, 0.465 mmol) and ammonium carbomate (44 mg, 0.465 mmol). The mixture was stirred at room temperature for 1 h. The reaction was purified by flash column chromatography (DCM / 10 % MeOH in DCM =100 / 0-60 / 40) to afford product (86 mg, 82%) as a white solid. LCMS: RT = 1.826 min, [M+H]+=569.2. Step 4: heptyl (imino) (1-(3-(piperazin-1-yl) benzoyl) indolin-5-yl)-l6-sulfanone To a solution of 4-(3-(5-(heptylsulfonimidoyl) indoline-1-carbonyl) phenyl) piperazine-1- carboxylate (65 mg, 0.114 mmol) in DCM (3 mL) was added TFA (130 mg, 1.14 mmol). The mixture was stirred at r.t for 1 h. The reaction was purified by flash column chromatography (DCM / 10 % MeOH in DCM =100 / 0-60 / 40) and prep-HPLC to afford product (16 mg, 30%) as white solid. LCMS: RT = 1.338 min, [M+H]+=469.3.1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.74 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.32 (dd, J = 9.0, 7.5 Hz, 1H), 7.07 (d, J = 6.2 Hz, 2H), 6.93 (d, J = 7.4 Hz, 1H), 4.18 – 4.00 (m, 3H), 3.14 (t, J = 8.4 Hz, 2H), 3.08 (dd, J = 12.7, 6.8 Hz, 6H), 2.89 – 2.77 (m, 4H), 1.47 (dd, J = 15.6, 7.9 Hz, 2H), 1.35 – 1.12 (m, 8H), 0.83 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C26H36N4O2S, 468.26; found, 469.3.

[0487] Example 13: N-(2-(5-((7-hydroxyheptyl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide 155WSGR Ref: 60134-709.601Step 1: N-(2-(5-((7-hydroxyheptyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (250 mg, 0.69 mmol) and Cs2CO3(450 mg, 1.38 mmol) and KI (11 mg, 0.069 mmol) in MeCN (6 mL ) was added 7-bromoheptan-1-ol (135 mg, 0.635 mmol)) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:4) to give product N-(2-(5-((7-hydroxyheptyl)thio)indoline-1-carbonyl)phenyl)- N-methylmethanesulfonamide (251 mg, 76.3 % yield) as a colorless oil. MS(ESI) calculated for: C24H32N2O4S2, 476.18; found, 477.2. Step 2: N-(2-(5-((7-hydroxyheptyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide To a solution of N-(2-(5-((7-hydroxyheptyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide (251 mg, 0.527 mmol) in DCM (6 ml) was added m-CPBA (273 mg, 1.580 mmol). The resulting mixture was stirred at room temperature for 1 h. 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: dichloromethane = 3:7) to give crude product. The crude was purified by Prep-HPLC (CH3CN / H2O, 0.1% NH3•H2O) to give product N-(2-(5-((7-hydroxyheptyl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide (106.3 mg, Y: 42.9 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 4.32 (s, 1H), 3.98 (t, J = 7.4 Hz, 156WSGR Ref: 60134-709.601 2H), 3.35 (t, J = 6.4 Hz, 2H), 3.27 – 3.21 (m, 2H), 3.19 (s, 3H), 3.11 (t, J = 8.3 Hz, 2H), 3.07 (s, 3H), 1.60 – 1.49 (m, 2H), 1.41 – 1.35 (m, 2H), 1.34 – 1.27 (m, 2H), 1.27 – 1.17 (m, 4H). MS(ESI) calculated for: C24H32N2O6S2, 508.17; found, 509.2.

[0488] Example 14: N-(2-(5-((8-aminooctyl)sulfonyl)indoline-1-carbonyl)phenyl)-N-Step 1: tert-butyl (8-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5-yl)thio)octyl)-l4- azanecarboxylate To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (250 mg, 0.69 mmol) and Cs2CO3 (450 mg, 1.38 mmol) and KI (20 mg in MeCN (5 mL ) was added tert-butyl (8-bromooctyl)carbamate (212 mg, 0.69 mmol)) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with DCM: methnol =97:3) to give product tert-butyl (8-((1-(2-(N- methylmethylsulfonamido)benzoyl)indolin-5-yl)thio)octyl)-l4-azanecarboxylate (267 mg, 65.5 % yield) as a colorless oil. MS(ESI) calculated for: C30H44N3O5S2, 589.26; found, 490.3. Step 2: tert-butyl (8-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)sulfonyl)octyl)carbamate To a solution of tert-butyl (8-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)thio)octyl)-l4-azanecarboxylate (267 mg, 0.45 mmol) in DCM (6 ml) was added m-CPBA (234 mg, 1.36 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with DCM and water. The combined organic phase was washed 157WSGR Ref: 60134-709.601 with brine, dried over sodium sulfate, then purified with silica column (elute with ethyl acetate: dichloromethane = 2:8) to give product tert-butyl (8-((1-(2-(N- methylmethylsulfonamido)benzoyl)indolin-5-yl)sulfonyl)octyl)carbamate (250 mg, 88.8 % yield) as a white solid. MS(ESI) calculated for: C30H44N3O7S2, 621.25; found, 522.2. Step 3: tert-butyl N-(2-(5-((8-aminooctyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide A mixture of tert-butyl (8-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)sulfonyl)octyl)carbamate (250 mg, 0.402 mmol) in HCl / dioxane (4 mol / L, 6 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo to give crude product. The crude was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to give product N-(2- (5-((8-aminooctyl)sulfonyl)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (113.5 mg HCl salt, Y: 50.6 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.89 (brs, 3H), 7.77 (d, J = 6.8 Hz, 2H), 7.70 – 7.63 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 3.99 (t, J = 7.4 Hz, 2H), 3.33 – 3.21 (m, 2H), 3.19 (s, 3H), 3.11 (t, J = 8.2 Hz, 2H), 3.07 (s, 3H), 2.78 – 2.69 (m, 2H), 1.61 – 1.48 (m, 4H), 1.37 – 1.20 (m, 8H). MS(ESI) calculated for: C25H35N3O5S2, 521.20; found, 522.3.

[0489] Example 15: N-methyl-N-(2-(5-((6-methylheptyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamideStep 1: N-methyl-N-(2-(5-((6-methylheptyl)thio)indoline-1- carbonyl)phenyl)methanesulfonamide To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (550 mg, 1.517 mmol) and Cs2CO3 (989 mg, 3.035 mmol) and KI (20 mg) in MeCN (12 mL ) was added 6-methylheptyl methanesulfonate (474 mg, 2.276 mmol)) at room temperature. The 158WSGR Ref: 60134-709.601 resulting mixture was stirred at 80oC under N2 via microwave irradiation for 1.5 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give product N-methyl-N-(2-(5-((6- methylheptyl)thio)indoline-1-carbonyl)phenyl)methanesulfonamide (376 mg, 52.2 % yield) as a colorless oil. MS(ESI) calculated for: C25H34N2O3S2, 474.20; found, 475.2. Step 2: N-methyl-N-(2-(5-((6-methylheptyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide To a solution of N-methyl-N-(2-(5-((6-methylheptyl)thio)indoline-1- carbonyl)phenyl)methanesulfonamide (356 mg, 0.75 mmol) in DCM (6 ml) was added m-CPBA (388 mg, 2.25 mmol). The resulting mixture was stirred at room temperature for 1 h. 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: PE = 6:4) to give crude product. The crude was purified by Prep-HPLC (CH3CN / H2O, 0.1% NH3•H2O) to give product N-methyl-N-(2-(5-((6-methylheptyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide (268.7 mg, Y: 70.2 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 8.5 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.53 – 7.48 (m, 1H), 3.98 (t, J = 7.6 Hz, 2H), 3.28 – 3.21 (m, 2H), 3.19 (s, 3H), 3.11 (t, J = 8.2 Hz, 2H), 3.06 (s, 3H), 1.61 – 1.50 (m, 2H), 1.50 – 1.42 (m, 1H), 1.34 – 1.26 (m, 2H), 1.25 – 1.17 (m, 2H), 1.13 – 1.05 (m, 2H), 0.83 (d, J = 6.8 Hz, 6H). MS(ESI) calculated for: C25H34N2O5S2, 506.19; found, 507.2.

[0490] Example 16: N-(2-(5-(heptylsulfonimidoyl) indoline-1-carbonyl) phenyl)-N- methylmethanesulfonamide159WSGR Ref: 60134-709.601 Step 1: N-(2-(5-(heptylthio) indoline-1-carbonyl) phenyl)-N-methylmethanesulfonamide To a solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (100 mg, 0.276 mmol) in MeCN (5 mL) was added 1-bromoheptane (51 mg, 0.29 mmol) and K2CO3(76 mg, 0.551 mmol) and KI(5 mg, 0.0276 mmol). The mixture was stirred at 85oC for 1 h. The reaction was extracted by EA, the crude product was purified by flash column chromatography (DCM / EA =100 / 0-90 / 10) to afford product (93 mg, 74%) as white solid. LCMS: RT = 2.176 min, [M+H]+=461.2. Step 2: N-(2-(5-(heptylsulfonimidoyl) indoline-1-carbonyl) phenyl)-N- methylmethanesulfonamide To a solution of N-(2-(5-(heptylthio)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (65 mg, 0.141 mmol) in MeOH (3 mL) was added phenyl-l3-iodanediyl diacetate (136 mg, 0.423 mmol) and ammonium carbomate (40 mg, 0.423 mmol). The mixture was stirred at room temeprature for 1 h. The reaction was purified by prep-HPLC to afford product (22 mg, 42%) as white solid. LCMS: RT = 1.549 min, [M+H]+=492.3.1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.50 (t, J = 7.1 Hz, 1H), 4.05 (s, 1H), 3.97 (t, J = 7.7 Hz, 2H), 3.18 (s, 3H), 3.10 (d, J = 4.9 Hz, 2H), 3.09 – 2.96 (m, 5H), 1.53 (s, 2H), 1.29 – 1.16 (m, 8H), 0.84 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C24H32N7O5S2, 491.67; found, 492.3.

[0491] Example 17: N-(2-(5-((2-hydroxyhexyl) sulfonyl) indoline-1-carbonyl) phenyl)-N-methylmethanesulfonamideStep 1: N-(2-(5-((2-hydroxyhexyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide To a solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (50 mg, 0.5 mmol) in H2O (5 mL) and dioxane (2 mL) was added 2-butyloxirane (199 mg, 0.55 mmol) and Bu3P (0.014 mL, 0.055 mmol). The mixture was stirred at r.t overnight. The reaction was extracted by DCM, the crude product was purified by flash column chromatography (PE / EA =100 / 0-60 / 40) to afford product (100 mg, 43%) as white solid. 160WSGR Ref: 60134-709.601 LCMS: RT = 1.740 min, [M+H]+=463.2. Step 2: N-(2-(5-((2-hydroxyhexyl) sulfonyl) indoline-1-carbonyl) phenyl)-N- methylmethanesulfonamide To a solution of N-(2-(5-((2-hydroxyhexyl) thio) indoline-1-carbonyl) phenyl)-N- methylmethanesulfonamide (50 mg, 0.108 mmol) in DCM (3 mL) was added m-CPBA (55 mg, 0.324 mmol). The mixture was stirred at r.t for 1 h. The reaction was added H2O and extracted by EA, the crude product was purified by prep-HPLC to afford product (50 mg, 47%) as white solid. LCMS: RT = 1.580 min, [M+H]+=495.2.1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.62 (dt, J = 23.8, 7.7 Hz, 3H), 7.50 (dd, J = 11.1, 4.4 Hz, 1H), 4.83 (s, 1H), 3.97 (d, J = 7.8 Hz, 2H), 3.86 (s, 1H), 3.31 (d, J = 6.9 Hz, 2H), 3.16 (d, J = 18.1 Hz, 3H), 3.15 – 3.03 (m, 5H), 1.55 – 1.41 (m, 1H), 1.42 – 1.28 (m, 1H), 1.28 – 1.13 (m, 4H), 0.91 – 0.78 (m, 3H). MS(ESI) calculated for C23H30N2O6S2, 494.15; found, 495.2.

[0492] Example 18: (6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)(5- (heptylsulfonyl)indolin-1-yl)methanoneStep 1: tert-butyl 2-(5-(heptylsulfonyl)indoline-1-carbonyl)-5,7-dihydro-6H-pyrrolo[3,4- b]pyridine-6-carboxylate 6-(tert-butoxycarbonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-carboxylic acid (220 mg, 0.83 mmol), 5-(heptylsulfonyl)indoline (234 mg, 0.83 mmol) was dissolved in ACN (8 mL) and TCFH (350 mg, 1.25 mmol) and NMI (205 mg, 2.50 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with EA (50 mLx3), the organic phase was separated, washed with brine (50 mLx3) and dried with Na2SO4 then concentrated and purified by flash chromatography eluted with PE:EA = 1:1 to 161WSGR Ref: 60134-709.601 give product 2-(5-(heptylsulfonyl)indoline-1-carbonyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine- 6-carboxylate (300 mg, 63.2%yield) as a light yellow solid. TLC: PE:EA = 1:1, UV Rf = 0.6 Step 2: (6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)(5-(heptylsulfonyl)indolin-1-yl)methanone tert-butyl 2-(5-(heptylsulfonyl)indoline-1-carbonyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6- carboxylate (300 mg, 0.57 mmol) was dissolved in DCM (8 mL) and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with NaHCO3(aq.) to pH=8, the mixture was extracted with EA (50 mLx3), the organic phase was separated, washed with brine (30 mLx3) and dried with Na2SO4then concentrated to purified by prep. HPLC to give product (6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)(5- (heptylsulfonyl)indolin-1-yl)methanone as a white solid (48.4 mg, 19.5% yield). TLC: DCM:MeOH = 20:1, UV Rf = 0.31H NMR (400 MHz, DMSO-d6) δ10.08 (s, 2H), 8.30 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 11.2 Hz, 3H), 4.67 (s, 2H), 4.56 (s, 2H), 4.28 (t, J = 8.5 Hz, 2H), 3.31 – 3.14 (m, 4H), 1.52 (dt, J = 15.3, 7.5 Hz, 2H), 1.36 – 1.27 (m, 2H), 1.26 – 1.13 (m, 6H), 0.84 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C23H29N3O3S3, 427.19; found, 428.2.

[0493] Example 19: N-(2-(5-((7-aminoheptyl)sulfonyl)indoline-1-carbonyl)phenyl)- N-methylmethanesulfonamideStep 1: tert-butyl (7-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)thio)heptyl)carbamate To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (300 mg, 0.829 mmol) and Cs2CO3(540 mg, 1.658 mmol) and KI (20 mg ) in MeCN (5 mL ) 162WSGR Ref: 60134-709.601 was added tert-butyl (7-bromoheptyl)carbamate (243 mg, 0.829 mmol)) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give product tert-butyl (7-((1-(2-(N- methylmethylsulfonamido)benzoyl)indolin-5-yl)thio)heptyl)carbamate (466 mg, 97.8 % yield) as a colorless oil. MS(ESI) calculated for: C29H41N3O5S2, 575.25; found, 476.3. Step 2: tert-butyl (7-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)sulfonyl)heptyl)carbamate To a solution of tert-butyl (7-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)thio)heptyl)carbamate (466 mg, 0.809 mmol) in DCM (6 ml) was added m-CPBA (419 mg, 2.428 mmol). The resulting mixture was stirred at room temperature for 1 h. 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: PE =7:3) to give product tert-butyl (7-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)sulfonyl)heptyl)carbamate (387 mg, 78.6 % yield) as a white solid. MS(ESI) calculated for: C29H41N3O7S2, 607.24; found, 508.2. Step 3: N-(2-(5-((7-aminoheptyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide A mixture of tert-butyl (7-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)sulfonyl)heptyl)carbamate (387 mg, 0.637 mmol) in HCl / dioxane (4 mol / L, 6 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give crude product. The crude was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to give product N-(2- (5-((7-aminoheptyl)sulfonyl)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (148.4 mg HCl salt, Y: 42.8 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.84 (brs, 3H), 7.77 (d, J = 7.2 Hz, 2H), 7.69 – 7.63 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 3.99 (t, J = 7.4 Hz, 2H), 3.31 – 3.22 (m, 2H), 3.18 (s, 3H), 3.11 (t, J = 8.3 Hz, 2H), 3.07 (s, 3H), 2.79 – 2.69 (m, 2H), 1.61 – 1.46 (m, 4H), 1.39 – 1.30 (m, 2H), 1.29 – 1.19 (m, 4H). MS(ESI) calculated for: C24H33N3O5S2, 507.19; found, 508.2.

[0494] Example 20: N-methyl-N-(2-(5-((6,6,6-trifluorohexyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide 163WSGR Ref: 60134-709.601Step 1: N-methyl-N-(2-(5-((6,6,6-trifluorohexyl)thio)indoline-1- carbonyl)phenyl)methanesulfonamide To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (140 mg, 0.386 mmol) and Cs2CO3(252 mg, 0.772 mmol) and KI (20 mg) in MeCN (5 mL) was added 6-bromo-1,1,1-trifluorohexane (85 mg, 0.386 mmol)) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give product N-methyl-N-(2-(5-((6,6,6-trifluorohexyl)thio)indoline-1- carbonyl)phenyl)methanesulfonamide (132 mg, 68.3 % yield) as a colorless oil. MS(ESI) calculated for: C23H27F3N2O3S2, 500.14; found, 501.2. Step 2: N-methyl-N-(2-(5-((6,6,6-trifluorohexyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide To a solution of N-methyl-N-(2-(5-((6,6,6-trifluorohexyl)thio)indoline-1- carbonyl)phenyl)methanesulfonamide (132 mg, 0.264 mmol) in DCM (6 ml) was added m- CPBA (137 mg, 0.791 mmol). The resulting mixture was stirred at room temperature for 1 h. 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: PE = 7:3) to give crude product. The crude was purified by Prep-HPLC (CH3CN / H2O, 0.1% NH3•H2O) to give product N-methyl-N-(2-(5-((6,6,6-trifluorohexyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide (93.2 mg, Y: 66.4 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 7.5 Hz, 2H), 7.65 (t, J = 8.4 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.50 (t, J = 7.0 Hz, 1H), 3.98 (t, J = 7.6 Hz, 2H), 3.30 – 164WSGR Ref: 60134-709.601 3.23 (m, 2H), 3.19 (s, 3H), 3.16 – 3.08 (m, 2H), 3.06 (s, 3H), 2.26 – 2.12 (m, 2H), 1.64 – 1.52 (m, 2H), 1.51 – 1.35 (m, 4H). MS(ESI) calculated for: C23H27F3N2O5S2, 532.13; found, 533.2.

[0495] Example 21: N-(2-(5-((3-cyclopropylpropyl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamideStep 1: N-(2-(5-((3-cyclopropylpropyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide To the solution of N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (250 mg, 0.691 mmol) and Cs2CO3 (451 mg, 1.382 mmol) and KI (20 mg) in MeCN (5 mL ) was added (3-bromopropyl)cyclopropane (112 mg, 0.691 mmol)) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The mixture was concentrated in vacuo. The residue was purified with silica column (elute with ethyl acetate: PE =1:1) to give product N-(2-(5-((3-cyclopropylpropyl)thio)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide (240 mg, 78.3 % yield) as a colorless oil. MS(ESI) calculated for: C23H28N2O3S2, 444.15; found, 445.2. Step 2: N-(2-(5-((3-cyclopropylpropyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide To a solution of N-(2-(5-((3-cyclopropylpropyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide (240 mg, 0.541 mmol) in DCM (5 ml) was added m-CPBA (280 mg, 1.622 mmol). The resulting mixture was stirred at room temperature for 1 h. 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: PE = 3:2) to give crude product. The crude was purified by Prep-HPLC (CH3CN / H2O, 0.1% NH3•H2O) to give product N-(2-(5-((3-cyclopropylpropyl)sulfonyl)indoline-1-carbonyl)phenyl)- N-methylmethanesulfonamide (133.5 mg, Y: 51.7 % ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 7.7 Hz, 2H), 7.65 (t, J = 6.8 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 3.99 (t, J = 7.5 Hz, 2H), 3.30 – 3.23 (m, 2H), 3.19 (s, 3H), 3.15 – 3.08 (m, 2H), 3.06 (s, 3H), 1.70 – 1.56 (m, 2H), 1.29 – 1.18 (m, 2H), 0.70 – 0.58 (m, 1H), 0.41 – 0.33 (m, 2H), -0.01 – -0.06 (m, 2H). 165WSGR Ref: 60134-709.601 MS(ESI) calculated for: C23H28N2O5S2, 476.14; found, 477.2.

[0496] Example 22: N-(4-chloro-2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H- pyrrol-1-yl)methanesulfonamideStep 1: Methy 1-amino-4-chloro-1H-pyrrolo-2-carboxylate Methyl 4-chloro-1-H-pyrrole-2-carboxylate (1.0 g, 6.27 mmol, bidepharm) was slowly added over 30 minutes to a mixture of NaH (60%, 0.4 g, 10.03 mmol) suspended in dimethylformamide (12 mL) at 0° C under nitrogen atmosphere. After stirring at 0° C. for 1 hour, a solution of O-(2,5-dinitrophenyl)hydroxylamine (1.87 g, 9.40 mmol，Accela) in dimethylformamide (6 mL) was added dropwise for 30 minutes. The resulting reaction mixture was stirred at 0° C. for 2.5 hours and the reaction was terminated by slowly adding saturated sodium thiosulfate aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with 10% lithium chloride aqueous solution, dried with sodium sulfate, and then filtered. The filtrate was concentrated. The resulting brown residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to give the target compound as an oil (900 mg, 85% yield). TLC: PE / EA = 6:1, UV, Rf = 0.3 Step 2: Methyl 4-chloro-1-(N-(methylsulfonyl)methylsulfonamido)-1H-pyrrole-2-carboxylate To the solution of methy 1-amino-4-chloro-1H-pyrrolo-2-carboxylate (900mg, 5.172 mmol) in DCM (10mL) was added triethylamine (1.31 g, 12.93mmol), then cooled to 0°C and MsCl (1.77 g, 15.52 mmol) was added dropwise into the mixture. The mixture was stirred at room temperature overnight. 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 =1:1) to give product methyl 2- (methylsulfonamido)benzoate (320mg, yield : 60%) as a white solid. 166WSGR Ref: 60134-709.601 TLC: PE / EA = 3:1, UV Rf = 0.4 Step 3: 4-chloro-1-(methylsulfonamido)-1H-pyrrole-2-carboxylic acid To the solution of methyl 4-chloro-1-(N-(methylsulfonyl)methylsulfonamido)-1H-pyrrole-2- carboxylate (300mg, 0.909 mmol) in THF (10 mL) was added the solution of LiOH (152mg, 3.668mmol) 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 EA to give product 4-chloro-1-(methylsulfonamido)- 1H-pyrrole-2-carboxylic acid (200mg, yield : 92.2%) as a white solid. LCMS: [M+1]+=239.1 Step 4: N-(4-chloro-2-(5-(heptylthio)indoline-1-carbonyl)-1H-pyrrol-1-yl)methanesulfonamide To the solution of 4-chloro-1-(methylsulfonamido)-1H-pyrrole-2-carboxylic acid (191 mg, 0.764mmol) in ACN (12 mL) were added 5-(heptylthio)indoline (190.4mg, 0.764mmol) and NMI (219.6mg, 2.675mmol). Then TCFH (321.7mg, 1.15mmol) was added, the reaction mixture was stirred at room temperature for 2 h. Water was added, extracted with EA, 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 (EtOAc / PE = 40 / 60) to give product (190 mg, 53% yield) as a white solid. LCMS: [M+1]+=470.1 Step 5: N-(4-chloro-2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-pyrrol-1- yl)methanesulfonamide To a solution of N-(4-chloro-2-(5-(heptylthio)indoline-1-carbonyl)-1H-pyrrol-1- yl)methanesulfonamide (170mg, 0.362mmol) in DCM (12 mL) was added m-CPBA (156mg, 0.91 mmol) at 0oC, the mixture was stirred for 2 h at room temperature. 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=2 / 98) and prep-HPLC to give product (63.3 mg, 35% yield) as a white solid.1H NMR (400 MHz, ) δ 11.07 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.81 – 7.68 (m, 2H), 7.43 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 4.28 (t, J = 8.4 Hz, 2H), 3.21 (d, J = 9.6 Hz, 4H), 3.08 (s, 3H), 1.62 – 1.44 (m, 2H), 1.40 – 1.11 (m, 8H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C21H28ClN3O5S2,501.12; found [M+H]+,502.1.

[0497] Example 23: N-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-3-methyl-1H- pyrazol-1-yl)methanesulfonamide 167WSGR Ref: 60134-709.601Prepared N-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-3-methyl-1H-pyrazol-1- yl)methanesulfonamide essentially as described for Example 22.1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.24 (s, 1H), 7.76 (d, J = 12.5 Hz, 2H), 6.61 (s, 1H), 4.13 (t, J = 8.5 Hz, 2H), 3.27 – 3.21 (m, 2H), 3.19 (d, J = 7.2 Hz, 3H), 3.16 (s, 2H), 2.24 (s, 3H), 1.52 (dd, J = 15.3, 7.8 Hz, 2H), 1.35 – 1.12 (m, 8H), 0.83 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C21H30N4O5S2, 482.2; found [M+H]+, 483.2.

[0498] Example 24: N-(2-(3,3-difluoro-5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamideStep 1: 5-bromo-3,3-difluoroindolin-2-one DAST (2.84 g, 17.6 mmol) was added into 5-bromoindoline-2,3-dione (1000 mg, 4.4 mmol) in 20 mL DCM under N2 in ice bath. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with H2O (20 mL) and the aqueous phase was extracted with ethyl acetate (15 mL) three times. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum. The resulting crude material was purified by silica gel chromatography eluted with PE: EA = 70:30 to give the product (1.2 g, yield: 99%) as a yellow solid. TLC: PE / EA = 5:1, UV Rf = 0.5 Step 2: 5-bromo-3,3-difluoroindoline A solution of 5-bromo-3,3-difluoroindolin-2-one (1000 mg) in THF (20 mL) was stirred at 0 °C. BH3 in dimethyl sulfide (4 mL) was added dropwise. The ice-water bath was removed after the addition was completed and the mixture was stirred at room temperature for 2 h. The reaction 168WSGR Ref: 60134-709.601 was quenched with 10% citric acid solution (5 mL) at 0 °C. Water (20 mL) was added and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum until about 30 mL remained. The solution containing the desired product was used immediately in the next Step without further purification (800 mg, yield: 85%). TLC: PE / EA = 3:1, UV Rf = 0.5 Step 3: N-(2-(5-bromo-3,3-difluoroindoline-1-carbonyl)phenyl)methanesulfonamide The solution of 5-bromo-3,3-difluoroindoline (800 mg, 3.42 mmol) in ACN (10 mL) were added 2-(methylsulfonamido)benzoic acid (882 mg, 4.1 mmol), TCFH (1.92 g, 6.84 mmol) and NMI (561 mg, 6.84 mmol). The reaction mixture was stirred for 2 h at 80oC. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EA = 50:50 to give product (470 mg, yield: 32%) as a white oil. TLC: PE / EA = 3:1, UV Rf = 0.5 Step 4: N-(2-(3,3-difluoro-5-(heptylthio)indoline-1-carbonyl)phenyl)methanesulfonamide The mixture of N-(2-(5-bromo-3,3-difluoroindoline-1-carbonyl)phenyl)methanesulfonamide (15 mg, 0.035 mmol, 1 eq) in dioxane (2 mL) wereadded heptane-1-thiol (5.5 mg, 0.042 mmol), Pd2(dba)3(3.2 mg, 0.0035 mmol), Xant-phos (40.5 mg, 0.07 mmol) and DIEA (13.5 mg, 0.105 mmol). The reaction mixture was stirred 2 h at 100oC. The reaction concentrated in vacuum. The residue was purified by silica gel chromatography (DCM / MeOH =97:3) to give product (330 mg, 91% yield) as a white solid. TLC: PE / EA = 5:1, UV Rf = 0.5 Step 5: N-(2-(3,3-difluoro-5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamide 1,1'-(phenyl-l3-iodanediyl)bis(propan-2-one) (135 mg, 0.42 mmol) and (NH3)2CO3(40 mg, 0.42 mmol) were added into N-(2-(5-bromo-3,3-difluoroindoline-1- carbonyl)phenyl)methanesulfonamide(80 mg, 0.166 mmol) in 2 mL MeOH. The reaction mixture was stirred 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC (base) to give the product (29.3 mg, yield: 34%) as a white solid.1H NMR (400 MHz, ) δ 10.79 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.88 – 7.80 (m, 2H), 7.63 – 7.51 (m, 2H), 7.50 – 7.38 (m, 2H), 4.53 (s, 2H), 4.23 (dd, J = 8.7, 7.2 Hz, 2H), 4.07 (s, 1H), 3.43 (dd, 169WSGR Ref: 60134-709.601 J = 8.6, 7.3 Hz, 2H), 3.15 – 2.98 (m, 2H), 1.60 – 1.41 (m, 2H), 1.21 (dt, J = 13.9, 6.6 Hz, 8H), 0.83 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C21H28N2O5S2, 513.16; found, 514.2.

[0499] Example 25: N-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-imidazol-1- yl)methanesulfonamideStep 1: Ethyl 1-(methylsulfonamido)-1H-imidazole-5-carboxylate To the solution of ethyl 1-amino-1H-imidazole-5-carboxylate (1.0 g, 6.44 mmol) in DCM (15 mL) was added TEA (1.95 g, 19.32 mmol) and MsCl (1.84 g, 16.11 mmol). The mixture was stirred at RT for 2 h. The reaction mixture was quenched by water, extracted with EA, washed with brine, and dried with Na2SO4then concentrated and purified by flash choromatography elute with DCM:MeOH = 49:1 to afford the title compound ethyl 1-(methylsulfonamido)-1H- imidazole-5-carboxylate (1.2 g, 79.9% yield) as a yellow solid. MS(ESI) calculated for C7H11N3O4S, 233.24; found,234.1 TLC: PE / EA = 1:1, UV, Rf = 0.4 Step 2: 1-(methylsulfonamido)-1H-imidazole-5-carboxylic acid To the solution of ethyl 1-(methylsulfonamido)-1H-imidazole-5-carboxylate (1.2 g, 3.86 mmol) in MeOH (21 mL) and NaOH (1.54 g, 38.6 mmol) in H2O (7 mL) was added. The mixture was stirred at RT for 2 h. The reaction mixture was neutralized with 2N HCl to pH=3, then extracted with EA, washed with brine, and dried with Na2SO4 then concentrated to afford the title compound 1-(methylsulfonamido)-1H-imidazole-5-carboxylic acid (500 mg, 63.1% yield) as a white solid. MS(ESI) calculated for C5H7N3O4S, 205.19; found, 206.1 TLC: DCM:MeOH=20:1, UV, Rf= 0.5 Step 3: N-(5-(5-(heptylthio)indoline-1-carbonyl)-1H-imidazol-1-yl)methanesulfonamide To the solution of 1-(methylsulfonamido)-1H-imidazole-5-carboxylic acid (100 mg, 0.49 mmol) in MeCN (10 mL) and 5-(heptylthio)indoline (120 mg, 0.49 mmol), TCFH (206 mg, 0.73 mmol) and NMI (121 mg, 1.47 mmol) were added. The mixture was stirred at RT for 1 h. The reaction 170WSGR Ref: 60134-709.601 mixture was extracted with EA, washed with brine and dried with Na2SO4 then concentrated and purified by flash chromatography eluted with PE / EA =1:1 to afford the title compound N-(5-(5- (heptylthio)indoline-1-carbonyl)-1H-imidazol-1-yl)methanesulfonamide (200 mg, 93.6% yield) as a yellow solid. MS(ESI) calculated for C20H28N4O3S2, 436.59; found, 437.2 TLC: PE:EA=1:1, UV, Rf= 0.3 Step 4: N-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-imidazol-1-yl)methanesulfonamide To the solution of N-(5-(5-(heptylthio)indoline-1-carbonyl)-1H-imidazol-1- yl)methanesulfonamide (180 mg, 0.41 mmol) in DCM (10 mL) was added m-CPBA (178 mg, 1.04 mmol) slowly at 0oC. The mixture was stirred at RT for 1 h. The reaction mixture was quenched by Na2SO3(aq), extracted with EA, washed with brine and dried with Na2SO4 then concentrated and purified by prep-HPLC. After prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to afford the title compound N-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-imidazol-1- yl)methanesulfonamide (30.5 mg, 15.9% yield) as white solid. MS(ESI) calculated for C20H28N4O5S2, 468.59; found, 469.21H NMR (400 MHz, DMSO-d6) δ11.20 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.09 (s, 1H), 7.78 (s, 1H), 7.76 – 7.72 (m, 1H), 7.66 (s, 1H), 4.36 (t, J = 8.5 Hz, 2H), 3.28 – 3.19 (m, 4H), 3.07 (s, 3H), 2.07 (s, 1H), 1.53 (dt, J = 15.3, 7.5 Hz, 2H), 1.35 – 1.26 (m, 2H), 1.21 (dt, J = 14.7, 6.1 Hz, 6H), 0.83 (t, J = 7.0 Hz, 3H).

[0500] Example 26: N-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)pyrazolo[1,5- a]pyrimidin-2-yl)methanesulfonamideStep 1: Ethyl 2-(N-(methylsulfonyl)methylsulfonamido)pyrazolo[1,5-a]pyrimidine-3-carboxylate To a solution of ethyl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate (300 mg, 1.455 mmol) in DCM (10 mL) were added DIPEA (564 mg, 4.365 mmol), DMAP (89 mg, 0.728mmol) and MsCl (1.67 g, 14.548 mmol) at 0℃, the mixture was stirred for 1h at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (MeOH / DCM=1 / 99) to give target product (188 mg, 35.7% yield) as a white solid. 171WSGR Ref: 60134-709.601 LCMS: RT =1.313 min, [M+1]+=363.1 Step 2: Ethyl 2-(methylsulfonamido)pyrazolo[1,5-a]pyrimidine-3-carboxylate To a solution of ethyl 2-(N-(methylsulfonyl)methylsulfonamido)pyrazolo[1,5-a]pyrimidine-3- carboxylate (168 mg, 0.464 mmol) in THF (7 mL) was added a solution of NaOH (130 mg, 3.245 mmol) in H2O (2 mL), the mixture was stirred for 30 min at room temperature. The mixture was added water and neutralize with 2N HCl, 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=0.9 / 99.1) to give target product (137 mg, 100% yield) as a white solid. LCMS: RT =1.158 min, [M+1]+=285.1 Step 3: 2-(methylsulfonamido)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid To a solution of ethyl 2-(methylsulfonamido)pyrazolo[1,5-a]pyrimidine-3-carboxylate (117 mg, 0.412 mmol) in MeOH (10 mL) was added a solution of LiOH.H2O (173 mg, 0.412 mmol) in H2O (2.5 mL), the mixture was heated to 50℃ and stirred overnight. The mixture was filtered and the solid was dissolved in water, the solvent was neutralized with HCl (2N), the target product (76 mg, 72% yield) was collected by filtered as a white solid. LCMS: RT =0.544 min, [M+1]+=257.1 Step 4: N-(3-(5-(heptylthio)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidin-2- yl)methanesulfonamide To a solution of 2-(methylsulfonamido)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (70 mg, 0.267 mmol) in ACN (5 mL) were added 5-(heptylthio)indoline (67 mg, 0.267 mmol), TCFH (150 mg, 0.534 mmol) and NMI (66 mg, 0.801mmol), The mixture was stirred for 21 hours 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=2.5 / 97.5) to give target product (111 mg, 76.8% yield) as a white solid. LCMS: RT =2.150 min, [M+1]+=488.1 Step 5: N-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidin-2- yl)methanesulfonamide To a solution of N-(3-(5-(heptylthio)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidin-2- yl)methanesulfonamide (100 mg, 0.205 mmol) in DCM (5 mL) was added m-CPBA (106 mg, 0.616 mmol), the mixture was stirred for 1h at room temperature. The mixture was added Na2S2O3(aq) 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 172WSGR Ref: 60134-709.601 chromatography (MeOH / DCM=3.5 / 965) and prep-HPLC (neutral) to give target product (70.7 mg, 66.4% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.18 (dd, J = 6.9, 1.6 Hz, 1H), 8.65 (dd, J = 4.2, 1.6 Hz, 1H), 8.10 (s, 1H), 7.78 – 7.69 (m, 2H), 7.18 (dd, J = 6.9, 4.3 Hz, 1H), 4.26 (t, J = 8.6 Hz, 2H), 3.30 (s, 3H), 3.26 – 3.16 (m, 4H), 1.59 – 1.48 (m, 2H), 1.35 – 1.28 (m, 2H), 1.22 (dd, J = 21.0, 7.8 Hz, 6H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C23H29N5O5S2, 519.2; found [M+H]+, 520.2

[0501] Example 27: (R)-N-(2-(5-((5-methylheptyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamidePrepared as described for Example 37.1H NMR (400 MHz, DMSO) δ 9.52 (s, 1H), 8.27 (s, 1H), 7.75 (s, 2H), 7.48 (s, 3H), 7.29 (s, 1H), 3.94 (s, 2H), 3.23 (d, J = 7.8 Hz, 2H), 3.14 (s, 2H), 2.97 (s, 3H), 1.50 (d, J = 7.9 Hz, 2H), 1.35 – 1.18 (m, 5H), 1.05 (dd, J = 10.6, 5.6 Hz, 2H), 0.86 – 0.75 (m, 6H). MS(ESI) calculated for C24H32N2O5S2, 492.18; found, 493.1.

[0502] Example 28: N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-pyrrol-1-yl)me thanesulfonamideStep 1: N-(2-(5-(heptylthio)indoline-1-carbonyl)-1H-pyrrol-1-yl)methanesulfonamide To the solution of 1-(methylsulfonamido)-1H-pyrrole-2-carboxylic acid (150 mg, 0.735 mmol) in ACN(15 mL) were added 5-(heptylthio)indoline (174mg, 0.698 mmol), TCFH (295 mg, 1.0478mmol) and NMI (201 mg, 2.451mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by flash chromatography eluted with PE:EA= 60:40 to afford the title compound N-(2-(5-(heptylthio)indoline-1-carbonyl)-1H-pyrrol- 1-yl)methanesulfonamide(185mg, 56% yield) as a white solid. LCMS: RT =2.126min, [M+H]+=436.2 Step 2: N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-pyrrol-1-yl)methanesulfonamide To a solution of N-(2-(5-(heptylthio)indoline-1-carbonyl)-1H-pyrrol-1-yl)methanesulfonamide (185 mg, 0.426mmol) in DCM (10 mL) was added m-CPBA (184 mg, 1.064 mmol) at 0oC, the 173WSGR Ref: 60134-709.601 mixture was stirred for 1 h at room temperature. 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, then concentrated to purified by prep-HPLC, after prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to afford the title compound N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-pyrrol-1- yl)methanesulfonamide (67.2 mg, 34% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.80 – 7.66 (m, 2H), 7.19 (dd, J = 2.9, 1.7 Hz, 1H), 6.79 (dd, J = 4.2, 1.7 Hz, 1H), 6.22 (dd, J = 4.3, 2.9 Hz, 1H), 4.32 (t, J = 8.4 Hz, 2H), 3.27 – 3.15 (m, 4H), 3.02 (s, 3H), 1.59 – 1.45 (m, 2H), 1.37 – 1.10 (m, 8H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C21H29N3O5S2, 467.15; found, 468.2.

[0503] Example 29: N-(3-methyl-5-(5-((5-methylhexyl)sulfonyl)indoline-1- carbonyl)-1H-pyrazol-1-yl)methanesulfonamideStep 1: 5-((5-methylhexyl)thio)indoline An ethanol (10 mL) solution of 5-thiocyanatoindoline (1 g, 5.674 mmol) was added to a solution of sodium sulfide (465 mg, 5.958 mmol) in water (2 mL), and the mixture was stirred at 50°C for 2 hours. Then the solution of 1-bromo-5-methylhexane (1.42 g., 7.944 mmol) in ethanol (2 mL) was added, and the mixture was stirred at 50°C for 2 hours. 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=10 / 90) to give target product (400 mg, 28.3% yield) as a white solid. LCMS: RT =1.611 min, [M+1]+=250.1 Step 2: N-(3-methyl-5-(5-((5-methylhexyl)thio)indoline-1-carbonyl)-1H-pyrazol-1- yl)methanesulfonamide 174WSGR Ref: 60134-709.601 To a solution of 5-((5-methylhexyl)thio)indoline (125 mg, 0.502 mmol) in ACN (5 mL) were added 3-methyl-1-(methylsulfonamido)-1H-pyrazole-5-carboxylic acid (110 mg, 0.502 mmol), NMI (123 mg, 1.506 mmol) and TCFH (281 mg, 1.004 mmol), the mixture was stirred for 1h. 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=50 / 50) to give target product (126 mg, 55.8% yield) as a white solid. LCMS: RT =2.085 min, [M+1]+=451.1 Step 3: N-(3-methyl-5-(5-((5-methylhexyl)sulfonyl)indoline-1-carbonyl)-1H-pyrazol-1- yl)methanesulfonamide To a solution of N-(3-methyl-5-(5-((5-methylhexyl)thio)indoline-1-carbonyl)-1H-pyrazol-1- yl)methanesulfonamide (100 mg, 0.222 mmol) in DCM (5 mL) was added m-CPBA (95.6 mg, 0.555 mmol), the mixture was stirred for 1h at room temperature. The mixture was directly purified by silica gel chromatography (EtOAC / PE=0~60 / 40) and prep-HPLC (base) to give target product (72.3 mg, 67.6% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.21 (s, 1H), 7.73 (d, J = 11.4 Hz, 2H), 6.38 (s, 1H), 4.15 (t, J = 8.5 Hz, 2H), 3.26 – 3.19 (m, 2H), 3.15 (t, J = 8.5 Hz, 2H), 2.96 (s, 3H), 2.20 (s, 3H), 1.61 – 1.38 (m, 3H), 1.36 – 1.23 (m, 2H), 1.10 (dd, J = 15.6, 6.8 Hz, 2H), 0.82 (s, 3H), 0.81 (s, 3H). MS(ESI) calculated for: C21H30N4O5S2, 482.2; found [M+H]+, 483.2

[0504] Example 30: N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-4-(piperazin-1- yl)phenyl)methanesulfonamideStep 1: methyl 5-bromo-2-(methylsulfonamido)benzoate To the solution of methyl 2-amino-5-bromobenzoate (5.0 g, 21.73 mmol) in Py (30 mL) was added MsCl (2.48 g, 21.73 mmol). The mixture was stirred at RT for 3 h. The reaction mixture was quenched by water, extracted with EA, washed with brine, and dried with Na2SO4 then concentrated and purified by flash choromatography elute with PE:EA=5:1 to afford the title compound methyl 5-bromo-2-(methylsulfonamido)benzoate (6.1 g, 94.5% yield) as a yellow oil. 175WSGR Ref: 60134-709.601 MS(ESI) calculated for C9H10BrNO4S, 308.15; found, 309.1 TLC: PE / EA = 5:1, UV, Rf= 0.5 Step 2: tert-butyl tert-butyl 4-(3-(methoxycarbonyl)-4-(methylsulfonamido)phenyl)piperazine-1- carboxylate To the solution of methyl 5-bromo-2-(methylsulfonamido)benzoate (2.76 g, 8.95 mmol) in dioxane (30 mL) was added tert-butyl piperazine-1-carboxylate (2.0 g, 10.74 mmol), RuPhosPdG4 (381 mg, 0.23 mmol) and Cs2CO3 (5.82 g, 17.90 mmol). The reaction mixture flushed with argon, and stirred at 100oC for 2 h. The reaction mixture was added 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 by flash choromatography elute with PE / EA=1:1 to give product tert-butyl 4-(3-(methoxycarbonyl)-4- (methylsulfonamido)phenyl)piperazine-1-carboxylate (3.0 g, 81.2% yield) as a yellow solid. MS(ESI) calculated for C18H27N3O6S, 413.49; found, 414.1 TLC: PE:EA=1:1, UV, Rf = 0.4 Step 3: 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(methylsulfonamido)benzoic acid To the solution of tert-butyl 4-(3-(methoxycarbonyl)-4-(methylsulfonamido)phenyl)piperazine- 1-carboxylate (1.0 g, 2.42 mmol) in MeOH (15 mL) and NaOH (775 mg, 19.35 mmol) in H2O (5 mL)was added. The mixture was stirred at 50oC for 2 h. The reaction mixture was neutralized with 2N HCl to pH=3, then extracted with EA, washed with brine, and dried with Na2SO4then concentrated to afford the title compound 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2- (methylsulfonamido)benzoic acid (900 mg, 93.2% yield) as a white solid. MS(ESI) calculated for C17H25N3O6S, 399.46; found, 400.1 TLC: DCM:MeOH=20:1, UV, Rf= 0.5 Step 4: tert-butyl 4-(3-(5-(heptylthio)indoline-1-carbonyl)-4- (methylsulfonamido)phenyl)piperazine-1-carboxylate To the solution of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(methylsulfonamido)benzoic acid (346 mg, 0.87 mmol) in MeCN (10 mL) and 5-(heptylthio)indoline (180 mg, 0.72 mmol), TCFH (304 mg, 1.08 mmol) and NMI (178 mg, 2.16 mmol) were added. The mixture was stirred at RT for 1 h. The reaction mixture was extracted with EA, washed with brine and dried with Na2SO4then concentrated and purified by flash chromatography eluted with PE / EA =5:1 to afford the title compound tert-butyl 4-(3-(5-(heptylthio)indoline-1-carbonyl)-4- (methylsulfonamido)phenyl)piperazine-1-carboxylate (340 mg, 62.0% yield) as a yellow solid. MS(ESI) calculated for C32H46N4O5S2, 630.86; found, 631.3 TLC: PE:EA=1:1, UV, Rf = 0.3 176WSGR Ref: 60134-709.601 Step 5: tert-butyl 4-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)-4- (methylsulfonamido)phenyl)piperazine-1-carboxylate To the solution of tert-butyl 4-(3-(5-(heptylthio)indoline-1-carbonyl)-4- (methylsulfonamido)phenyl)piperazine-1-carboxylate (170 mg, 0.27 mmol) in DCM (10 mL) was added m-CPBA (140 mg, 0.81 mmol) at 0oC. The mixture was stirred at RT for 1 h. The reaction mixture was quenched by Na2SO3(aq), extracted with PE / EA=1:1, washed with brine, and dried with Na2SO4 then concentrated and purified by flash choromatography elute with DCM:MeOH=20:1 to afford the title compound tert-butyl 4-(3-(5-(heptylsulfonyl)indoline-1- carbonyl)-4-(methylsulfonamido)phenyl)piperazine-1-carboxylate (90 mg, 50.3%yield) as a yellow solid. MS(ESI) calculated for C32H46N4O7S2, 662.86; found, 663.3 TLC: DCM:MeOH=20:1, UV, Rf= 0.4 Step 6: N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-4-(piperazin-1- yl)phenyl)methanesulfonamide To the solution of tert-butyl 4-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)-4- (methylsulfonamido)phenyl)piperazine-1-carboxylate (80 mg, 0.12 mmol) in DCM (5 mL) and TFA (1 mL) was added. The mixture was stirred at RT for 1 h. The reaction mixture was neutralized with NaHCO3 (aq) to pH=8 and extracted with EA, washed with brine and dried with Na2SO4, then concentrated and purified by prep-HPLC. After prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to afford the title compound N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-4- (piperazin-1-yl)phenyl)methanesulfonamide (22.1 mg, 32.7% yield) as white solid.1H NMR (400 MHz, DMSO-d6) δ8.28 (s, 1H), 7.74 (s, 2H), 7.26 (d, J = 8.9 Hz, 1H), 7.08 – 6.88 (m, 2H), 3.93 (s, 2H), 3.26 – 3.18 (m, 2H), 3.11 (d, J = 8.1 Hz, 2H), 3.06 (s, 4H), 2.87 (s, 3H), 2.81 (d, J = 4.6 Hz, 4H), 1.51 (s, 2H), 1.34 – 1.27 (m, 2H), 1.23 (dd, J = 12.8, 6.2 Hz, 6H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C27H38N4O5S2, 562.74; found, 563.3

[0505] Example 31: N-(2-(5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamide 177WSGR Ref: 60134-709.601Step 1: tert-butyl 4-(3-(5-bromoindoline-1-carbonyl)phenyl)piperazine-1-carboxylate To a solution of tert-butyl 5-bromoindoline-1-carboxylate (2.0 g, 6.7 mmol) in dioxane (20 mL) was added heptane-1-thiol (1.06 g, 8.04 mmol) and Pd2(dba)3 (306 mg, 0.335 mmol), DIEA (1.72 g, 13.4 mmol) and Xant-phos (387 mg, 0.67 mmol) under Ar atmosphere. The mixture was stirred at 100oC overnight. The reaction was purified by flash column chromatography (PE / EA =95 / 5) to ...

Claims

WSGR Ref: 60134-709.601 CLAIMS We claim:

1. A compound of Formula (I-a), or a pharmaceutically acceptable salt or solvate thereof,(I-a) wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; 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-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; G is a bivalent radical selected from:256WSGR Ref: 60134-709.601 *-C(R4)2-C(R5)2-N(R3)-; where the * denotes the bond to N; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl; each R6is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3alkyl; or two R6groups together form an oxo; or two R6groups together form a 3- or 4-membered carbocyclyl; or two R6groups together form 4-membered heterocyclyl; each R7is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; or two R7groups together form an oxo; or two R7groups together form a 3- or 4-membered carbocyclyl; or two R7groups together form 4-membered heterocyclyl; and R3is hydrogen or optionally substituted C1-C3alkyl; with the proviso that B is not.

2. A compound of Formula (I-b), or a pharmaceutically acceptable salt or solvate thereof,(I-b) wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 4- to 10-membered carbocyclyl, or optionally substituted heterocyclyl; X is N or C-R; Y is N or C-R; 257WSGR Ref: 60134-709.601 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 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; G is a bivalent radical selected from: *-C(R4)2-C(R5)2-; *-C(R4)2-C(R5)2-C(R6)2-; *-C(R4)2-C(R7)2-O-; *-C(R4)2-C(R5)2-N(R3)-; where the * denotes the bond to N; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl; each R6is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R6groups together form an oxo; or two R6groups together form a 3- or 4-membered carbocyclyl; or two R6groups together form 4-membered heterocyclyl; each R7is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; 258WSGR Ref: 60134-709.601 or two R7groups together form an oxo; or two R7groups together form a 3- or 4-membered carbocyclyl; or two R7groups together form 4-membered heterocyclyl; and R3is hydrogen or optionally substituted C1-C3 alkyl.

3. A compound of Formula (I-c), or a pharmaceutically acceptable salt or solvate thereof,(I-c) wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5- to 10-membered carbocyclyl, or optionally substituted heterocyclyl; 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; 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; G is a bivalent radical selected from:259WSGR Ref: 60134-709.601the * denotes the bond to N; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl; each R6is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3alkyl; or two R6groups together form an oxo; or two R6groups together form a 3- or 4-membered carbocyclyl; or two R6groups together form 4-membered heterocyclyl; each R7is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7groups together form an oxo; or two R7groups together form a 3- or 4-membered carbocyclyl; or two R7groups together form 4-membered heterocyclyl; and R3is hydrogen or optionally substituted C1-C3 alkyl. . The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein G is *-C(R4)2-C(R5)2-; where the * denotes the bond to N. . The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein G is *-CH2-C(R5)2-; where the * denotes the bond to N. . The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein G is *-C(R4)2-CH2-; where the * denotes the bond to N. . The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein G is -CH2-CH2-. . The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein G is -CH2-CF2-. . The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein G is *-C(R4)2-C(R5)2-C(R6)2-; where the * denotes the bond to N. 260WSGR Ref: 60134-709.601 10. The compound of any one of claims 1-3 or 9, or a pharmaceutically acceptable salt or solvate thereof, wherein G is -CH2-CH2-CH2-, *-CH2-CH2-CHF-, or *-CH2-CH2-CF2-; where the * denotes the bond to N.

11. The compound of any one of claims 1-3 or 9-10, or a pharmaceutically acceptable salt or solvate thereof, wherein G is -CH2-CH2-CH2-.

12. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein G is *-C(R4)2-C(R7)2-O-; where the * denotes the bond to N.

13. The compound of any one of claims 1-3 or 12, or a pharmaceutically acceptable salt or solvate thereof, wherein G is *-CH2-CH2-O-; where the * denotes the bond to N.

14. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein G is *-C(R4)2-C(R5)2-N(R3)-; where the * denotes the bond to N.

15. The compound of any one of claims 1-3 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein G is *-CH2-CH2-NH-, or *-CH2-C(=O)-NH-; where the * denotes the bond to N.

16. A compound of any one of claims 1-3, wherein the compound is a compound of Formula (II-c),(II-c) or a pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5- to 10-membered carbocyclyl, or optionally substituted heterocyclyl; 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; 261WSGR Ref: 60134-709.601 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; each R4is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; or two R4groups together form an oxo; or two R4groups together form a 3- or 4-membered carbocyclyl; or two R4groups together form a 4-membered heterocyclyl; and each R5is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3alkyl; or two R5groups together form an oxo; or two R5groups together form a 3- or 4-membered carbocyclyl; or two R5groups together form 4-membered heterocyclyl.

17. The compound of claim 16, or a pharmaceutically acceptable salt or solvate thereof, wherein, each R4is independently hydrogen, deuterium, or optionally substituted C1-C3alkyl; and each R5is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl.

18. The compound of claim 16 or 17, or a pharmaceutically acceptable salt or solvate thereof, wherein, each R4is independently hydrogen, deuterium, or C1-C3 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or - NMe2; and each R5is independently hydrogen, deuterium, or C1-C3alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or - NMe2.

19. The compound of claim 16 or 17, or a pharmaceutically acceptable salt or solvate thereof, wherein, each R4is independently hydrogen, deuterium, or optionally substituted C1 alkyl; and each R5is independently hydrogen, deuterium, or optionally substituted C1alkyl.

20. The compound of claim 16 or 19, or a pharmaceutically acceptable salt or solvate thereof, wherein, 262WSGR Ref: 60134-709.601 each R4is independently hydrogen, deuterium, or optionally substituted C1 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2; and each R5is independently hydrogen, deuterium, or optionally substituted C1 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2.

21. The compound of any one of claims 16-20, or a pharmaceutically acceptable salt or solvate thereof, wherein, each R4is independently hydrogen or deuterium; and each R5is independently hydrogen, deuterium, or fluoro.

22. The compound of any one of claims 16-21, or a pharmaceutically acceptable salt or solvate thereof, wherein, each R4is independently hydrogen or deuterium; and each R5is independently hydrogen or deuterium.

23. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt or solvate thereof, wherein 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.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 4 to 8-membered heterocyclyl.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein 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.

26. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 5 to 8-membered heterocyclyl.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or solvate thereof, wherein 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. 263WSGR Ref: 60134-709.601 28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered carbocyclyl.

29. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered heterocyclyl.

30. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered C-heterocyclyl.

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

32. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4- to 8-membered carbocyclyl.

33. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5- to 8-membered carbocyclyl.

34. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5- to 6-membered carbocyclyl.

35. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4-membered carbocyclyl.

36. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5-membered carbocyclyl.

37. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 6-membered carbocyclyl.

38. The compound of any one of claims 1-22 or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted heterocyclyl.

39. The compound of claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4 to 6-membered heterocyclyl.

40. The compound of claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4-membered heterocyclyl.

41. The compound of claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5-membered heterocyclyl.

42. The compound of claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 6-membered heterocyclyl. 264WSGR Ref: 60134-709.601 43. The compound of claim 38 or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted C-heterocyclyl.

44. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4 to 6-membered C-heterocyclyl.

45. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4-membered C-heterocyclyl.

46. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5-membered C-heterocyclyl.

47. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 6-membered C-heterocyclyl.

48. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted heteroaryl.

49. The compound of any one of claims 1-22 or 48, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5- to 10-membered heteroaryl.

50. The compound of any one of claims 1-22 or 48-49, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5- to 6-membered heteroaryl.

51. The compound of any one of claims 1-22 or 48-50, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5-membered heteroaryl.

52. The compound of any one of claims 1-22 or 48-51, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, or optionally substituted thiophenyl.

53. The compound of any one of claims 1-22 or 48-50, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 6-membered heteroaryl.

54. The compound of any one of claims 1-22 or 48-50, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted pyridinyl, or optionally substituted pyrimidinyl.

55. The compound of any one of claims 1-22 or 48-49, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 9-membered heteroaryl.

56. The compound of any one of claims 1-22 or 48-49, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted pyrazolopyrimidinyl.

57. The compound of any one of claims 1-22 or 48-49, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 10-membered heteroaryl.

58. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted aryl. 265WSGR Ref: 60134-709.601 59. The compound of claim 58, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted phenyl.

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituent selected from the group consisting ofC1-C6alkyl, amino, cyano, halogen, optionally substituted morpholinyl, 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 ofL 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 RPis independently 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; 266WSGR Ref: 60134-709.601 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.

61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituent selected from the group consisting ofsubstituted 3-aminopyrrolidin-1-yl,and optionally substituted piperazin-1-yl; or two adjacent atoms of B are substituted by the divalent group consisting ofL 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 RPis independently 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; 267WSGR Ref: 60134-709.601 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.

62. The compound of any one of claims 1-61, wherein B is substituted with one or more substituents selected from: .

63. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

64. The compound of any one of claims 1-61, 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-C5 alkynyl, -ORj, or -N(Rj)2; each Rjis hydrogen or -CH3; each Rnis independently hydrogen, -F, -Cl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3. 268WSGR Ref: 60134-709.601 65. The compound of any one of claims 1-61, wherein B is substituted with one or more substituents selected from: ; RSis optionally substituted C1-C5alkyl, optionally substituted C2-C5alkenyl, or optionally substituted C2-C5alkynyl; each Rjis independently hydrogen or -CH3.

66. The compound of any one of claims 1-61, wherein B is substituted with one or more substituents selected from: ; RSis optionally substituted C1-C3alkyl; and Rjis independently hydrogen or -CH3.

67. The compound of any one of claims 1-61, wherein B is substituted with one or more substituents selected from:; RSis -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2; and Rjis hydrogen or -CH3.

68. The compound of any one of claims 1-61, wherein B is substituted with one or more substituents selected from: ; RSis -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2.

69. The compound of any one of claims 1-61, 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 1-61, wherein B is substituted with one or more substituents selected from:; RSis -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2.

71. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: 269WSGR Ref: 60134-709.

601.

72. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

73. The compound of any one of claims 1-61, wherein B is substituted with one or more substituents selected from: ; RSis optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5alkynyl.

74. The compound of any one of claims 1-61, wherein B is substituted with one or more substituents selected from: ; RSis -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2.

75. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:.

76. The compound of any one of claims 1-61, 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-C3 alkyl; or two Rjgroups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl. 270WSGR Ref: 60134-709.601 77. The compound of any one of claims 1-61, wherein B is substituted with one or more substituents selected from:.

78. The compound of any one of claims 1-61, 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.

79. The compound of any one of claims 1-61, 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.

80. The compound of any one of claims 1-61, wherein B is substituted with one or more substituents selected from: ; RSis -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2.

81. The compound of any one of claims 1-61, 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 1-61, 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. 271WSGR Ref: 60134-709.601 83. The compound of any one of claims 1-61, 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 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:L is -NH-, -N(CH3)-, -CH2-, or -O-; wherein each RPis independently optionally substituted C1-C3alkyl; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl.

85. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:L is -NH-, -N(CH3)-, or -CH2-; wherein each RPis independently optionally substituted C1-C3 alkyl; or two RPare taken together to form an optionally substituted 3 to 10-membered heterocyclyl.

86. The compound of any one of claims 1-61, 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 1-61, 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 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: 272WSGR Ref: 60134-709.601alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.

89. The compound of any one of claims 1-61, 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, and optionally substituted piperazin-1-yl.

90. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:each Rjis independently hydrogen or -CH3.

91. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:.

92. The compound of any one of claims 1-61, 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 1-61, 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. 273WSGR Ref: 60134-709.601 94. The compound of any one of claims 1-61, 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 1-61, 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 1-61, 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 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:.

98. The compound of any one of claims 1-61, 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 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:each Rjis independently hydrogen or -CH3. 274WSGR Ref: 60134-709.601 100. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:each Rjis independently hydrogen or -CH3. each Rkis independently hydrogen, -F, -Cl, -CH3, or -OH.

101. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:.

102. The compound of any one of claims 1-61, 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.

103. The compound of any one of claims 1-61, 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 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: optionally substituted piperazin-1-yl.

105. The compound of any one of claims 1-61, 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 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:. 275WSGR Ref: 60134-709.601 107. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:each Rmis independently optionally substituted C1-C3 alkyl; or two Rmgroups are optionally cyclized to form an optionally substituted 3 to 6- membered heterocyclyl.

108. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:.

109. The compound of any one of claims 1-61, 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="IMGF000277_0003" / >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.

110. The compound of any one of claims 1-61, 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="IMGF000277_0004" / >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.

111. The compound of any one of claims 1-61, 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="IMGF000277_0005" / >. 276WSGR Ref: 60134-709.601 112. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:cyano, or halogen.

113. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:, 277WSGR Ref: 60134-709.601114. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from:

115. The compound of any one of claims 1-114, or a pharmaceutically acceptable salt or ,, 278WSGR Ref: 60134-709.601116. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

117. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-R.

118. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N. 279WSGR Ref: 60134-709.601 119. The compound of any one of claims 1-117, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C-R.

120. The compound of any one of claims 1-119, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N.

121. The compound of any one of claims 1-119, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C-R.

122. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt or solvate thereof, wherein: X is CR; Y is CR; and Z is CR.

123. The compound of any one of claim 1-115 or 122, or a pharmaceutically acceptable salt or solvate thereof, wherein: X is CH; Y is CH; and Z is CH.

124. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt or solvate thereof, wherein: X is N; Y is CR; and Z is CR.

125. The compound of any one of claims 1-115 or 124, or a pharmaceutically acceptable salt or solvate thereof, wherein: X is N; Y is CH; and Z is CH.

126. The compound of any one of claims 1-122 or 124, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1alkyl.

127. The compound of any one of claims 1-122 or 124, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen, deuterium, halogen, -CN, or -CH3.

128. The compound of any one of claims 1-122 or 124, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen, deuterium, or halogen. 280WSGR Ref: 60134-709.601 129. The compound of any one of claims 1-122 or 124, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen or deuterium.

130. The compound of any one of claims 1-129, or a pharmaceutically acceptable salt or solvate thereof, wherein E is absent.

131. The compound of any one of claims 1-129, or a pharmaceutically acceptable salt or solvate thereof, wherein E is O.

132. The compound of any one of claims 1-129, or a pharmaceutically acceptable salt or solvate thereof, wherein E is N-R1.

133. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen.

134. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted alkyl.

135. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C5 alkyl substituted with one or more group selected from -CO2H.

136. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -H, -CH2CO2H, or -CH(CH3)CO2H.

137. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH2CO2H or -CH(CH3)CO2H.

138. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH2CO2H.

139. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH(CH3)CO2H.

140. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH.

141. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -C(O)R8.

142. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -C(O)CH3.

143. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -C(O)N(R9)2.

144. The compound of claim 132 or 143, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -C(O)N(CH3)2.

145. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C4-C10 alkyl, optionally substituted - (C1-C3 alkylene)-O-(C1-C8 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 281WSGR Ref: 60134-709.601 alkyl)(heteroaryl), optionally substituted C4-C10 alkenyl, optionally substituted C4-C10 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

146. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C5-C10alkyl, optionally substituted - (C1-C3 alkylene)-O-(C1-C8 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C5-C10 alkenyl, optionally substituted C5-C10 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

147. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C4-C10alkyl, optionally substituted - (C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C10 alkenyl, optionally substituted C4-C10 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.

148. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C5-C12alkyl, optionally substituted - (C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted -(C1-C3alkylene)-N(C1-C3alkyl)(heteroaryl), optionally substituted C5-C12 alkenyl, optionally substituted C5-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.

149. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C4-C12alkyl, optionally substituted - (C1-C3alkylene)-O-(C1-C10alkyl), optionally substituted C4-C12alkenyl, or optionally substituted C4-C12 alkynyl.

150. The compound of any one of claims 1-144, 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.

151. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C5-C12alkyl, optionally substituted C5-C12 alkenyl, or optionally substituted C5-C12 alkynyl. 282WSGR Ref: 60134-709.601 152. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted C6-C12alkyl, optionally substituted C6-C12alkenyl, or optionally substituted C6-C12alkynyl.

153. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C10 alkyl.

154. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted, linear C4-C10 alkyl.

155. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an unsubstituted, linear C4-C10alkyl.

156. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C12 alkenyl.

157. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C10alkenyl.

158. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C12 alkynyl.

159. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C10 alkynyl.

160. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted carbocyclyl.

161. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C3-C8 carbocyclyl.

162. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C4-C8carbocyclyl.

163. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C5-C8 carbocyclyl.

164. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 4-membered carbocyclyl.

165. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted aralkyl.

166. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted heteroarylalkyl.

167. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted carbocyclylalkyl.

168. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted heterocyclylalkyl. 283WSGR Ref: 60134-709.601 169. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C-heterocyclyl.

170. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 4 to 8-membered C-heterocyclyl.

171. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 5 to 6-membered C-heterocyclyl.

172. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 4 to 5-membered C-heterocyclyl.

173. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 4 to 6-membered C-heterocyclyl.

174. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted 6-membered C-heterocyclyl.

175. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C-pyperidinyl.

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

177. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted oxetanyl.

178. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis an optionally substituted C-azetidinyl.

179. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted -(C1-C3alkylene)-N-(C1-C3alkyl)(heteroaryl).

180. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted -(C1-C2 alkylene)-O-(C1-C10 alkyl).

181. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted -(C1alkylene)-O-(C1-C10alkyl).

182. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis optionally substituted -CH2O(C1-C10alkyl).

183. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis selected from the group consisting of:,, 284WSGR Ref: 60134-709.601184. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis selected from the group consisting of:, ,.

185. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis selected from the group consisting of:, ,186. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis selected from the group consisting of: , 285WSGR Ref: 60134-709.601286WSGR Ref: 60134-709.

601.

187. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis selected from the group consisting of:,287WSGR Ref: 60134-709.

601.

188. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RLis selected from the group consisting of:,288WSGR Ref: 60134-709.601189. A compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 1 or 2.

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

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

192. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1-191 and a pharmaceutically acceptable excipient.

193. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of claims 1-191, and a pharmaceutically acceptable carrier.

194. A compound of any one of claims 1-191, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

195. A compound of any one of claims 1-191, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of infection by at least one Gram-negative pathogen.

196. Use of a compound of any one of claims 1-191, 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. 289WSGR Ref: 60134-709.601 197. 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 1-191, or pharmaceutically acceptable salt or solvate thereof.

198. 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 1-191, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

199. The use of claim 196, or the method of claim 197 or 198, 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.

200. The use of claim 196, or the method of claim 197 or 198, wherein the at least one Gram- negative pathogen is selected from the group consisting of Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Citrobacter freundii or Proteus mirabilis.

201. A method of inhibiting LpxH enzyme comprising contacting the enzyme with a compound of any one of claims 1-191 wherein the LpxH enzyme is contacted in an in vitro setting.

202. A method of inhibiting LpxH enzyme comprising contacting the enzyme with a compound of any one of claims 1-191, wherein the LpxH enzyme is contacted in an in vivo setting. 290

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